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Genes, Volume 8, Issue 5 (May 2017)

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Cover Story A helicase of archaeal phylogeny named HepA is encoded in the genome of all the Thermus spp. so far [...] Read more.
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Research

Jump to: Review

Open AccessArticle Deoxynucleoside Salvage in Fission Yeast Allows Rescue of Ribonucleotide Reductase Deficiency but Not Spd1-Mediated Inhibition of Replication
Genes 2017, 8(5), 128; doi:10.3390/genes8050128
Received: 9 March 2017 / Revised: 10 April 2017 / Accepted: 20 April 2017 / Published: 25 April 2017
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Abstract
In fission yeast, the small, intrinsically disordered protein S-phase delaying protein 1 (Spd1) blocks DNA replication and causes checkpoint activation at least in part, by inhibiting the enzyme ribonucleotide reductase, which is responsible for the synthesis of DNA building blocks. The CRL4Cdt2
[...] Read more.
In fission yeast, the small, intrinsically disordered protein S-phase delaying protein 1 (Spd1) blocks DNA replication and causes checkpoint activation at least in part, by inhibiting the enzyme ribonucleotide reductase, which is responsible for the synthesis of DNA building blocks. The CRL4Cdt2 E3 ubiquitin ligase mediates degradation of Spd1 and the related protein Spd2 at S phase of the cell cycle. We have generated a conditional allele of CRL4Cdt2, by expressing the highly unstable substrate-recruiting protein Cdt2 from a repressible promoter. Unlike Spd1, Spd2 does not regulate deoxynucleotide triphosphate (dNTP) pools; yet we find that Spd1 and Spd2 together inhibit DNA replication upon Cdt2 depletion. To directly test whether this block of replication was solely due to insufficient dNTP levels, we established a deoxy-nucleotide salvage pathway in fission yeast by expressing the human equilibrative nucleoside transporter 1 (hENT1) and the Drosophila deoxynucleoside kinase. We present evidence that this salvage pathway is functional, as 2 µM of deoxynucleosides in the culture medium is able to rescue the growth of two different temperature-sensitive alleles controlling ribonucleotide reductase. However, salvage completely failed to rescue S phase delay, checkpoint activation, and damage sensitivity, which was caused by CRL4Cdt2 inactivation, suggesting that Spd1—in addition to repressing dNTP synthesis—together with Spd2, can inhibit other replication functions. We propose that this inhibition works at the point of the replication clamp proliferating cell nuclear antigen, a co-factor for DNA replication. Full article
(This article belongs to the Special Issue DNA Replication Controls)
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Open AccessArticle Telomerase Inhibitory Effects of Red Pigment Rubropunctatin and Statin Monacolin L Isolated from Red Yeast Rice
Genes 2017, 8(5), 129; doi:10.3390/genes8050129
Received: 13 December 2016 / Revised: 13 April 2017 / Accepted: 21 April 2017 / Published: 26 April 2017
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Abstract
In addition to the cholesterol-lowering activity of red yeast rice (RYR), its anticancer activities have been frequently reported. However, the mechanism of action of the anticancer activity of RYR is not yet fully understood. The objective of the current study was to elucidate
[...] Read more.
In addition to the cholesterol-lowering activity of red yeast rice (RYR), its anticancer activities have been frequently reported. However, the mechanism of action of the anticancer activity of RYR is not yet fully understood. The objective of the current study was to elucidate anticancer compositions and anticancer mechanism of actions of RYR. The isolated compounds from RYR were subjected to anti-proliferation assay, apoptosis assay via flow cytometry, and telomerase inhibitory assay via telomeric repeat amplification protocol-PCR (TRAP-PCR) assay, and Western blotting assay in an in vitro cell culture system. The results showed that a statin, monacolin L, and a red pigment, rubropunctatin, from RYR exhibited very strong cancer cell proliferation inhibitory effects; the rubropunctatin was comparable with anticancer drug cis-platinum, taxol, and 10-hydroxy-camptothecin (HCPT) in their IC50 values. Monacolin L and rubropunctatin exerted their anticancer activity via telomerase inhibitory effects. Monacolin L and rubropunctatin presented the similar telomerase inhibitory effects as the anticancer drug cis-platinum, while the anticancer drug HCPT presented a weak telomerase inhibitory effect in the TRAP-PCR assay. Meanwhile, rubropunctatin and cis-platinum did not present strong apoptosis induction activity as the momacolin L and HCPT did. These results indicate that the RYR may exert anticancer effects through the telomerase inhibitory effect of rubropunctatin and the apoptosis-induction effect of monacolin L. Full article
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Open AccessArticle Role of Archaeal HerA Protein in the Biology of the Bacterium Thermus thermophilus
Genes 2017, 8(5), 130; doi:10.3390/genes8050130
Received: 15 March 2017 / Revised: 21 April 2017 / Accepted: 24 April 2017 / Published: 27 April 2017
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Abstract
Intense gene flux between prokaryotes result in high percentage of archaeal genes in the genome of the thermophilic bacteria Thermus spp. Among these archaeal genes a homolog to the Sulfolobus spp. HerA protein appears in all of the Thermus spp. strains so far
[...] Read more.
Intense gene flux between prokaryotes result in high percentage of archaeal genes in the genome of the thermophilic bacteria Thermus spp. Among these archaeal genes a homolog to the Sulfolobus spp. HerA protein appears in all of the Thermus spp. strains so far sequenced (HepA). The role of HepA in Thermus thermophilus HB27 has been analyzed using deletion mutants, and its structure resolved at low resolution by electron microscopy. Recombinant HepA shows DNA-dependent ATPase activity and its structure revealed a double ring, conically-shaped hexamer with an upper diameter of 150 Å and a bottom module of 95 Å. A central pore was detected in the structure that ranges from 13 Å at one extreme, to 30 Å at the other. Mutants lacking HepA show defective natural competence and DNA donation capability in a conjugation-like process termed “transjugation”, and also high sensitivity to UV and dramatic sensitivity to high temperatures. These data support that acquisition of an ancestral archaeal HerA has been fundamental for the adaptation of Thermus spp. to high temperatures. Full article
(This article belongs to the Special Issue Horizontal Gene Transfer)
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Open AccessArticle The Stearoyl-CoA Desaturase-1 (Desat1) in Drosophila cooperated with Myc to Induce Autophagy and Growth, a Potential New Link to Tumor Survival
Genes 2017, 8(5), 131; doi:10.3390/genes8050131
Received: 27 March 2017 / Revised: 21 April 2017 / Accepted: 21 April 2017 / Published: 28 April 2017
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Abstract
Lipids are an important energy supply in our cells and can be stored or used to produce macromolecules during lipogenesis when cells experience nutrient starvation. Our proteomic analysis reveals that the Drosophila homologue of human Stearoyl-CoA desaturase-1 (Desat1) is an indirect target of
[...] Read more.
Lipids are an important energy supply in our cells and can be stored or used to produce macromolecules during lipogenesis when cells experience nutrient starvation. Our proteomic analysis reveals that the Drosophila homologue of human Stearoyl-CoA desaturase-1 (Desat1) is an indirect target of Myc in fat cells. Stearoyl-CoA desaturases are key enzymes in the synthesis of monounsaturated fatty acids critical for the formation of complex lipids such as triglycerides and phospholipids. Their function is fundamental for cellular physiology, however in tumors, overexpression of SCD-1 and SCD-5 has been found frequently associated with a poor prognosis. Another gene that is often upregulated in tumors is the proto-oncogene c-myc, where its overexpression or increased protein stability, favor cellular growth. Here, we report a potential link between Myc and Desat1 to control autophagy and growth. Using Drosophila, we found that expression of Desat1, in metabolic tissues like the fat body, in the gut and in epithelial cells, is necessary for Myc function to induce autophagy a cell eating mechanism important for energy production. In addition, we observed that reduction of Desat1 affects Myc ability to induce growth in epithelial cells. Our data also identify, in prostatic tumor cells, a significant correlation between the expression of Myc and SCD-1 proteins, suggesting the existence of a potential functional relationship between the activities of these proteins in sustaining tumor progression. Full article
(This article belongs to the Special Issue MYC Networks)
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Open AccessArticle AKR1C1 as a Biomarker for Differentiating the Biological Effects of Combustible from Non-Combustible Tobacco Products
Genes 2017, 8(5), 132; doi:10.3390/genes8050132
Received: 24 January 2017 / Revised: 31 March 2017 / Accepted: 25 April 2017 / Published: 3 May 2017
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Abstract
Smoking has been established as a major risk factor for developing oral squamous cell carcinoma (OSCC), but less attention has been paid to the effects of smokeless tobacco products. Our objective is to identify potential biomarkers to distinguish the biological effects of combustible
[...] Read more.
Smoking has been established as a major risk factor for developing oral squamous cell carcinoma (OSCC), but less attention has been paid to the effects of smokeless tobacco products. Our objective is to identify potential biomarkers to distinguish the biological effects of combustible tobacco products from those of non-combustible ones using oral cell lines. Normal human gingival epithelial cells (HGEC), non-metastatic (101A) and metastatic (101B) OSCC cell lines were exposed to different tobacco product preparations (TPPs) including cigarette smoke total particulate matter (TPM), whole-smoke conditioned media (WS-CM), smokeless tobacco extract in complete artificial saliva (STE), or nicotine (NIC) alone. We performed microarray-based gene expression profiling and found 3456 probe sets from 101A, 1432 probe sets from 101B, and 2717 probe sets from HGEC to be differentially expressed. Gene Set Enrichment Analysis (GSEA) revealed xenobiotic metabolism and steroid biosynthesis were the top two pathways that were upregulated by combustible but not by non-combustible TPPs. Notably, aldo-keto reductase genes, AKR1C1 and AKR1C2, were the core genes in the top enriched pathways and were statistically upregulated more than eight-fold by combustible TPPs. Quantitative real time polymerase chain reaction (qRT-PCR) results statistically support AKR1C1 as a potential biomarker for differentiating the biological effects of combustible from non-combustible tobacco products. Full article
(This article belongs to the Section Clinical Genomics in Genetic Diseases and Cancer)
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Open AccessArticle A Genetic Population Isolate in The Netherlands Showing Extensive Haplotype Sharing and Long Regions of Homozygosity
Genes 2017, 8(5), 133; doi:10.3390/genes8050133
Received: 9 March 2017 / Accepted: 20 April 2017 / Published: 4 May 2017
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Abstract
Genetic isolated populations have features that may facilitate genetic analyses and can be leveraged to improve power of mapping genes to complex traits. Our aim was to test the extent to which a population with a former history of geographic isolation and religious
[...] Read more.
Genetic isolated populations have features that may facilitate genetic analyses and can be leveraged to improve power of mapping genes to complex traits. Our aim was to test the extent to which a population with a former history of geographic isolation and religious endogamy, and currently with one of the highest fertility rates in The Netherlands, shows signs of genetic isolation. For this purpose, genome-wide genotype data was collected of 72 unrelated individuals from this population as well as in a sample of 104 random control subjects from The Netherlands. Additional reference data from different populations and population isolates was available through HapMap and the Human Genome Diversity Project. We performed a number of analyses to compare the genetic structure between these populations: we calculated the pairwise genetic distance between populations, examined the extent of identical-by-descent (IBD) sharing and estimated the effective population size. Genetic analysis of this population showed consistent patterns of a population isolate at all levels tested. We confirmed that this population is most closely related to the Dutch control subjects, and detected high levels of IBD sharing and runs of homozygosity at equal or even higher levels than observed in previously described population isolates. The effective population size of this population was estimated to be several orders of magnitude smaller than that of the Dutch control sample. We conclude that the geographic isolation of this population combined with rapid population growth has resulted in a genetic isolate with great potential value for future genetic studies. Full article
(This article belongs to the Section Human Genetics and Genomics)
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Open AccessArticle MB0 and MBI Are Independent and Distinct Transactivation Domains in MYC that Are Essential for Transformation
Genes 2017, 8(5), 134; doi:10.3390/genes8050134
Received: 10 February 2017 / Revised: 24 April 2017 / Accepted: 28 April 2017 / Published: 6 May 2017
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Abstract
MYC is a transcription factor that is essential for cellular proliferation and development. Deregulation or overexpression of MYC occurs in a variety of human cancers. Ectopic expression of MYC causes hyperproliferation and transformation of cells in culture and tumorigenesis in several transgenic mouse
[...] Read more.
MYC is a transcription factor that is essential for cellular proliferation and development. Deregulation or overexpression of MYC occurs in a variety of human cancers. Ectopic expression of MYC causes hyperproliferation and transformation of cells in culture and tumorigenesis in several transgenic mouse models. Deregulation of MYC can also induce apoptosis through activation of p53 and/or ARF tumor suppressors as a safeguard to prevent tumorigenesis. MYC binds to thousands of genomic sites and regulates hundreds of target genes in a context-dependent fashion to mediate these diverse biological roles. The N-terminal region of MYC contains several conserved domains or MYC Boxes (MB), which influence the different MYC transcriptional and biological activities to varying degrees. However, the specific domains that mediate the ability of MYC to activate transcription remain ill defined. In this report, we have identified a new conserved transactivation domain (TAD), MB0, which is essential for MYC transactivation and target gene induction. We demonstrate that MB0 and MBI represent two distinct and independent TADs within the N-terminal 62 amino acids of MYC. In addition, both MB0 and MBI are essential for MYC transformation of primary fibroblasts in cooperation with activated RAS, while MB0 is necessary for efficient MYC-induced p53-independent apoptosis. Full article
(This article belongs to the Special Issue MYC Networks)
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Open AccessArticle Rectal Cancer in a Patient with Bartter Syndrome: A Case Report
Genes 2017, 8(5), 139; doi:10.3390/genes8050139
Received: 22 February 2017 / Revised: 30 March 2017 / Accepted: 3 May 2017 / Published: 12 May 2017
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Abstract
A woman with rectal cancer was scheduled for surgery. However, she also had hypokalemia, hyperreninemia, and hyperaldosteronism in the absence of any known predisposing factors or endocrine tumors. She was given intravenous potassium, and her blood abnormalities stabilized after tumor resection. Genetic analysis
[...] Read more.
A woman with rectal cancer was scheduled for surgery. However, she also had hypokalemia, hyperreninemia, and hyperaldosteronism in the absence of any known predisposing factors or endocrine tumors. She was given intravenous potassium, and her blood abnormalities stabilized after tumor resection. Genetic analysis revealed mutations in several genes associated with Bartter syndrome (BS) and Gitelman syndrome, including SLC12A1, CLCNKB, CASR, SLC26A3, and SLC12A3. Prostaglandin E2 (PGE2) plays an important role in BS and worsens electrolyte abnormalities. The PGE2 level is reportedly increased in colorectal cancer, and in the present case, immunohistochemical examination revealed an increased PGE2 level in the tumor. We concluded that the tumor-related PGE2 elevation had worsened the patient’s BS, which became more manageable after tumor resection. Full article
(This article belongs to the Special Issue Cancer Genetics)
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Open AccessArticle Mutational and Kinetic Analysis of Lesion Recognition by Escherichia coli Endonuclease VIII
Genes 2017, 8(5), 140; doi:10.3390/genes8050140
Received: 27 February 2017 / Revised: 3 May 2017 / Accepted: 9 May 2017 / Published: 13 May 2017
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Abstract
Escherichia coli endonuclease VIII (Endo VIII) is a DNA glycosylase with substrate specificity for a wide range of oxidatively damaged pyrimidine bases. Endo VIII catalyzes hydrolysis of the N-glycosidic bond and β, δ-elimination of 3′- and 5′-phosphate groups of an apurinic/apyrimidinic site. Single
[...] Read more.
Escherichia coli endonuclease VIII (Endo VIII) is a DNA glycosylase with substrate specificity for a wide range of oxidatively damaged pyrimidine bases. Endo VIII catalyzes hydrolysis of the N-glycosidic bond and β, δ-elimination of 3′- and 5′-phosphate groups of an apurinic/apyrimidinic site. Single mutants of Endo VIII L70S, L70W, Y71W, F121W, F230W, and P253W were analyzed here with the aim to elucidate the kinetic mechanism of protein conformational adjustment during damaged-nucleotide recognition and catalytic-complex formation. F121W substitution leads to a slight reduction of DNA binding and catalytic activity. F230W substitution slows the rate of the δ-elimination reaction indicating that interaction of Phe230 with a 5′-phosphate group proceeds in the latest catalytic step. P253W Endo VIII has the same activity as the wild type (WT) enzyme. Y71W substitution slightly reduces the catalytic activity due to the effect on the later steps of catalytic-complex formation. Both L70S and L70W substitutions significantly decrease the catalytic activity, indicating that Leu70 plays an important role in the course of enzyme-DNA catalytic complex formation. Our data suggest that Leu70 forms contacts with DNA earlier than Tyr71 does. Therefore, most likely, Leu70 plays the role of a DNA lesion “sensor”, which is used by Endo VIII for recognition of a DNA damage site. Full article
(This article belongs to the Special Issue Protein-DNA Interactions)
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Open AccessArticle Variability of DNA Methylation within Schizophrenia Risk Loci across Subregions of Human Hippocampus
Genes 2017, 8(5), 143; doi:10.3390/genes8050143
Received: 7 March 2017 / Revised: 9 May 2017 / Accepted: 11 May 2017 / Published: 15 May 2017
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Abstract
Identification of 108 genomic regions significantly associated with schizophrenia risk by the Psychiatric Genomics Consortium was a milestone for the field, and much work is now focused on determining the mechanism of risk associated with each locus. Within these regions, we investigated variability
[...] Read more.
Identification of 108 genomic regions significantly associated with schizophrenia risk by the Psychiatric Genomics Consortium was a milestone for the field, and much work is now focused on determining the mechanism of risk associated with each locus. Within these regions, we investigated variability of DNA methylation, a low-level cellular phenotype closely linked to genotype, in two highly similar cellular populations sampled from the human hippocampus, to draw inferences about the elaboration of genotype to phenotype within these loci enriched for schizophrenia risk. DNA methylation was assessed with the Illumina HumanMethylation450 BeadArray in tissue laser-microdissected from the stratum oriens of subfield CA1 or CA2/3, regions having unique connectivity with intrinsic and extrinsic fiber systems within the hippocampus. Samples consisted of postmortem human hippocampus tissue from eight schizophrenia patients, eight bipolar disorder patients, and eight healthy control subjects. Within these genomic regions, we observed far greater difference in methylation patterns between circuit locations within subjects than in a single subregion between subjects across diagnostic groups, demonstrating the complexity of genotype to phenotype elaboration across the diverse circuitry of the human brain. Full article
(This article belongs to the Special Issue Role of Epigenetic Gene Regulation in Brain Function)
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Open AccessArticle DNA Methylation Targets Influenced by Bisphenol A and/or Genistein Are Associated with Survival Outcomes in Breast Cancer Patients
Genes 2017, 8(5), 144; doi:10.3390/genes8050144
Received: 10 March 2017 / Revised: 25 April 2017 / Accepted: 9 May 2017 / Published: 15 May 2017
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Abstract
Early postnatal exposures to Bisphenol A (BPA) and genistein (GEN) have been reported to predispose for and against mammary cancer, respectively, in adult rats. Since the changes in cancer susceptibility occurs in the absence of the original chemical exposure, we have investigated the
[...] Read more.
Early postnatal exposures to Bisphenol A (BPA) and genistein (GEN) have been reported to predispose for and against mammary cancer, respectively, in adult rats. Since the changes in cancer susceptibility occurs in the absence of the original chemical exposure, we have investigated the potential of epigenetics to account for these changes. DNA methylation studies reveal that prepubertal BPA exposure alters signaling pathways that contribute to carcinogenesis. Prepubertal exposure to GEN and BPA + GEN revealed pathways involved in maintenance of cellular function, indicating that the presence of GEN either reduces or counters some of the alterations caused by the carcinogenic properties of BPA. We subsequently evaluated the potential of epigenetic changes in the rat mammary tissues to predict survival in breast cancer patients via the Cancer Genomic Atlas (TCGA). We identified 12 genes that showed strong predictive values for long-term survival in estrogen receptor positive patients. Importantly, two genes associated with improved long term survival, HPSE and RPS9, were identified to be hypomethylated in mammary glands of rats exposed prepuberally to GEN or to GEN + BPA respectively, reinforcing the suggested cancer suppressive properties of GEN. Full article
(This article belongs to the Special Issue Integrative Genomics and Systems Medicine in Cancer)
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Open AccessArticle The Clinical Course of Patients with Preschool Manifestation of Type 1 Diabetes Is Independent of the HLA DR-DQ Genotype
Genes 2017, 8(5), 146; doi:10.3390/genes8050146
Received: 30 January 2017 / Revised: 3 May 2017 / Accepted: 16 May 2017 / Published: 19 May 2017
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Abstract
Introduction: Major histocompatibility complex class II genes are considered major genetic risk factors for autoimmune diabetes. We analysed Human Leukocyte Antigen (HLA) DR and DQ haplotypes in a cohort with early-onset (age < 5 years), long term type 1 diabetes (T1D) and explored
[...] Read more.
Introduction: Major histocompatibility complex class II genes are considered major genetic risk factors for autoimmune diabetes. We analysed Human Leukocyte Antigen (HLA) DR and DQ haplotypes in a cohort with early-onset (age < 5 years), long term type 1 diabetes (T1D) and explored their influence on clinical and laboratory parameters. Methods: Intermediate resolution HLA-DRB1, DQA1 and DQB1 typing was performed in 233 samples from the German Paediatric Diabetes Biobank and compared with a local control cohort of 19,544 cases. Clinical follow-up data of 195 patients (diabetes duration 14.2 ± 2.9 years) and residual C-peptide levels were compared between three HLA risk groups using multiple linear regression analysis. Results: Genetic variability was low, 44.6% (104/233) of early-onset T1D patients carried the highest-risk genotype HLA-DRB1*03:01-DQA1*05:01-DQB1*02:01/DRB1*04-DQA1*03:01-DQB1*03:02 (HLA-DRB1*04 denoting 04:01/02/04/05), and 231 of 233 individuals carried at least one of six risk haplotypes. Comparing clinical data between the highest (n = 83), moderate (n = 106) and low risk (n = 6) genotypes, we found no difference in age at diagnosis (mean age 2.8 ± 1.1 vs. 2.8 ± 1.2 vs. 3.2 ± 1.5 years), metabolic control, or frequency of associated autoimmune diseases between HLA risk groups (each p > 0.05). Residual C-peptide was detectable in 23.5% and C-peptide levels in the highest-risk group were comparable to levels in moderate to high risk genotypes. Conclusion: In this study, we saw no evidence for a different clinical course of early-onset T1D based on the HLA genotype within the first ten years after manifestation. Full article
(This article belongs to the Special Issue Genetics and Functional Genomics of Diabetes Mellitus)
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Review

Jump to: Research

Open AccessReview Combination of RNA Interference and Stem Cells for Treatment of Central Nervous System Diseases
Genes 2017, 8(5), 135; doi:10.3390/genes8050135
Received: 22 February 2017 / Revised: 27 April 2017 / Accepted: 28 April 2017 / Published: 6 May 2017
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Abstract
RNA interference (RNAi), including microRNAs, is an important player in the mediation of differentiation and migration of stem cells via target genes. It is used as a potential strategy for gene therapy for central nervous system (CNS) diseases. Stem cells are considered vectors
[...] Read more.
RNA interference (RNAi), including microRNAs, is an important player in the mediation of differentiation and migration of stem cells via target genes. It is used as a potential strategy for gene therapy for central nervous system (CNS) diseases. Stem cells are considered vectors of RNAi due to their capacity to deliver RNAi to other cells. In this review, we discuss the recent advances in studies of RNAi pathways in controlling neuronal differentiation and migration of stem cells. We also highlight the utilization of a combination of RNAi and stem cells in treatment of CNS diseases. Full article
(This article belongs to the Special Issue RNA Interference 2016)
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Open AccessReview The Role of the N-Terminal Domains of Bacterial Initiator DnaA in the Assembly and Regulation of the Bacterial Replication Initiation Complex
Genes 2017, 8(5), 136; doi:10.3390/genes8050136
Received: 23 March 2017 / Revised: 28 April 2017 / Accepted: 4 May 2017 / Published: 10 May 2017
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Abstract
The primary role of the bacterial protein DnaA is to initiate chromosomal replication. The DnaA protein binds to DNA at the origin of chromosomal replication (oriC) and assembles into a filament that unwinds double-stranded DNA. Through interaction with various other proteins,
[...] Read more.
The primary role of the bacterial protein DnaA is to initiate chromosomal replication. The DnaA protein binds to DNA at the origin of chromosomal replication (oriC) and assembles into a filament that unwinds double-stranded DNA. Through interaction with various other proteins, DnaA also controls the frequency and/or timing of chromosomal replication at the initiation step. Escherichia coli DnaA also recruits DnaB helicase, which is present in unwound single-stranded DNA and in turn recruits other protein machinery for replication. Additionally, DnaA regulates the expression of certain genes in E. coli and a few other species. Acting as a multifunctional factor, DnaA is composed of four domains that have distinct, mutually dependent roles. For example, C-terminal domain IV interacts with double-stranded DnaA boxes. Domain III drives ATP-dependent oligomerization, allowing the protein to form a filament that unwinds DNA and subsequently binds to and stabilizes single-stranded DNA in the initial replication bubble; this domain also interacts with multiple proteins that control oligomerization. Domain II constitutes a flexible linker between C-terminal domains III–IV and N-terminal domain I, which mediates intermolecular interactions between DnaA and binds to other proteins that affect DnaA activity and/or formation of the initiation complex. Of these four domains, the role of the N-terminus (domains I–II) in the assembly of the initiation complex is the least understood and appears to be the most species-dependent region of the protein. Thus, in this review, we focus on the function of the N-terminus of DnaA in orisome formation and the regulation of its activity in the initiation complex in different bacteria. Full article
(This article belongs to the Special Issue DNA Replication Controls)
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Open AccessReview Chromatin Switches during Neural Cell Differentiation and Their Dysregulation by Prenatal Alcohol Exposure
Genes 2017, 8(5), 137; doi:10.3390/genes8050137
Received: 31 January 2017 / Revised: 1 May 2017 / Accepted: 6 May 2017 / Published: 11 May 2017
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Abstract
Prenatal alcohol exposure causes persistent neuropsychiatric deficits included under the term fetal alcohol spectrum disorders (FASD). Cellular identity emerges from a cascade of intrinsic and extrinsic (involving cell-cell interactions and signaling) processes that are partially initiated and maintained through changes in chromatin structure.
[...] Read more.
Prenatal alcohol exposure causes persistent neuropsychiatric deficits included under the term fetal alcohol spectrum disorders (FASD). Cellular identity emerges from a cascade of intrinsic and extrinsic (involving cell-cell interactions and signaling) processes that are partially initiated and maintained through changes in chromatin structure. Prenatal alcohol exposure influences neuronal and astrocyte development, permanently altering brain connectivity. Prenatal alcohol exposure also alters chromatin structure through histone and DNA modifications. However, the data linking alcohol-induced differentiation changes with developmental alterations in chromatin structure remain to be elucidated. In the first part of this review, we discuss the sequence of chromatin structural changes involved in neural cell differentiation during normal development. We then discuss the effects of prenatal alcohol on developmental histone modifications and DNA methylation in the context of neurogenesis and astrogliogenesis. We attempt to synthesize the developmental literature with the FASD literature, proposing that alcohol-induced changes to chromatin structure account for altered neurogenesis and astrogliogenesis as well as altered neuron and astrocyte differentiation. Together these changes may contribute to the cognitive and behavioral abnormalities in FASD. Future studies using standardized alcohol exposure paradigms at specific developmental stages will advance the understanding of how chromatin structural changes impact neural cell fate and maturation in FASD. Full article
(This article belongs to the Special Issue Role of Epigenetic Gene Regulation in Brain Function)
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Open AccessReview DNA Methylation Dynamics and Cocaine in the Brain: Progress and Prospects
Genes 2017, 8(5), 138; doi:10.3390/genes8050138
Received: 8 March 2017 / Accepted: 4 April 2017 / Published: 12 May 2017
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Abstract
Cytosine modifications, including DNA methylation, are stable epigenetic marks that may translate environmental change into transcriptional regulation. Research has begun to investigate DNA methylation dynamics in relation to cocaine use disorders. Specifically, DNA methylation machinery, including methyltransferases and binding proteins, are dysregulated in
[...] Read more.
Cytosine modifications, including DNA methylation, are stable epigenetic marks that may translate environmental change into transcriptional regulation. Research has begun to investigate DNA methylation dynamics in relation to cocaine use disorders. Specifically, DNA methylation machinery, including methyltransferases and binding proteins, are dysregulated in brain reward pathways after chronic cocaine exposure. In addition, numerous methylome-wide and candidate promoter studies have identified differential methylation, at the nucleotide level, in rodent models of cocaine abuse and drug seeking behavior. This review highlights the current progress in the field of cocaine-related methylation, and offers considerations for future research. Full article
(This article belongs to the Special Issue Role of Epigenetic Gene Regulation in Brain Function)
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Open AccessReview The Crucial Role of DNA Methylation and MeCP2 in Neuronal Function
Genes 2017, 8(5), 141; doi:10.3390/genes8050141
Received: 16 February 2017 / Revised: 25 April 2017 / Accepted: 5 May 2017 / Published: 13 May 2017
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Abstract
A neuron is unique in its ability to dynamically modify its transcriptional output in response to synaptic activity while maintaining a core gene expression program that preserves cellular identity throughout a lifetime that is longer than almost every other cell type in the
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A neuron is unique in its ability to dynamically modify its transcriptional output in response to synaptic activity while maintaining a core gene expression program that preserves cellular identity throughout a lifetime that is longer than almost every other cell type in the body. A contributing factor to the immense adaptability of a neuron is its unique epigenetic landscape that elicits locus-specific alterations in chromatin architecture, which in turn influences gene expression. One such epigenetic modification that is sensitive to changes in synaptic activity, as well as essential for maintaining cellular identity, is DNA methylation. The focus of this article is on the importance of DNA methylation in neuronal function, summarizing recent studies on critical players in the establishment of (the “writing”), the modification or erasure of (the “editing”), and the mediation of (the “reading”) DNA methylation in neurodevelopment and neuroplasticity. One “reader” of DNA methylation in particular, methyl-CpG-binding protein 2 (MeCP2), is highlighted, given its undisputed importance in neuronal function. Full article
(This article belongs to the Special Issue Role of Epigenetic Gene Regulation in Brain Function)
Open AccessReview MYC—Master Regulator of the Cancer Epigenome and Transcriptome
Genes 2017, 8(5), 142; doi:10.3390/genes8050142
Received: 28 February 2017 / Revised: 9 May 2017 / Accepted: 10 May 2017 / Published: 13 May 2017
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Abstract
Overexpression of MYC is a hallmark of many human cancers. The MYC oncogene has long been thought to execute its neoplastic functions by acting as a classic transcription factor, deregulating the expression of a large number of specific target genes. However, MYC’s influence
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Overexpression of MYC is a hallmark of many human cancers. The MYC oncogene has long been thought to execute its neoplastic functions by acting as a classic transcription factor, deregulating the expression of a large number of specific target genes. However, MYC’s influence on many of these target genes is rather modest and there is little overlap between MYC regulated genes in different cell types, leaving many mechanistic questions unanswered. Recent advances in the field challenge the dogma further, revealing a role for MYC that extends beyond the traditional concept of a sequence-specific transcription factor. In this article, we review MYC’s function as a regulator of the cancer epigenome and transcriptome. We outline our current understanding of how MYC regulates chromatin structure in both a site-specific and genome-wide fashion, and highlight the implications for therapeutic strategies for cancers with high MYC expression. Full article
(This article belongs to the Special Issue MYC Networks)
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Open AccessReview Epigenetic Regulation of Telomere Maintenance for Therapeutic Interventions in Gliomas
Genes 2017, 8(5), 145; doi:10.3390/genes8050145
Received: 29 March 2017 / Revised: 8 May 2017 / Accepted: 12 May 2017 / Published: 17 May 2017
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Abstract
High-grade astrocytoma of WHO grade 4 termed glioblastoma multiforme (GBM) is a common human brain tumor with poor patient outcome. Astrocytoma demonstrates two known telomere maintenance mechanisms (TMMs) based on telomerase activity (TA) and on alternative lengthening of telomeres (ALT). ALT is associated
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High-grade astrocytoma of WHO grade 4 termed glioblastoma multiforme (GBM) is a common human brain tumor with poor patient outcome. Astrocytoma demonstrates two known telomere maintenance mechanisms (TMMs) based on telomerase activity (TA) and on alternative lengthening of telomeres (ALT). ALT is associated with lower tumor grades and better outcome. In contrast to ALT, regulation of TA in tumors by direct mutation and epigenetic activation of the hTERT promoter is well established. Here, we summarize the genetic background of TMMs in non-malignant cells and in cancer, in addition to clinical and pathological features of gliomas. Furthermore, we present new evidence for epigenetic mechanisms (EMs) involved in regulation of ALT and TA with special emphasis on human diffuse gliomas as potential therapeutic drug targets. We discuss the role of TMM associated telomeric chromatin factors such as DNA and histone modifying enzymes and non-coding RNAs including microRNAs and long telomeric TERRA transcripts. Full article
(This article belongs to the Special Issue Role of Epigenetic Gene Regulation in Brain Function)
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