Editor’s Choice Articles

Editor’s Choice articles are based on recommendations by the scientific editors of MDPI journals from around the world. Editors select a small number of articles recently published in the journal that they believe will be particularly interesting to readers, or important in the respective research area. The aim is to provide a snapshot of some of the most exciting work published in the various research areas of the journal.

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Review

29 pages, 2184 KiB  
Review
Mechanisms of Photoreceptor Death in Retinitis Pigmentosa
by Fay Newton and Roly Megaw
Genes 2020, 11(10), 1120; https://doi.org/10.3390/genes11101120 - 24 Sep 2020
Cited by 97 | Viewed by 10438
Abstract
Retinitis pigmentosa (RP) is the most common cause of inherited blindness and is characterised by the progressive loss of retinal photoreceptors. However, RP is a highly heterogeneous disease and, while much progress has been made in developing gene replacement and gene editing treatments [...] Read more.
Retinitis pigmentosa (RP) is the most common cause of inherited blindness and is characterised by the progressive loss of retinal photoreceptors. However, RP is a highly heterogeneous disease and, while much progress has been made in developing gene replacement and gene editing treatments for RP, it is also necessary to develop treatments that are applicable to all causative mutations. Further understanding of the mechanisms leading to photoreceptor death is essential for the development of these treatments. Recent work has therefore focused on the role of apoptotic and non-apoptotic cell death pathways in RP and the various mechanisms that trigger these pathways in degenerating photoreceptors. In particular, several recent studies have begun to elucidate the role of microglia and innate immune response in the progression of RP. Here, we discuss some of the recent progress in understanding mechanisms of rod and cone photoreceptor death in RP and summarise recent clinical trials targeting these pathways. Full article
(This article belongs to the Special Issue Genomics and Therapeutics of Hereditary Eye Disease)
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27 pages, 1865 KiB  
Review
An Overview of Alternative Splicing Defects Implicated in Myotonic Dystrophy Type I
by Andrea López-Martínez, Patricia Soblechero-Martín, Laura de-la-Puente-Ovejero, Gisela Nogales-Gadea and Virginia Arechavala-Gomeza
Genes 2020, 11(9), 1109; https://doi.org/10.3390/genes11091109 - 22 Sep 2020
Cited by 55 | Viewed by 9084
Abstract
Myotonic dystrophy type I (DM1) is the most common form of adult muscular dystrophy, caused by expansion of a CTG triplet repeat in the 3′ untranslated region (3′UTR) of the myotonic dystrophy protein kinase (DMPK) gene. The pathological CTG repeats result [...] Read more.
Myotonic dystrophy type I (DM1) is the most common form of adult muscular dystrophy, caused by expansion of a CTG triplet repeat in the 3′ untranslated region (3′UTR) of the myotonic dystrophy protein kinase (DMPK) gene. The pathological CTG repeats result in protein trapping by expanded transcripts, a decreased DMPK translation and the disruption of the chromatin structure, affecting neighboring genes expression. The muscleblind-like (MBNL) and CUG-BP and ETR-3-like factors (CELF) are two families of tissue-specific regulators of developmentally programmed alternative splicing that act as antagonist regulators of several pre-mRNA targets, including troponin 2 (TNNT2), insulin receptor (INSR), chloride channel 1 (CLCN1) and MBNL2. Sequestration of MBNL proteins and up-regulation of CELF1 are key to DM1 pathology, inducing a spliceopathy that leads to a developmental remodelling of the transcriptome due to an adult-to-foetal splicing switch, which results in the loss of cell function and viability. Moreover, recent studies indicate that additional pathogenic mechanisms may also contribute to disease pathology, including a misregulation of cellular mRNA translation, localization and stability. This review focuses on the cause and effects of MBNL and CELF1 deregulation in DM1, describing the molecular mechanisms underlying alternative splicing misregulation for a deeper understanding of DM1 complexity. To contribute to this analysis, we have prepared a comprehensive list of transcript alterations involved in DM1 pathogenesis, as well as other deregulated mRNA processing pathways implications. Full article
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19 pages, 2927 KiB  
Review
Regulation of mTORC2 Signaling
by Wenxiang Fu and Michael N. Hall
Genes 2020, 11(9), 1045; https://doi.org/10.3390/genes11091045 - 04 Sep 2020
Cited by 113 | Viewed by 11857
Abstract
Mammalian target of rapamycin (mTOR), a serine/threonine protein kinase and a master regulator of cell growth and metabolism, forms two structurally and functionally distinct complexes, mTOR complex 1 (mTORC1) and mTORC2. While mTORC1 signaling is well characterized, mTORC2 is relatively poorly understood. mTORC2 [...] Read more.
Mammalian target of rapamycin (mTOR), a serine/threonine protein kinase and a master regulator of cell growth and metabolism, forms two structurally and functionally distinct complexes, mTOR complex 1 (mTORC1) and mTORC2. While mTORC1 signaling is well characterized, mTORC2 is relatively poorly understood. mTORC2 appears to exist in functionally distinct pools, but few mTORC2 effectors/substrates have been identified. Here, we review recent advances in our understanding of mTORC2 signaling, with particular emphasis on factors that control mTORC2 activity. Full article
(This article belongs to the Special Issue Cellular Growth Control by TOR Signaling)
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35 pages, 2504 KiB  
Review
Knee Osteoarthritis: A Review of Pathogenesis and State-Of-The-Art Non-Operative Therapeutic Considerations
by Dragan Primorac, Vilim Molnar, Eduard Rod, Željko Jeleč, Fabijan Čukelj, Vid Matišić, Trpimir Vrdoljak, Damir Hudetz, Hana Hajsok and Igor Borić
Genes 2020, 11(8), 854; https://doi.org/10.3390/genes11080854 - 26 Jul 2020
Cited by 172 | Viewed by 20635
Abstract
Being the most common musculoskeletal progressive condition, osteoarthritis is an interesting target for research. It is estimated that the prevalence of knee osteoarthritis (OA) among adults 60 years of age or older is approximately 10% in men and 13% in women, making knee [...] Read more.
Being the most common musculoskeletal progressive condition, osteoarthritis is an interesting target for research. It is estimated that the prevalence of knee osteoarthritis (OA) among adults 60 years of age or older is approximately 10% in men and 13% in women, making knee OA one of the leading causes of disability in elderly population. Today, we know that osteoarthritis is not a disease characterized by loss of cartilage due to mechanical loading only, but a condition that affects all of the tissues in the joint, causing detectable changes in tissue architecture, its metabolism and function. All of these changes are mediated by a complex and not yet fully researched interplay of proinflammatory and anti-inflammatory cytokines, chemokines, growth factors and adipokines, all of which can be measured in the serum, synovium and histological samples, potentially serving as biomarkers of disease stage and progression. Another key aspect of disease progression is the epigenome that regulates all the genetic expression through DNA methylation, histone modifications, and mRNA interference. A lot of work has been put into developing non-surgical treatment options to slow down the natural course of osteoarthritis to postpone, or maybe even replace extensive surgeries such as total knee arthroplasty. At the moment, biological treatments such as platelet-rich plasma, bone marrow mesenchymal stem cells and autologous microfragmented adipose tissue containing stromal vascular fraction are ordinarily used. Furthermore, the latter two mentioned cell-based treatment options seem to be the only methods so far that increase the quality of cartilage in osteoarthritis patients. Yet, in the future, gene therapy could potentially become an option for orthopedic patients. In the following review, we summarized all of the latest and most important research in basic sciences, pathogenesis, and non-operative treatment. Full article
(This article belongs to the Special Issue Genes at Ten)
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25 pages, 1133 KiB  
Review
Therapeutic Strategies for Duchenne Muscular Dystrophy: An Update
by Chengmei Sun, Luoan Shen, Zheng Zhang and Xin Xie
Genes 2020, 11(8), 837; https://doi.org/10.3390/genes11080837 - 23 Jul 2020
Cited by 80 | Viewed by 22000
Abstract
Neuromuscular disorders encompass a heterogeneous group of conditions that impair the function of muscles, motor neurons, peripheral nerves, and neuromuscular junctions. Being the most common and most severe type of muscular dystrophy, Duchenne muscular dystrophy (DMD), is caused by mutations in the X-linked [...] Read more.
Neuromuscular disorders encompass a heterogeneous group of conditions that impair the function of muscles, motor neurons, peripheral nerves, and neuromuscular junctions. Being the most common and most severe type of muscular dystrophy, Duchenne muscular dystrophy (DMD), is caused by mutations in the X-linked dystrophin gene. Loss of dystrophin protein leads to recurrent myofiber damage, chronic inflammation, progressive fibrosis, and dysfunction of muscle stem cells. Over the last few years, there has been considerable development of diagnosis and therapeutics for DMD, but current treatments do not cure the disease. Here, we review the current status of DMD pathogenesis and therapy, focusing on mutational spectrum, diagnosis tools, clinical trials, and therapeutic approaches including dystrophin restoration, gene therapy, and myogenic cell transplantation. Furthermore, we present the clinical potential of advanced strategies combining gene editing, cell-based therapy with tissue engineering for the treatment of muscular dystrophy. Full article
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18 pages, 1049 KiB  
Review
Regulation of Ergosterol Biosynthesis in Saccharomyces cerevisiae
by Tania Jordá and Sergi Puig
Genes 2020, 11(7), 795; https://doi.org/10.3390/genes11070795 - 15 Jul 2020
Cited by 197 | Viewed by 15075
Abstract
Ergosterol is an essential component of fungal cell membranes that determines the fluidity, permeability and activity of membrane-associated proteins. Ergosterol biosynthesis is a complex and highly energy-consuming pathway that involves the participation of many enzymes. Deficiencies in sterol biosynthesis cause pleiotropic defects that [...] Read more.
Ergosterol is an essential component of fungal cell membranes that determines the fluidity, permeability and activity of membrane-associated proteins. Ergosterol biosynthesis is a complex and highly energy-consuming pathway that involves the participation of many enzymes. Deficiencies in sterol biosynthesis cause pleiotropic defects that limit cellular proliferation and adaptation to stress. Thereby, fungal ergosterol levels are tightly controlled by the bioavailability of particular metabolites (e.g., sterols, oxygen and iron) and environmental conditions. The regulation of ergosterol synthesis is achieved by overlapping mechanisms that include transcriptional expression, feedback inhibition of enzymes and changes in their subcellular localization. In the budding yeast Saccharomyces cerevisiae, the sterol regulatory element (SRE)-binding proteins Upc2 and Ecm22, the heme-binding protein Hap1 and the repressor factors Rox1 and Mot3 coordinate ergosterol biosynthesis (ERG) gene expression. Here, we summarize the sterol biosynthesis, transport and detoxification systems of S. cerevisiae, as well as its adaptive response to sterol depletion, low oxygen, hyperosmotic stress and iron deficiency. Because of the large number of ERG genes and the crosstalk between different environmental signals and pathways, many aspects of ergosterol regulation are still unknown. The study of sterol metabolism and its regulation is highly relevant due to its wide applications in antifungal treatments, as well as in food and pharmaceutical industries. Full article
(This article belongs to the Special Issue Genes at Ten)
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32 pages, 365 KiB  
Review
Single-Step Genomic Evaluations from Theory to Practice: Using SNP Chips and Sequence Data in BLUPF90
by Daniela Lourenco, Andres Legarra, Shogo Tsuruta, Yutaka Masuda, Ignacio Aguilar and Ignacy Misztal
Genes 2020, 11(7), 790; https://doi.org/10.3390/genes11070790 - 14 Jul 2020
Cited by 72 | Viewed by 9435
Abstract
Single-step genomic evaluation became a standard procedure in livestock breeding, and the main reason is the ability to combine all pedigree, phenotypes, and genotypes available into one single evaluation, without the need of post-analysis processing. Therefore, the incorporation of data on genotyped and [...] Read more.
Single-step genomic evaluation became a standard procedure in livestock breeding, and the main reason is the ability to combine all pedigree, phenotypes, and genotypes available into one single evaluation, without the need of post-analysis processing. Therefore, the incorporation of data on genotyped and non-genotyped animals in this method is straightforward. Since 2009, two main implementations of single-step were proposed. One is called single-step genomic best linear unbiased prediction (ssGBLUP) and uses single nucleotide polymorphism (SNP) to construct the genomic relationship matrix; the other is the single-step Bayesian regression (ssBR), which is a marker effect model. Under the same assumptions, both models are equivalent. In this review, we focus solely on ssGBLUP. The implementation of ssGBLUP into the BLUPF90 software suite was done in 2009, and since then, several changes were made to make ssGBLUP flexible to any model, number of traits, number of phenotypes, and number of genotyped animals. Single-step GBLUP from the BLUPF90 software suite has been used for genomic evaluations worldwide. In this review, we will show theoretical developments and numerical examples of ssGBLUP using SNP data from regular chips to sequence data. Full article
(This article belongs to the Special Issue Genomic Prediction Methods for Sequencing Data)
19 pages, 2462 KiB  
Review
PTEN Alterations and Their Role in Cancer Management: Are We Making Headway on Precision Medicine?
by Nicola Fusco, Elham Sajjadi, Konstantinos Venetis, Gabriella Gaudioso, Gianluca Lopez, Chiara Corti, Elena Guerini Rocco, Carmen Criscitiello, Umberto Malapelle and Marco Invernizzi
Genes 2020, 11(7), 719; https://doi.org/10.3390/genes11070719 - 28 Jun 2020
Cited by 64 | Viewed by 5622
Abstract
Alterations in the tumor suppressor phosphatase and tensin homolog (PTEN) occur in a substantial proportion of solid tumors. These events drive tumorigenesis and tumor progression. Given its central role as a downregulator of the phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) [...] Read more.
Alterations in the tumor suppressor phosphatase and tensin homolog (PTEN) occur in a substantial proportion of solid tumors. These events drive tumorigenesis and tumor progression. Given its central role as a downregulator of the phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway, PTEN is deeply involved in cell growth, proliferation, and survival. This gene is also implicated in the modulation of the DNA damage response and in tumor immune microenvironment modeling. Despite the actionability of PTEN alterations, their role as biomarkers remains controversial in clinical practice. To date, there is still a substantial lack of validated guidelines and/or recommendations for PTEN testing. Here, we provide an update on the current state of knowledge on biologic and genetic alterations of PTEN across the most frequent solid tumors, as well as on their actual and/or possible clinical applications. We focus on possible tailored schemes for cancer patients’ clinical management, including risk assessment, diagnosis, prognostication, and treatment. Full article
(This article belongs to the Special Issue Molecular Biomarkers in Solid Tumors)
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Graphical abstract

35 pages, 2840 KiB  
Review
DNA Replication Stress and Chromosomal Instability: Dangerous Liaisons
by Therese Wilhelm, Maha Said and Valeria Naim
Genes 2020, 11(6), 642; https://doi.org/10.3390/genes11060642 - 10 Jun 2020
Cited by 73 | Viewed by 6737
Abstract
Chromosomal instability (CIN) is associated with many human diseases, including neurodevelopmental or neurodegenerative conditions, age-related disorders and cancer, and is a key driver for disease initiation and progression. A major source of structural chromosome instability (s-CIN) leading to structural chromosome aberrations is “replication [...] Read more.
Chromosomal instability (CIN) is associated with many human diseases, including neurodevelopmental or neurodegenerative conditions, age-related disorders and cancer, and is a key driver for disease initiation and progression. A major source of structural chromosome instability (s-CIN) leading to structural chromosome aberrations is “replication stress”, a condition in which stalled or slowly progressing replication forks interfere with timely and error-free completion of the S phase. On the other hand, mitotic errors that result in chromosome mis-segregation are the cause of numerical chromosome instability (n-CIN) and aneuploidy. In this review, we will discuss recent evidence showing that these two forms of chromosomal instability can be mechanistically interlinked. We first summarize how replication stress causes structural and numerical CIN, focusing on mechanisms such as mitotic rescue of replication stress (MRRS) and centriole disengagement, which prevent or contribute to specific types of structural chromosome aberrations and segregation errors. We describe the main outcomes of segregation errors and how micronucleation and aneuploidy can be the key stimuli promoting inflammation, senescence, or chromothripsis. At the end, we discuss how CIN can reduce cellular fitness and may behave as an anticancer barrier in noncancerous cells or precancerous lesions, whereas it fuels genomic instability in the context of cancer, and how our current knowledge may be exploited for developing cancer therapies. Full article
(This article belongs to the Special Issue Protective Mechanisms Against DNA Replication Stress)
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17 pages, 1892 KiB  
Review
CDK-Independent and PCNA-Dependent Functions of p21 in DNA Replication
by Sabrina Florencia Mansilla, María Belén De La Vega, Nicolás Luis Calzetta, Sebastián Omar Siri and Vanesa Gottifredi
Genes 2020, 11(6), 593; https://doi.org/10.3390/genes11060593 - 28 May 2020
Cited by 63 | Viewed by 7447
Abstract
p21Waf/CIP1 is a small unstructured protein that binds and inactivates cyclin-dependent kinases (CDKs). To this end, p21 levels increase following the activation of the p53 tumor suppressor. CDK inhibition by p21 triggers cell-cycle arrest in the G1 and G2 phases of the [...] Read more.
p21Waf/CIP1 is a small unstructured protein that binds and inactivates cyclin-dependent kinases (CDKs). To this end, p21 levels increase following the activation of the p53 tumor suppressor. CDK inhibition by p21 triggers cell-cycle arrest in the G1 and G2 phases of the cell cycle. In the absence of exogenous insults causing replication stress, only residual p21 levels are prevalent that are insufficient to inhibit CDKs. However, research from different laboratories has demonstrated that these residual p21 levels in the S phase control DNA replication speed and origin firing to preserve genomic stability. Such an S-phase function of p21 depends fully on its ability to displace partners from chromatin-bound proliferating cell nuclear antigen (PCNA). Vice versa, PCNA also regulates p21 by preventing its upregulation in the S phase, even in the context of robust p21 induction by γ irradiation. Such a tight regulation of p21 in the S phase unveils the potential that CDK-independent functions of p21 may have for the improvement of cancer treatments. Full article
(This article belongs to the Special Issue Protective Mechanisms Against DNA Replication Stress)
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13 pages, 316 KiB  
Review
The Changing Epidemiology of Cystic Fibrosis: Incidence, Survival and Impact of the CFTR Gene Discovery
by Virginie Scotet, Carine L’Hostis and Claude Férec
Genes 2020, 11(6), 589; https://doi.org/10.3390/genes11060589 - 26 May 2020
Cited by 141 | Viewed by 16088
Abstract
Significant advances in the management of cystic fibrosis (CF) in recent decades have dramatically changed the epidemiology and prognosis of this serious disease, which is no longer an exclusively pediatric disease. This paper aims to review the changes in the incidence and survival [...] Read more.
Significant advances in the management of cystic fibrosis (CF) in recent decades have dramatically changed the epidemiology and prognosis of this serious disease, which is no longer an exclusively pediatric disease. This paper aims to review the changes in the incidence and survival of CF and to assess the impact of the discovery of the responsible gene (the CFTR gene) on these changes. The incidence of CF appears to be decreasing in most countries and patient survival, which can be monitored by various indicators, has improved substantially, with an estimated median age of survival of approximately50 years today. Cloning of the CFTR gene 30 years ago and efforts to identify its many mutations have greatly improved the management of CF. Implementation of genetic screening policies has enabled earlier diagnosis (via newborn screening), in addition to prevention within families or in the general population in some areas (via prenatal diagnosis, family testing or population carrier screening). In the past decade, in-depth knowledge of the molecular bases of CF has also enabled the emergence of CFTR modulator therapies which have led to major clinical advances in the treatment of CF. All of these phenomena have contributed to changing the face of CF. The advent of targeted therapies has paved the way for precision medicine and is expected to further improve survival in the coming years. Full article
(This article belongs to the Special Issue Molecular Basis and Gene Therapies of Cystic Fibrosis)
49 pages, 13573 KiB  
Review
Histone Deacetylases (HDACs): Evolution, Specificity, Role in Transcriptional Complexes, and Pharmacological Actionability
by Giorgio Milazzo, Daniele Mercatelli, Giulia Di Muzio, Luca Triboli, Piergiuseppe De Rosa, Giovanni Perini and Federico M. Giorgi
Genes 2020, 11(5), 556; https://doi.org/10.3390/genes11050556 - 15 May 2020
Cited by 163 | Viewed by 15685
Abstract
Histone deacetylases (HDACs) are evolutionary conserved enzymes which operate by removing acetyl groups from histones and other protein regulatory factors, with functional consequences on chromatin remodeling and gene expression profiles. We provide here a review on the recent knowledge accrued on the zinc-dependent [...] Read more.
Histone deacetylases (HDACs) are evolutionary conserved enzymes which operate by removing acetyl groups from histones and other protein regulatory factors, with functional consequences on chromatin remodeling and gene expression profiles. We provide here a review on the recent knowledge accrued on the zinc-dependent HDAC protein family across different species, tissues, and human pathologies, specifically focusing on the role of HDAC inhibitors as anti-cancer agents. We will investigate the chemical specificity of different HDACs and discuss their role in the human interactome as members of chromatin-binding and regulatory complexes. Full article
(This article belongs to the Special Issue Evolution of Gene Regulatory Networks)
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17 pages, 918 KiB  
Review
The Microbiome in Cystic Fibrosis Pulmonary Disease
by Alice Françoise and Geneviève Héry-Arnaud
Genes 2020, 11(5), 536; https://doi.org/10.3390/genes11050536 - 11 May 2020
Cited by 57 | Viewed by 6441
Abstract
Cystic fibrosis (CF) is a genetic disease with mutational changes leading to profound dysbiosis, both pulmonary and intestinal, from a very young age. This dysbiosis plays an important role in clinical manifestations, particularly in the lungs, affected by chronic infection. The range of [...] Read more.
Cystic fibrosis (CF) is a genetic disease with mutational changes leading to profound dysbiosis, both pulmonary and intestinal, from a very young age. This dysbiosis plays an important role in clinical manifestations, particularly in the lungs, affected by chronic infection. The range of microbiological tools has recently been enriched by metagenomics based on next-generation sequencing (NGS). Currently applied essentially in a gene-targeted manner, metagenomics has enabled very exhaustive description of bacterial communities in the CF lung niche and, to a lesser extent, the fungi. Aided by progress in bioinformatics, this now makes it possible to envisage shotgun sequencing and opens the door to other areas of the microbial world, the virome, and the archaeome, for which almost everything remains to be described in cystic fibrosis. Paradoxically, applying NGS in microbiology has seen a rebirth of bacterial culture, but in an extended manner (culturomics), which has proved to be a perfectly complementary approach to NGS. Animal models have also proved indispensable for validating microbiome pathophysiological hypotheses. Description of pathological microbiomes and correlation with clinical status and therapeutics (antibiotic therapy, cystic fibrosis transmembrane conductance regulator (CFTR) modulators) revealed the richness of microbiome data, enabling description of predictive and follow-up biomarkers. Although monogenic, CF is a multifactorial disease, and both genotype and microbiome profiles are crucial interconnected factors in disease progression. Microbiome-genome interactions are thus important to decipher. Full article
(This article belongs to the Special Issue Molecular Basis and Gene Therapies of Cystic Fibrosis)
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15 pages, 1883 KiB  
Review
Farnesol and Tyrosol: Secondary Metabolites with a Crucial quorum-sensing Role in Candida Biofilm Development
by Célia F. Rodrigues and Lucia Černáková
Genes 2020, 11(4), 444; https://doi.org/10.3390/genes11040444 - 18 Apr 2020
Cited by 55 | Viewed by 6689
Abstract
When living in biological and interactive communities, microorganisms use quorum-sensing mechanisms for their communication. According to cell density, bacteria and fungi can produce signaling molecules (e.g., secondary metabolites), which participate, for example, in the regulation of gene expression and coordination of collective behavior [...] Read more.
When living in biological and interactive communities, microorganisms use quorum-sensing mechanisms for their communication. According to cell density, bacteria and fungi can produce signaling molecules (e.g., secondary metabolites), which participate, for example, in the regulation of gene expression and coordination of collective behavior in their natural niche. The existence of these secondary metabolites plays a main role in competence, colonization of host tissues and surfaces, morphogenesis, and biofilm development. Therefore, for the design of new antibacterials or antifungals and understanding on how these mechanisms occur, to inhibit the secretion of quorum-sensing (e.g., farnesol and tyrosol) molecules leading the progress of microbial infections seems to be an interesting option. In yeasts, farnesol has a main role in the morphological transition, inhibiting hyphae production in a concentration-dependent manner, while tyrosol has a contrary function, stimulating transition from spherical cells to germ tube form. It is beyond doubt that secretion of both molecules by fungi has not been fully described, but specific meaning for their existence has been found. This brief review summarizes the important function of these two compounds as signaling chemicals participating mainly in Candida morphogenesis and regulatory mechanisms. Full article
(This article belongs to the Special Issue Omics Studies Focused on Fungal Secondary Metabolism)
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17 pages, 792 KiB  
Review
RET Gene Fusions in Malignancies of the Thyroid and Other Tissues
by Massimo Santoro, Marialuisa Moccia, Giorgia Federico and Francesca Carlomagno
Genes 2020, 11(4), 424; https://doi.org/10.3390/genes11040424 - 15 Apr 2020
Cited by 71 | Viewed by 7578
Abstract
Following the identification of the BCR-ABL1 (Breakpoint Cluster Region-ABelson murine Leukemia) fusion in chronic myelogenous leukemia, gene fusions generating chimeric oncoproteins have been recognized as common genomic structural variations in human malignancies. This is, in particular, a frequent mechanism in the oncogenic conversion [...] Read more.
Following the identification of the BCR-ABL1 (Breakpoint Cluster Region-ABelson murine Leukemia) fusion in chronic myelogenous leukemia, gene fusions generating chimeric oncoproteins have been recognized as common genomic structural variations in human malignancies. This is, in particular, a frequent mechanism in the oncogenic conversion of protein kinases. Gene fusion was the first mechanism identified for the oncogenic activation of the receptor tyrosine kinase RET (REarranged during Transfection), initially discovered in papillary thyroid carcinoma (PTC). More recently, the advent of highly sensitive massive parallel (next generation sequencing, NGS) sequencing of tumor DNA or cell-free (cfDNA) circulating tumor DNA, allowed for the detection of RET fusions in many other solid and hematopoietic malignancies. This review summarizes the role of RET fusions in the pathogenesis of human cancer. Full article
(This article belongs to the Special Issue Thyroid Cancer: Genetics and Targeted Therapies)
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26 pages, 1692 KiB  
Review
Replication Stress, DNA Damage, Inflammatory Cytokines and Innate Immune Response
by Sandrine Ragu, Gabriel Matos-Rodrigues and Bernard S. Lopez
Genes 2020, 11(4), 409; https://doi.org/10.3390/genes11040409 - 09 Apr 2020
Cited by 70 | Viewed by 7917
Abstract
Complete and accurate DNA replication is essential to genome stability maintenance during cellular division. However, cells are routinely challenged by endogenous as well as exogenous agents that threaten DNA stability. DNA breaks and the activation of the DNA damage response (DDR) arising from [...] Read more.
Complete and accurate DNA replication is essential to genome stability maintenance during cellular division. However, cells are routinely challenged by endogenous as well as exogenous agents that threaten DNA stability. DNA breaks and the activation of the DNA damage response (DDR) arising from endogenous replication stress have been observed at pre- or early stages of oncogenesis and senescence. Proper detection and signalling of DNA damage are essential for the autonomous cellular response in which the DDR regulates cell cycle progression and controls the repair machinery. In addition to this autonomous cellular response, replicative stress changes the cellular microenvironment, activating the innate immune response that enables the organism to protect itself against the proliferation of damaged cells. Thereby, the recent descriptions of the mechanisms of the pro-inflammatory response activation after replication stress, DNA damage and DDR defects constitute important conceptual novelties. Here, we review the links of replication, DNA damage and DDR defects to innate immunity activation by pro-inflammatory paracrine effects, highlighting the implications for human syndromes and immunotherapies. Full article
(This article belongs to the Special Issue Protective Mechanisms Against DNA Replication Stress)
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18 pages, 1910 KiB  
Review
Transcriptional Factors Regulate Plant Stress Responses Through Mediating Secondary Metabolism
by Tehseen Ahmad Meraj, Jingye Fu, Muhammad Ali Raza, Chenying Zhu, Qinqin Shen, Dongbei Xu and Qiang Wang
Genes 2020, 11(4), 346; https://doi.org/10.3390/genes11040346 - 25 Mar 2020
Cited by 126 | Viewed by 7733
Abstract
Plants are adapted to sense numerous stress stimuli and mount efficient defense responses by directing intricate signaling pathways. They respond to undesirable circumstances to produce stress-inducible phytochemicals that play indispensable roles in plant immunity. Extensive studies have been made to elucidate the underpinnings [...] Read more.
Plants are adapted to sense numerous stress stimuli and mount efficient defense responses by directing intricate signaling pathways. They respond to undesirable circumstances to produce stress-inducible phytochemicals that play indispensable roles in plant immunity. Extensive studies have been made to elucidate the underpinnings of defensive molecular mechanisms in various plant species. Transcriptional factors (TFs) are involved in plant defense regulations through acting as mediators by perceiving stress signals and directing downstream defense gene expression. The cross interactions of TFs and stress signaling crosstalk are decisive in determining accumulation of defense metabolites. Here, we collected the major TFs that are efficient in stress responses through regulating secondary metabolism for the direct cessation of stress factors. We focused on six major TF families including AP2/ERF, WRKY, bHLH, bZIP, MYB, and NAC. This review is the compilation of studies where researches were conducted to explore the roles of TFs in stress responses and the contribution of secondary metabolites in combating stress influences. Modulation of these TFs at transcriptional and post-transcriptional levels can facilitate molecular breeding and genetic improvement of crop plants regarding stress sensitivity and response through production of defensive compounds. Full article
(This article belongs to the Section Plant Genetics and Genomics)
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29 pages, 1115 KiB  
Review
Controlling Apomixis: Shared Features and Distinct Characteristics of Gene Regulation
by Anja Schmidt
Genes 2020, 11(3), 329; https://doi.org/10.3390/genes11030329 - 20 Mar 2020
Cited by 47 | Viewed by 8383
Abstract
In higher plants, sexual and asexual reproduction through seeds (apomixis) have evolved as alternative strategies. As apomixis leads to the formation of clonal offspring, its great potential for agricultural applications has long been recognized. However, the genetic basis and the molecular control underlying [...] Read more.
In higher plants, sexual and asexual reproduction through seeds (apomixis) have evolved as alternative strategies. As apomixis leads to the formation of clonal offspring, its great potential for agricultural applications has long been recognized. However, the genetic basis and the molecular control underlying apomixis and its evolutionary origin are to date not fully understood. Both in sexual and apomictic plants, reproduction is tightly controlled by versatile mechanisms regulating gene expression, translation, and protein abundance and activity. Increasing evidence suggests that interrelated pathways including epigenetic regulation, cell-cycle control, hormonal pathways, and signal transduction processes are relevant for apomixis. Additional molecular mechanisms are being identified that involve the activity of DNA- and RNA-binding proteins, such as RNA helicases which are increasingly recognized as important regulators of reproduction. Together with other factors including non-coding RNAs, their association with ribosomes is likely to be relevant for the formation and specification of the apomictic reproductive lineage. Subsequent seed formation appears to involve an interplay of transcriptional activation and repression of developmental programs by epigenetic regulatory mechanisms. In this review, insights into the genetic basis and molecular control of apomixis are presented, also taking into account potential relations to environmental stress, and considering aspects of evolution. Full article
(This article belongs to the Special Issue Molecular Basis of Apomixis in Plants)
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45 pages, 2020 KiB  
Review
History of DNA Helicases
by Robert M. Brosh, Jr. and Steven W. Matson
Genes 2020, 11(3), 255; https://doi.org/10.3390/genes11030255 - 27 Feb 2020
Cited by 54 | Viewed by 11542
Abstract
Since the discovery of the DNA double helix, there has been a fascination in understanding the molecular mechanisms and cellular processes that account for: (i) the transmission of genetic information from one generation to the next and (ii) the remarkable stability of the [...] Read more.
Since the discovery of the DNA double helix, there has been a fascination in understanding the molecular mechanisms and cellular processes that account for: (i) the transmission of genetic information from one generation to the next and (ii) the remarkable stability of the genome. Nucleic acid biologists have endeavored to unravel the mysteries of DNA not only to understand the processes of DNA replication, repair, recombination, and transcription but to also characterize the underlying basis of genetic diseases characterized by chromosomal instability. Perhaps unexpectedly at first, DNA helicases have arisen as a key class of enzymes to study in this latter capacity. From the first discovery of ATP-dependent DNA unwinding enzymes in the mid 1970’s to the burgeoning of helicase-dependent pathways found to be prevalent in all kingdoms of life, the story of scientific discovery in helicase research is rich and informative. Over four decades after their discovery, we take this opportunity to provide a history of DNA helicases. No doubt, many chapters are left to be written. Nonetheless, at this juncture we are privileged to share our perspective on the DNA helicase field – where it has been, its current state, and where it is headed. Full article
(This article belongs to the Special Issue DNA Helicases: Mechanisms, Biological Pathways, and Disease Relevance)
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19 pages, 1767 KiB  
Review
Genetic Modifiers and Rare Mendelian Disease
by K. M. Tahsin Hassan Rahit and Maja Tarailo-Graovac
Genes 2020, 11(3), 239; https://doi.org/10.3390/genes11030239 - 25 Feb 2020
Cited by 81 | Viewed by 10435
Abstract
Despite advances in high-throughput sequencing that have revolutionized the discovery of gene defects in rare Mendelian diseases, there are still gaps in translating individual genome variation to observed phenotypic outcomes. While we continue to improve genomics approaches to identify primary disease-causing variants, it [...] Read more.
Despite advances in high-throughput sequencing that have revolutionized the discovery of gene defects in rare Mendelian diseases, there are still gaps in translating individual genome variation to observed phenotypic outcomes. While we continue to improve genomics approaches to identify primary disease-causing variants, it is evident that no genetic variant acts alone. In other words, some other variants in the genome (genetic modifiers) may alleviate (suppress) or exacerbate (enhance) the severity of the disease, resulting in the variability of phenotypic outcomes. Thus, to truly understand the disease, we need to consider how the disease-causing variants interact with the rest of the genome in an individual. Here, we review the current state-of-the-field in the identification of genetic modifiers in rare Mendelian diseases and discuss the potential for future approaches that could bridge the existing gap. Full article
(This article belongs to the Special Issue Bioinformatic Analysis for Rare Diseases)
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20 pages, 978 KiB  
Review
The Roles of the NLRP3 Inflammasome in Neurodegenerative and Metabolic Diseases and in Relevant Advanced Therapeutic Interventions
by Rameez Hassan Pirzada, Nasir Javaid and Sangdun Choi
Genes 2020, 11(2), 131; https://doi.org/10.3390/genes11020131 - 27 Jan 2020
Cited by 51 | Viewed by 9903
Abstract
Inflammasomes are intracellular multiprotein complexes in the cytoplasm that regulate inflammation activation in the innate immune system in response to pathogens and to host self-derived molecules. Recent advances greatly improved our understanding of the activation of nucleotide-binding oligomerization domain-like receptor (NLR) family pyrin [...] Read more.
Inflammasomes are intracellular multiprotein complexes in the cytoplasm that regulate inflammation activation in the innate immune system in response to pathogens and to host self-derived molecules. Recent advances greatly improved our understanding of the activation of nucleotide-binding oligomerization domain-like receptor (NLR) family pyrin domain containing 3 (NLRP3) inflammasomes at the molecular level. The NLRP3 belongs to the subfamily of NLRP which activates caspase 1, thus causing the production of proinflammatory cytokines (interleukin 1β and interleukin 18) and pyroptosis. This inflammasome is involved in multiple neurodegenerative and metabolic disorders including Alzheimer’s disease, multiple sclerosis, type 2 diabetes mellitus, and gout. Therefore, therapeutic targeting to the NLRP3 inflammasome complex is a promising way to treat these diseases. Recent research advances paved the way toward drug research and development using a variety of machine learning-based and artificial intelligence-based approaches. These state-of-the-art approaches will lead to the discovery of better drugs after the training of such a system. Full article
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25 pages, 1364 KiB  
Review
Understanding the Relevance of DNA Methylation Changes in Immune Differentiation and Disease
by Carlos de la Calle-Fabregat, Octavio Morante-Palacios and Esteban Ballestar
Genes 2020, 11(1), 110; https://doi.org/10.3390/genes11010110 - 18 Jan 2020
Cited by 49 | Viewed by 7972
Abstract
Immune cells are one of the most complex and diverse systems in the human organism. Such diversity implies an intricate network of different cell types and interactions that are dependently interconnected. The processes by which different cell types differentiate from progenitors, mature, and [...] Read more.
Immune cells are one of the most complex and diverse systems in the human organism. Such diversity implies an intricate network of different cell types and interactions that are dependently interconnected. The processes by which different cell types differentiate from progenitors, mature, and finally exert their function requires an orchestrated succession of molecular processes that determine cell phenotype and function. The acquisition of these phenotypes is highly dependent on the establishment of unique epigenetic profiles that confer identity and function on the various types of effector cells. These epigenetic mechanisms integrate microenvironmental cues into the genome to establish specific transcriptional programs. Epigenetic modifications bridge environment and genome regulation and play a role in human diseases by their ability to modulate physiological programs through external stimuli. DNA methylation is one of the most ubiquitous, stable, and widely studied epigenetic modifications. Recent technological advances have facilitated the generation of a vast amount of genome-wide DNA methylation data, providing profound insights into the roles of DNA methylation in health and disease. This review considers the relevance of DNA methylation to immune system cellular development and function, as well as the participation of DNA methylation defects in immune-mediated pathologies, illustrated by selected paradigmatic diseases. Full article
(This article belongs to the Special Issue DNA Methylation in Health and Diseases)
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17 pages, 1783 KiB  
Review
Clustered DNA Double-Strand Breaks: Biological Effects and Relevance to Cancer Radiotherapy
by Jac A. Nickoloff, Neelam Sharma and Lynn Taylor
Genes 2020, 11(1), 99; https://doi.org/10.3390/genes11010099 - 15 Jan 2020
Cited by 109 | Viewed by 7357
Abstract
Cells manage to survive, thrive, and divide with high accuracy despite the constant threat of DNA damage. Cells have evolved with several systems that efficiently repair spontaneous, isolated DNA lesions with a high degree of accuracy. Ionizing radiation and a few radiomimetic chemicals [...] Read more.
Cells manage to survive, thrive, and divide with high accuracy despite the constant threat of DNA damage. Cells have evolved with several systems that efficiently repair spontaneous, isolated DNA lesions with a high degree of accuracy. Ionizing radiation and a few radiomimetic chemicals can produce clustered DNA damage comprising complex arrangements of single-strand damage and DNA double-strand breaks (DSBs). There is substantial evidence that clustered DNA damage is more mutagenic and cytotoxic than isolated damage. Radiation-induced clustered DNA damage has proven difficult to study because the spectrum of induced lesions is very complex, and lesions are randomly distributed throughout the genome. Nonetheless, it is fairly well-established that radiation-induced clustered DNA damage, including non-DSB and DSB clustered lesions, are poorly repaired or fail to repair, accounting for the greater mutagenic and cytotoxic effects of clustered lesions compared to isolated lesions. High linear energy transfer (LET) charged particle radiation is more cytotoxic per unit dose than low LET radiation because high LET radiation produces more clustered DNA damage. Studies with I-SceI nuclease demonstrate that nuclease-induced DSB clusters are also cytotoxic, indicating that this cytotoxicity is independent of radiogenic lesions, including single-strand lesions and chemically “dirty” DSB ends. The poor repair of clustered DSBs at least in part reflects inhibition of canonical NHEJ by short DNA fragments. This shifts repair toward HR and perhaps alternative NHEJ, and can result in chromothripsis-mediated genome instability or cell death. These principals are important for cancer treatment by low and high LET radiation. Full article
(This article belongs to the Special Issue DNA Damage and Repair after Radiation)
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13 pages, 667 KiB  
Review
Pathogenesis of Ischemic Stroke: Role of Epigenetic Mechanisms
by Rosita Stanzione, Maria Cotugno, Franca Bianchi, Simona Marchitti, Maurizio Forte, Massimo Volpe and Speranza Rubattu
Genes 2020, 11(1), 89; https://doi.org/10.3390/genes11010089 - 13 Jan 2020
Cited by 51 | Viewed by 7627
Abstract
Epigenetics is the branch of molecular biology that studies modifications able to change gene expression without altering the DNA sequence. Epigenetic modulations include DNA methylation, histone modifications, and noncoding RNAs. These gene modifications are heritable and modifiable and can be triggered by lifestyle [...] Read more.
Epigenetics is the branch of molecular biology that studies modifications able to change gene expression without altering the DNA sequence. Epigenetic modulations include DNA methylation, histone modifications, and noncoding RNAs. These gene modifications are heritable and modifiable and can be triggered by lifestyle and nutritional factors. In recent years, epigenetic changes have been associated with the pathogenesis of several diseases such as diabetes, obesity, renal pathology, and different types of cancer. They have also been related with the pathogenesis of cardiovascular diseases including ischemic stroke. Importantly, since epigenetic modifications are reversible processes they could assist with the development of new therapeutic approaches for the treatment of human diseases. In the present review article, we aim to collect the most recent evidence concerning the impact of epigenetic modifications on the pathogenesis of ischemic stroke in both animal models and humans. Full article
(This article belongs to the Special Issue DNA Methylation in Health and Diseases)
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18 pages, 499 KiB  
Perspective
Genome Chaos, Information Creation, and Cancer Emergence: Searching for New Frameworks on the 50th Anniversary of the “War on Cancer”
by Julie Heng and Henry H. Heng
Genes 2022, 13(1), 101; https://doi.org/10.3390/genes13010101 - 31 Dec 2021
Cited by 25 | Viewed by 4286
Abstract
The year 2021 marks the 50th anniversary of the National Cancer Act, signed by President Nixon, which declared a national “war on cancer.” Powered by enormous financial support, this past half-century has witnessed remarkable progress in understanding the individual molecular mechanisms of cancer, [...] Read more.
The year 2021 marks the 50th anniversary of the National Cancer Act, signed by President Nixon, which declared a national “war on cancer.” Powered by enormous financial support, this past half-century has witnessed remarkable progress in understanding the individual molecular mechanisms of cancer, primarily through the characterization of cancer genes and the phenotypes associated with their pathways. Despite millions of publications and the overwhelming volume data generated from the Cancer Genome Project, clinical benefits are still lacking. In fact, the massive, diverse data also unexpectedly challenge the current somatic gene mutation theory of cancer, as well as the initial rationales behind sequencing so many cancer samples. Therefore, what should we do next? Should we continue to sequence more samples and push for further molecular characterizations, or should we take a moment to pause and think about the biological meaning of the data we have, integrating new ideas in cancer biology? On this special anniversary, we implore that it is time for the latter. We review the Genome Architecture Theory, an alternative conceptual framework that departs from gene-based theories. Specifically, we discuss the relationship between genes, genomes, and information-based platforms for future cancer research. This discussion will reinforce some newly proposed concepts that are essential for advancing cancer research, including two-phased cancer evolution (which reconciles evolutionary contributions from karyotypes and genes), stress-induced genome chaos (which creates new system information essential for macroevolution), the evolutionary mechanism of cancer (which unifies diverse molecular mechanisms to create new karyotype coding during evolution), and cellular adaptation and cancer emergence (which explains why cancer exists in the first place). We hope that these ideas will usher in new genomic and evolutionary conceptual frameworks and strategies for the next 50 years of cancer research. Full article
(This article belongs to the Section Human Genomics and Genetic Diseases)
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21 pages, 1276 KiB  
Systematic Review
A Systematic Review on the Therapeutic Potentiality of PD-L1-Inhibiting MicroRNAs for Triple-Negative Breast Cancer: Toward Single-Cell Sequencing-Guided Biomimetic Delivery
by Mahdi Abdoli Shadbad, Sahar Safaei, Oronzo Brunetti, Afshin Derakhshani, Parisa Lotfinejad, Ahad Mokhtarzadeh, Nima Hemmat, Vito Racanelli, Antonio Giovanni Solimando, Antonella Argentiero, Nicola Silvestris and Behzad Baradaran
Genes 2021, 12(8), 1206; https://doi.org/10.3390/genes12081206 - 04 Aug 2021
Cited by 30 | Viewed by 3776
Abstract
The programmed death-ligand 1 (PD-L1)/programmed cell death protein 1 (PD-1) is a well-established inhibitory immune checkpoint axis in triple-negative breast cancer (TNBC). Growing evidence indicates that tumoral PD-L1 can lead to TNBC development. Although conventional immune checkpoint inhibitors have improved TNBC patients’ prognosis, [...] Read more.
The programmed death-ligand 1 (PD-L1)/programmed cell death protein 1 (PD-1) is a well-established inhibitory immune checkpoint axis in triple-negative breast cancer (TNBC). Growing evidence indicates that tumoral PD-L1 can lead to TNBC development. Although conventional immune checkpoint inhibitors have improved TNBC patients’ prognosis, their effect is mainly focused on improving anti-tumoral immune responses without substantially regulating oncogenic signaling pathways in tumoral cells. Moreover, the conventional immune checkpoint inhibitors cannot impede the de novo expression of oncoproteins, like PD-L1, in tumoral cells. Accumulating evidence has indicated that the restoration of specific microRNAs (miRs) can downregulate tumoral PD-L1 and inhibit TNBC development. Since miRs can target multiple mRNAs, miR-based gene therapy can be an appealing approach to inhibit the de novo expression of oncoproteins, like PD-L1, restore anti-tumoral immune responses, and regulate various intracellular singling pathways in TNBC. Therefore, we conducted the current systematic review based on the preferred reporting items for systematic reviews and meta-analyses (PRISMA) to provide a comprehensive and unbiased synthesis of currently available evidence regarding the effect of PD-L1-inhibiting miRs restoration on TNBC development and tumor microenvironment. For this purpose, we systematically searched the Cochrane Library, Embase, Scopus, PubMed, ProQuest, Web of Science, Ovid, and IranDoc databases to obtain the relevant peer-reviewed studies published before 25 May 2021. Based on the current evidence, the restoration of miR-424-5p, miR-138-5p, miR-570-3p, miR-200c-3p, miR-383-5p, miR-34a-5p, miR-3609, miR-195-5p, and miR-497-5p can inhibit tumoral PD-L1 expression, transform immunosuppressive tumor microenvironment into the pro-inflammatory tumor microenvironment, inhibit tumor proliferation, suppress tumor migration, enhance chemosensitivity of tumoral cells, stimulate tumor apoptosis, arrest cell cycle, repress the clonogenicity of tumoral cells, and regulate various oncogenic signaling pathways in TNBC cells. Concerning the biocompatibility of biomimetic carriers and the valuable insights provided by the single-cell sequencing technologies, single-cell sequencing-guided biomimetic delivery of these PD-L1-inhibiting miRs can decrease the toxicity of traditional approaches, increase the specificity of miR-delivery, enhance the efficacy of miR delivery, and provide the affected patients with personalized cancer therapy. Full article
(This article belongs to the Special Issue Transcription Factors in Cancer Progression)
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8 pages, 1033 KiB  
Case Report
MCAT Mutations Cause Nuclear LHON-like Optic Neuropathy
by Sylvie Gerber, Christophe Orssaud, Josseline Kaplan, Catrine Johansson and Jean-Michel Rozet
Genes 2021, 12(4), 521; https://doi.org/10.3390/genes12040521 - 02 Apr 2021
Cited by 21 | Viewed by 2362
Abstract
Pathological variants in the nuclear malonyl-CoA-acyl carrier protein transacylase (MCAT) gene, which encodes a mitochondrial protein involved in fatty-acid biogenesis, have been reported in two siblings from China affected by insidious optic nerve degeneration in childhood, leading to blindness in the [...] Read more.
Pathological variants in the nuclear malonyl-CoA-acyl carrier protein transacylase (MCAT) gene, which encodes a mitochondrial protein involved in fatty-acid biogenesis, have been reported in two siblings from China affected by insidious optic nerve degeneration in childhood, leading to blindness in the first decade of life. After analysing 51 families with negative molecular diagnostic tests, from a cohort of 200 families with hereditary optic neuropathy (HON), we identified two novel MCAT mutations in a female patient who presented with acute, sudden, bilateral, yet asymmetric, central visual loss at the age of 20. This presentation is consistent with a Leber hereditary optic neuropathy (LHON)-like phenotype, whose existence and association with NDUFS2 and DNAJC30 has only recently been described. Our findings reveal a wider phenotypic presentation of MCAT mutations, and a greater genetic heterogeneity of nuclear LHON-like phenotypes. Although MCAT pathological variants are very uncommon, this gene should be investigated in HON patients, irrespective of disease presentation. Full article
(This article belongs to the Special Issue Genetics in Ophthalmology)
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11 pages, 1976 KiB  
Commentary
Optical Genome Mapping as a Next-Generation Cytogenomic Tool for Detection of Structural and Copy Number Variations for Prenatal Genomic Analyses
by Nikhil Shri Sahajpal, Hayk Barseghyan, Ravindra Kolhe, Alex Hastie and Alka Chaubey
Genes 2021, 12(3), 398; https://doi.org/10.3390/genes12030398 - 11 Mar 2021
Cited by 49 | Viewed by 17664
Abstract
Global medical associations (ACOG, ISUOG, ACMG) recommend diagnostic prenatal testing for the detection and prevention of genetic disorders. Historically, cytogenetic methods such as karyotype analysis, fluorescent in situ hybridization (FISH) and chromosomal microarray (CMA) are utilized worldwide to diagnose common syndromes. However, the [...] Read more.
Global medical associations (ACOG, ISUOG, ACMG) recommend diagnostic prenatal testing for the detection and prevention of genetic disorders. Historically, cytogenetic methods such as karyotype analysis, fluorescent in situ hybridization (FISH) and chromosomal microarray (CMA) are utilized worldwide to diagnose common syndromes. However, the limitations of each of these methods, either performed in tandem or simultaneously, demonstrates the need of a revolutionary technology that can alleviate the need for multiple technologies. Optical genome mapping (OGM) is a novel method that fills this void by being able to detect all classes of structural variations (SVs), including copy number variations (CNVs). OGM is being adopted by laboratories as a tool for both postnatal constitutional genetic disorders and hematological malignancies. This commentary highlights the potential for OGM to become a standard of care in prenatal genetic testing based on its capability to comprehensively identify large balanced and unbalanced SVs (currently the strength of karyotyping and metaphase FISH), CNVs (by CMA), repeat contraction disorders (by Southern blotting) and multiple repeat expansion disorders (by PCR-based methods or Southern blotting). Next-generation sequencing (NGS) methods are excellent at detecting sequence variants, but they are unable to accurately resolve repeat regions of the genome, which limits their ability to detect all classes of SVs. Notably, multiple molecular methods are used to identify repeat expansion and contraction disorders in routine clinical laboratories around the world. With non-invasive prenatal testing (NIPT) becoming the standard of care screening assay for all global pregnancies, we anticipate that OGM can provide a high-resolution, cytogenomic assay to be employed following a positive NIPT screen or for high-risk pregnancies with an abnormal ultrasound. Accurate detection of all types of genetic disorders by OGM, such as liveborn aneuploidies, sex chromosome anomalies, microdeletion/microduplication syndromes, repeat expansion/contraction disorders is key to reducing the global burden of genetic disorders. Full article
(This article belongs to the Special Issue Advances in Prenatal Genetic Screening and Diagnosis Technologies)
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20 pages, 421 KiB  
Perspective
The Regulation of RNA Modification Systems: The Next Frontier in Epitranscriptomics?
by Matthias R. Schaefer
Genes 2021, 12(3), 345; https://doi.org/10.3390/genes12030345 - 26 Feb 2021
Cited by 23 | Viewed by 3580
Abstract
RNA modifications, long considered to be molecular curiosities embellishing just abundant and non-coding RNAs, have now moved into the focus of both academic and applied research. Dedicated research efforts (epitranscriptomics) aim at deciphering the underlying principles by determining RNA modification landscapes and investigating [...] Read more.
RNA modifications, long considered to be molecular curiosities embellishing just abundant and non-coding RNAs, have now moved into the focus of both academic and applied research. Dedicated research efforts (epitranscriptomics) aim at deciphering the underlying principles by determining RNA modification landscapes and investigating the molecular mechanisms that establish, interpret and modulate the information potential of RNA beyond the combination of four canonical nucleotides. This has resulted in mapping various epitranscriptomes at high resolution and in cataloguing the effects caused by aberrant RNA modification circuitry. While the scope of the obtained insights has been complex and exciting, most of current epitranscriptomics appears to be stuck in the process of producing data, with very few efforts to disentangle cause from consequence when studying a specific RNA modification system. This article discusses various knowledge gaps in this field with the aim to raise one specific question: how are the enzymes regulated that dynamically install and modify RNA modifications? Furthermore, various technologies will be highlighted whose development and use might allow identifying specific and context-dependent regulators of epitranscriptomic mechanisms. Given the complexity of individual epitranscriptomes, determining their regulatory principles will become crucially important, especially when aiming at modifying specific aspects of an epitranscriptome both for experimental and, potentially, therapeutic purposes. Full article
(This article belongs to the Special Issue Functions and Dynamics of RNA Modifications)
9 pages, 1598 KiB  
Brief Report
Relative Abundance of SARS-CoV-2 Entry Genes in the Enterocytes of the Lower Gastrointestinal Tract
by Jaewon J. Lee, Scott Kopetz, Eduardo Vilar, John Paul Shen, Ken Chen and Anirban Maitra
Genes 2020, 11(6), 645; https://doi.org/10.3390/genes11060645 - 11 Jun 2020
Cited by 53 | Viewed by 5180
Abstract
There is increasing evidence of gastrointestinal (GI) infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We surveyed the co-expression of SARS-CoV-2 entry genes ACE2 and TMPRSS2 throughout the GI tract to assess potential sites of infection. Publicly available and in-house single-cell RNA-sequencing [...] Read more.
There is increasing evidence of gastrointestinal (GI) infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We surveyed the co-expression of SARS-CoV-2 entry genes ACE2 and TMPRSS2 throughout the GI tract to assess potential sites of infection. Publicly available and in-house single-cell RNA-sequencing datasets from the GI tract were queried. Enterocytes from the small intestine and colonocytes showed the highest proportions of cells co-expressing ACE2 and TMPRSS2. Therefore, the lower GI tract represents the most likely site of SARS-CoV-2 entry leading to GI infection. Full article
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