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Evolution of Epigenetic Mechanisms and Signatures
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Evolution of Epigenetic Mechanisms and Signatures

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cell Nuclei: Function, Transport and Receptors".

Deadline for manuscript submissions: closed (31 August 2020) | Viewed by 93311

Special Issue Editors

Prof. Dr. Anton Buzdin

E-Mail Website
Guest Editor
1. Subgroup of Bioinformatics and Biostatistics, European Organization for Research and Treatment of Cancer, Brussels, Belgium
2. Group for Genomic Analysis of Cell Signaling Systems, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, 117997 Moscow, Russia
3. Institute of Personalized Medicine, I.M. Sechenov First Moscow State Medical University, 119991 Moscow, Russia
4. Omicsway Corp., Walnut, CA 91789, USA
Interests: systems biology; omics molecular medicine; personalized oncology; molecular diagnostics of cancer; targeted therapy
Special Issues, Collections and Topics in MDPI journals
Dr. Alla Kalmykova

E-Mail Website1 Website2
Guest Editor
Head of Laboratory of Developmental Epigenetics, Koltzov Institute of Developmental Biology of RAS, 119334 Moscow, Russia
Interests: telomeres; development; germline; epigenetics
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

For many years epigenetics has been considered a hot topic in basic and applied biosciences. Many mechanisms have been elucidated governing genome activity regulation at the levels of chromatin organization, the transcription of DNA, RNA stability and translation. These include but are not limited to DNA methylation and hydroxmethylation; histone modifications; and various types of non-coding RNAs like circular RNAs, small interfering RNAs, and micro RNA machinery. Numerous applications have been found in fundamental studies, bioengineering, and molecular diagnostics.

Many epigenetic mechanisms have been investigated in detail in such biologically distinct objects as mammals (human, mouse), teleosts (zebrafish), insects (drosophila), nematodes (C.elegans), and plants (Arabidopsis). This has been immensely enhanced by the recent progress in massive parallel screening technologies such as next-generation sequencing and modern proteomic approaches. Rich materials have been accumulated and the time has arrived to take a panoramic view of epigenetic mechanisms in the context of molecular evolution. In this Special Issue, the authors are invited to submit all formats of manuscripts dealing with the evolutionary aspects of epigenetic mechanisms. Both bioinformatic and experimental research papers and reviews will be accepted.

Dr. Anton Buzdin
Dr. Alla Kalmykova
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Epigenetics
  • Molecular evolution
  • Regulation of gene expression
  • Systems biology

Published Papers (21 papers)

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Editorial

Jump to: Research, Review

3 pages, 190 KiB  
Editorial
Evolution of Epigenetic Mechanisms and Signatures
by Alla Kalmykova and Anton Buzdin
Cells 2023, 12(1), 109; https://doi.org/10.3390/cells12010109 - 27 Dec 2022
Viewed by 1206
Abstract
DNA methylation, histone posttranslational modifications, higher-order chromatin organization and regulation by noncoding RNAs are considered as the basic mechanisms underlying the epigenetic memory [...] Full article
(This article belongs to the Special Issue Evolution of Epigenetic Mechanisms and Signatures)

Research

Jump to: Editorial, Review

23 pages, 2340 KiB  
Article
A Transposon Story: From TE Content to TE Dynamic Invasion of Drosophila Genomes Using the Single-Molecule Sequencing Technology from Oxford Nanopore
by Mourdas Mohamed, Nguyet Thi-Minh Dang, Yuki Ogyama, Nelly Burlet, Bruno Mugat, Matthieu Boulesteix, Vincent Mérel, Philippe Veber, Judit Salces-Ortiz, Dany Severac, Alain Pélisson, Cristina Vieira, François Sabot, Marie Fablet and Séverine Chambeyron
Cells 2020, 9(8), 1776; https://doi.org/10.3390/cells9081776 - 25 Jul 2020
Cited by 17 | Viewed by 4998
Abstract
Transposable elements (TEs) are the main components of genomes. However, due to their repetitive nature, they are very difficult to study using data obtained with short-read sequencing technologies. Here, we describe an efficient pipeline to accurately recover TE insertion (TEI) sites and sequences [...] Read more.
Transposable elements (TEs) are the main components of genomes. However, due to their repetitive nature, they are very difficult to study using data obtained with short-read sequencing technologies. Here, we describe an efficient pipeline to accurately recover TE insertion (TEI) sites and sequences from long reads obtained by Oxford Nanopore Technology (ONT) sequencing. With this pipeline, we could precisely describe the landscapes of the most recent TEIs in wild-type strains of Drosophila melanogaster and Drosophila simulans. Their comparison suggests that this subset of TE sequences is more similar than previously thought in these two species. The chromosome assemblies obtained using this pipeline also allowed recovering piRNA cluster sequences, which was impossible using short-read sequencing. Finally, we used our pipeline to analyze ONT sequencing data from a D. melanogaster unstable line in which LTR transposition was derepressed for 73 successive generations. We could rely on single reads to identify new insertions with intact target site duplications. Moreover, the detailed analysis of TEIs in the wild-type strains and the unstable line did not support the trap model claiming that piRNA clusters are hotspots of TE insertions. Full article
(This article belongs to the Special Issue Evolution of Epigenetic Mechanisms and Signatures)
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Graphical abstract

19 pages, 5764 KiB  
Article
Conserved Small Nucleotidic Elements at the Origin of Concerted piRNA Biogenesis from Genes and lncRNAs
by Silke Jensen, Emilie Brasset, Elise Parey, Hugues Roest Crollius, Igor V. Sharakhov and Chantal Vaury
Cells 2020, 9(6), 1491; https://doi.org/10.3390/cells9061491 - 18 Jun 2020
Cited by 9 | Viewed by 2883
Abstract
PIWI-interacting RNAs (piRNAs) target transcripts by sequence complementarity serving as guides for RNA slicing in animal germ cells. The piRNA pathway is increasingly recognized as critical for essential cellular functions such as germline development and reproduction. In the Anopheles gambiae ovary, as much [...] Read more.
PIWI-interacting RNAs (piRNAs) target transcripts by sequence complementarity serving as guides for RNA slicing in animal germ cells. The piRNA pathway is increasingly recognized as critical for essential cellular functions such as germline development and reproduction. In the Anopheles gambiae ovary, as much as 11% of piRNAs map to protein-coding genes. Here, we show that ovarian mRNAs and long non-coding RNAs (lncRNAs) are processed into piRNAs that can direct other transcripts into the piRNA biogenesis pathway. Targeting piRNAs fuel transcripts either into the ping-pong cycle of piRNA amplification or into the machinery of phased piRNA biogenesis, thereby creating networks of inter-regulating transcripts. RNAs of the same network share related genomic repeats. These repeats give rise to piRNAs, which target other transcripts and lead to a cascade of concerted RNA slicing. While ping-pong networks are based on repeats of several hundred nucleotides, networks that rely on phased piRNA biogenesis operate through short ~40-nucleotides long repeats, which we named snetDNAs. Interestingly, snetDNAs are recurring in evolution from insects to mammals. Our study brings to light a new type of conserved regulatory pathway, the snetDNA-pathway, by which short sequences can include independent genes and lncRNAs in the same biological pathway. Full article
(This article belongs to the Special Issue Evolution of Epigenetic Mechanisms and Signatures)
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25 pages, 4738 KiB  
Article
Sex Chromosomes and Sex Phenotype Contribute to Biased DNA Methylation in Mouse Liver
by Qinwei Kim-Wee Zhuang, Jose Hector Galvez, Qian Xiao, Najla AlOgayil, Jeffrey Hyacinthe, Teruko Taketo, Guillaume Bourque and Anna K. Naumova
Cells 2020, 9(6), 1436; https://doi.org/10.3390/cells9061436 - 09 Jun 2020
Cited by 11 | Viewed by 4594
Abstract
Sex biases in the genome-wide distribution of DNA methylation and gene expression levels are some of the manifestations of sexual dimorphism in mammals. To advance our understanding of the mechanisms that contribute to sex biases in DNA methylation and gene expression, we conducted [...] Read more.
Sex biases in the genome-wide distribution of DNA methylation and gene expression levels are some of the manifestations of sexual dimorphism in mammals. To advance our understanding of the mechanisms that contribute to sex biases in DNA methylation and gene expression, we conducted whole genome bisulfite sequencing (WGBS) as well as RNA-seq on liver samples from mice with different combinations of sex phenotype and sex-chromosome complement. We compared groups of animals with different sex phenotypes, but the same genetic sexes, and vice versa, same sex phenotypes, but different sex-chromosome complements. We also compared sex-biased DNA methylation in mouse and human livers. Our data show that sex phenotype, X-chromosome dosage, and the presence of Y chromosome shape the differences in DNA methylation between males and females. We also demonstrate that sex bias in autosomal methylation is associated with sex bias in gene expression, whereas X-chromosome dosage-dependent methylation differences are not, as expected for a dosage-compensation mechanism. Furthermore, we find partial conservation between the repertoires of mouse and human genes that are associated with sex-biased methylation, an indication that gene function is likely to be an important factor in this phenomenon. Full article
(This article belongs to the Special Issue Evolution of Epigenetic Mechanisms and Signatures)
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19 pages, 3546 KiB  
Article
Epigenetic Requirements for Triggering Heterochromatinization and Piwi-Interacting RNA Production from Transgenes in the Drosophila Germline
by Pavel A. Komarov, Olesya Sokolova, Natalia Akulenko, Emilie Brasset, Silke Jensen and Alla Kalmykova
Cells 2020, 9(4), 922; https://doi.org/10.3390/cells9040922 - 10 Apr 2020
Cited by 6 | Viewed by 3275
Abstract
Transgenes containing a fragment of the I retrotransposon represent a powerful model of piRNA cluster de novo formation in the Drosophila germline. We revealed that the same transgenes located at different genomic loci form piRNA clusters with various capacity of small RNA production. [...] Read more.
Transgenes containing a fragment of the I retrotransposon represent a powerful model of piRNA cluster de novo formation in the Drosophila germline. We revealed that the same transgenes located at different genomic loci form piRNA clusters with various capacity of small RNA production. Transgenic piRNA clusters are not established in piRNA pathway mutants. However, in the wild-type context, the endogenous ancestral I-related piRNAs heterochromatinize and convert the I-containing transgenes into piRNA-producing loci. Here, we address how the quantitative level of piRNAs influences the heterochromatinization and piRNA production. We show that a minimal amount of maternal piRNAs from ancestral I-elements is sufficient to form the transgenic piRNA clusters. Supplemental piRNAs stemming from active I-element copies do not stimulate additional chromatin changes or piRNA production from transgenes. Therefore, chromatin changes and piRNA production are initiated by a minimum threshold level of complementary piRNAs, suggesting a selective advantage of prompt cell response to the lowest level of piRNAs. It is noteworthy that the weak piRNA clusters do not transform into strong ones after being targeted by abundant I-specific piRNAs, indicating the importance of the genomic context for piRNA cluster establishment. Analysis of ovarian transcription profiles suggests that regions facilitating convergent transcription favor the formation of transgenic piRNA clusters. Full article
(This article belongs to the Special Issue Evolution of Epigenetic Mechanisms and Signatures)
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25 pages, 2973 KiB  
Article
Three-dimensional Organization of Polytene Chromosomes in Somatic and Germline Tissues of Malaria Mosquitoes
by Phillip George, Nicholas A. Kinney, Jiangtao Liang, Alexey V. Onufriev and Igor V. Sharakhov
Cells 2020, 9(2), 339; https://doi.org/10.3390/cells9020339 - 01 Feb 2020
Cited by 10 | Viewed by 4717
Abstract
Spatial organization of chromosome territories and interactions between interphase chromosomes themselves, as well as with the nuclear periphery, play important roles in epigenetic regulation of the genome function. However, the interplay between inter-chromosomal contacts and chromosome-nuclear envelope attachments in an organism’s development is [...] Read more.
Spatial organization of chromosome territories and interactions between interphase chromosomes themselves, as well as with the nuclear periphery, play important roles in epigenetic regulation of the genome function. However, the interplay between inter-chromosomal contacts and chromosome-nuclear envelope attachments in an organism’s development is not well-understood. To address this question, we conducted microscopic analyses of the three-dimensional chromosome organization in malaria mosquitoes. We employed multi-colored oligonucleotide painting probes, spaced 1 Mb apart along the euchromatin, to quantitatively study chromosome territories in larval salivary gland cells and adult ovarian nurse cells of Anopheles gambiae, An. coluzzii, and An. merus. We found that the X chromosome territory has a significantly smaller volume and is more compact than the autosomal arm territories. The number of inter-chromosomal, and the percentage of the chromosome–nuclear envelope, contacts were conserved among the species within the same cell type. However, the percentage of chromosome regions located at the nuclear periphery was typically higher, while the number of inter-chromosomal contacts was lower, in salivary gland cells than in ovarian nurse cells. The inverse correlation was considerably stronger for the autosomes. Consistent with previous theoretical arguments, our data indicate that, at the genome-wide level, there is an inverse relationship between chromosome-nuclear envelope attachments and chromosome–chromosome interactions, which is a key feature of the cell type-specific nuclear architecture. Full article
(This article belongs to the Special Issue Evolution of Epigenetic Mechanisms and Signatures)
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Graphical abstract

22 pages, 5386 KiB  
Article
Painting of Fourth and the X-Linked 1.688 Satellite in D. melanogaster Is Involved in Chromosome-Wide Gene Regulation
by Samaneh Ekhteraei-Tousi, Jacob Lewerentz and Jan Larsson
Cells 2020, 9(2), 323; https://doi.org/10.3390/cells9020323 - 30 Jan 2020
Cited by 5 | Viewed by 2641
Abstract
Chromosome-specific regulatory mechanisms provide a model to understand the coordinated regulation of genes on entire chromosomes or on larger genomic regions. In fruit flies, two chromosome-wide systems have been characterized: The male-specific lethal (MSL) complex, which mediates dosage compensation and primarily acts on [...] Read more.
Chromosome-specific regulatory mechanisms provide a model to understand the coordinated regulation of genes on entire chromosomes or on larger genomic regions. In fruit flies, two chromosome-wide systems have been characterized: The male-specific lethal (MSL) complex, which mediates dosage compensation and primarily acts on the male X-chromosome, and Painting of fourth (POF), which governs chromosome-specific regulation of genes located on the 4th chromosome. How targeting of one specific chromosome evolves is still not understood; but repeated sequences, in forms of satellites and transposable elements, are thought to facilitate the evolution of chromosome-specific targeting. The highly repetitive 1.688 satellite has been functionally connected to both these systems. Considering the rapid evolution and the necessarily constant adaptation of regulatory mechanisms, such as dosage compensation, we hypothesised that POF and/or 1.688 may still show traces of dosage-compensation functions. Here, we test this hypothesis by transcriptome analysis. We show that loss of Pof decreases not only chromosome 4 expression but also reduces the X-chromosome expression in males. The 1.688 repeat deletion, Zhr1 (Zygotic hybrid rescue), does not affect male dosage compensation detectably; however, Zhr1 in females causes a stimulatory effect on X-linked genes with a strong binding affinity to the MSL complex (genes close to high-affinity sites). Lack of pericentromeric 1.688 also affected 1.688 expression in trans and was linked to the differential expression of genes involved in eggshell formation. We discuss our results with reference to the connections between POF, the 1.688 satellite and dosage compensation, and the role of the 1.688 satellite in hybrid lethality. Full article
(This article belongs to the Special Issue Evolution of Epigenetic Mechanisms and Signatures)
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9 pages, 1328 KiB  
Article
Predicted Archaic 3D Genome Organization Reveals Genes Related to Head and Spinal Cord Separating Modern from Archaic Humans
by Daniel Batyrev, Elisheva Lapid, Liran Carmel and Eran Meshorer
Cells 2020, 9(1), 48; https://doi.org/10.3390/cells9010048 - 24 Dec 2019
Cited by 6 | Viewed by 3256
Abstract
High coverage sequences of archaic humans enabled the reconstruction of their DNA methylation patterns. This allowed comparing gene regulation between human groups, and linking such regulatory changes to phenotypic differences. In a previous work, a detailed comparison of DNA methylation in modern humans, [...] Read more.
High coverage sequences of archaic humans enabled the reconstruction of their DNA methylation patterns. This allowed comparing gene regulation between human groups, and linking such regulatory changes to phenotypic differences. In a previous work, a detailed comparison of DNA methylation in modern humans, archaic humans, and chimpanzees revealed 873 modern human-derived differentially methylated regions (DMRs). To understand the regulatory implications of these DMRs, we defined differentially methylated genes (DMGs) as genes that harbor DMRs in their promoter or gene body. While most of the modern human-derived DMRs could be linked to DMGs, many others remained unassigned. Here, we used information on 3D genome organization to link ~70 out of the remaining 288 unassigned DMRs to genes. Combined with the previously identified DMGs, we reinforce the enrichment of these genes with vocal and facial anatomy, and additionally find significant enrichment with the spinal column, chin, hair, and scalp. These results reveal the importance of 3D genomic organization in understanding gene regulation by DNA methylation. Full article
(This article belongs to the Special Issue Evolution of Epigenetic Mechanisms and Signatures)
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22 pages, 2648 KiB  
Article
Retroelement-Linked H3K4me1 Histone Tags Uncover Regulatory Evolution Trends of Gene Enhancers and Feature Quickly Evolving Molecular Processes in Human Physiology
by Daniil Nikitin, Nikita Kolosov, Anastasiia Murzina, Karina Pats, Anton Zamyatin, Victor Tkachev, Maxim Sorokin, Philippe Kopylov and Anton Buzdin
Cells 2019, 8(10), 1219; https://doi.org/10.3390/cells8101219 - 08 Oct 2019
Cited by 5 | Viewed by 3374
Abstract
Background: Retroelements (REs) are mobile genetic elements comprising ~40% of human DNA. They can reshape expression patterns of nearby genes by providing various regulatory sequences. The proportion of regulatory sequences held by REs can serve a measure of regulatory evolution rate of the [...] Read more.
Background: Retroelements (REs) are mobile genetic elements comprising ~40% of human DNA. They can reshape expression patterns of nearby genes by providing various regulatory sequences. The proportion of regulatory sequences held by REs can serve a measure of regulatory evolution rate of the respective genes and molecular pathways. Methods: We calculated RE-linked enrichment scores for individual genes and molecular pathways based on ENCODE project epigenome data for enhancer-specific histone modification H3K4me1 in five human cell lines. We identified consensus groups of molecular processes that are enriched and deficient in RE-linked H3K4me1 regulation. Results: We calculated H3K4me1 RE-linked enrichment scores for 24,070 human genes and 3095 molecular pathways. We ranked genes and pathways and identified those statistically significantly enriched and deficient in H3K4me1 RE-linked regulation. Conclusion: Non-coding RNA genes were statistically significantly enriched by RE-linked H3K4me1 regulatory modules, thus suggesting their high regulatory evolution rate. The processes of gene silencing by small RNAs, DNA metabolism/chromatin structure, sensory perception/neurotransmission and lipids metabolism showed signs of the fastest regulatory evolution, while the slowest processes were connected with immunity, protein ubiquitination/degradation, cell adhesion, migration and interaction, metals metabolism/ion transport, cell death, intracellular signaling pathways. Full article
(This article belongs to the Special Issue Evolution of Epigenetic Mechanisms and Signatures)
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16 pages, 3254 KiB  
Article
H3K4me3, H3K9ac, H3K27ac, H3K27me3 and H3K9me3 Histone Tags Suggest Distinct Regulatory Evolution of Open and Condensed Chromatin Landmarks
by Anna A. Igolkina, Arsenii Zinkevich, Kristina O. Karandasheva, Aleksey A. Popov, Maria V. Selifanova, Daria Nikolaeva, Victor Tkachev, Dmitry Penzar, Daniil M. Nikitin and Anton Buzdin
Cells 2019, 8(9), 1034; https://doi.org/10.3390/cells8091034 - 05 Sep 2019
Cited by 58 | Viewed by 7312
Abstract
Background: Transposons are selfish genetic elements that self-reproduce in host DNA. They were active during evolutionary history and now occupy almost half of mammalian genomes. Close insertions of transposons reshaped structure and regulation of many genes considerably. Co-evolution of transposons and host DNA [...] Read more.
Background: Transposons are selfish genetic elements that self-reproduce in host DNA. They were active during evolutionary history and now occupy almost half of mammalian genomes. Close insertions of transposons reshaped structure and regulation of many genes considerably. Co-evolution of transposons and host DNA frequently results in the formation of new regulatory regions. Previously we published a concept that the proportion of functional features held by transposons positively correlates with the rate of regulatory evolution of the respective genes. Methods: We ranked human genes and molecular pathways according to their regulatory evolution rates based on high throughput genome-wide data on five histone modifications (H3K4me3, H3K9ac, H3K27ac, H3K27me3, H3K9me3) linked with transposons for five human cell lines. Results: Based on the total of approximately 1.5 million histone tags, we ranked regulatory evolution rates for 25075 human genes and 3121 molecular pathways and identified groups of molecular processes that showed signs of either fast or slow regulatory evolution. However, histone tags showed different regulatory patterns and formed two distinct clusters: promoter/active chromatin tags (H3K4me3, H3K9ac, H3K27ac) vs. heterochromatin tags (H3K27me3, H3K9me3). Conclusion: In humans, transposon-linked histone marks evolved in a coordinated way depending on their functional roles. Full article
(This article belongs to the Special Issue Evolution of Epigenetic Mechanisms and Signatures)
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17 pages, 2726 KiB  
Article
Binding of SU(VAR)3-9 Partially Depends on SETDB1 in the Chromosomes of Drosophila melanogaster
by Daniil A. Maksimov and Dmitry E. Koryakov
Cells 2019, 8(9), 1030; https://doi.org/10.3390/cells8091030 - 05 Sep 2019
Cited by 7 | Viewed by 3360
Abstract
H3K9 methylation is known to play a critical role in gene silencing. This modification is established and maintained by several enzymes, but relationships between them are not fully understood. In the present study, we decipher the interplay between two Drosophila H3K9-specific histone methyltransferases, [...] Read more.
H3K9 methylation is known to play a critical role in gene silencing. This modification is established and maintained by several enzymes, but relationships between them are not fully understood. In the present study, we decipher the interplay between two Drosophila H3K9-specific histone methyltransferases, SU(VAR)3-9 and SETDB1. We asked whether SETDB1 is required for targeting of SU(VAR)3-9. Using DamID-seq, we obtained SU(VAR)3-9 binding profiles for the chromosomes from larval salivary glands and germline cells from adult females, and compared profiles between the wild type and SETDB1-mutant backgrounds. Our analyses indicate that the vast majority of single copy genes in euchromatin are targeted by SU(VAR)3-9 only in the presence of SETDB1, whereas SU(VAR)3-9 binding at repeated sequences in heterochromatin is largely SETDB1-independent. Interestingly, piRNA clusters 42AB and 38C in salivary gland chromosomes bind SU(VAR)3-9 regardless of SETDB1, whereas binding to the same regions in the germline cells is SETDB1-dependent. In addition, we compared SU(VAR)3-9 profiles in female germline cells at different developmental stages (germarium cells in juvenile ovaries and mature nurse cells). It turned out that SU(VAR)3-9 binding is influenced both by the presence of SETDB1, as well as by the differentiation stage. Full article
(This article belongs to the Special Issue Evolution of Epigenetic Mechanisms and Signatures)
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16 pages, 2063 KiB  
Article
Discordant Effects of Putative Lysine Acetyltransferase Inhibitors in Biochemical and Living Systems
by Ryan A. Henry, Yin-Ming Kuo, Zarek S. Siegel, Timothy J. Yen, Jennifer Rhodes, Erika A. Taylor and Andrew J. Andrews
Cells 2019, 8(9), 1022; https://doi.org/10.3390/cells8091022 - 02 Sep 2019
Cited by 4 | Viewed by 2572
Abstract
Lysine acetyltransferases (KATs) are exquisitely fine-tuned to target specific lysine residues on many proteins, including histones, with aberrant acetylation at distinct lysines implicated in different pathologies. However, researchers face a lack of molecular tools to probe the importance of site-specific acetylation events in [...] Read more.
Lysine acetyltransferases (KATs) are exquisitely fine-tuned to target specific lysine residues on many proteins, including histones, with aberrant acetylation at distinct lysines implicated in different pathologies. However, researchers face a lack of molecular tools to probe the importance of site-specific acetylation events in vivo. Because of this, there can be a disconnect between the predicted in silico or in vitro effects of a drug and the actual observable in vivo response. We have previously reported on how an in vitro biochemical analysis of the site-specific effects of the compound C646 in combination with the KAT p300 can accurately predict changes in histone acetylation induced by the same compound in cells. Here, we build on this effort by further analyzing a number of reported p300 modulators, while also extending the analysis to correlate the effects of these drugs to developmental and phenotypical changes, utilizing cellular and zebrafish model systems. While this study demonstrates the utility of biochemical models as a starting point for predicting in vivo activity of multi-site targeting KATs, it also highlights the need for the development of new enzyme inhibitors that are more specific to the regulation of KAT activity in vivo. Full article
(This article belongs to the Special Issue Evolution of Epigenetic Mechanisms and Signatures)
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Review

Jump to: Editorial, Research

21 pages, 3545 KiB  
Review
Epitranscriptomics of Mammalian Mitochondrial Ribosomal RNA
by Ivan Laptev, Olga Dontsova and Petr Sergiev
Cells 2020, 9(10), 2181; https://doi.org/10.3390/cells9102181 - 27 Sep 2020
Cited by 9 | Viewed by 3393
Abstract
Modified nucleotides are present in all ribosomal RNA molecules. Mitochondrial ribosomes are unique to have a set of methylated residues that includes universally conserved ones, those that could be found either in bacterial or in archaeal/eukaryotic cytosolic ribosomes and those that are present [...] Read more.
Modified nucleotides are present in all ribosomal RNA molecules. Mitochondrial ribosomes are unique to have a set of methylated residues that includes universally conserved ones, those that could be found either in bacterial or in archaeal/eukaryotic cytosolic ribosomes and those that are present exclusively in mitochondria. A single pseudouridine within the mt-rRNA is located in the peptidyltransferase center at a position similar to that in bacteria. After recent completion of the list of enzymes responsible for the modification of mammalian mitochondrial rRNA it became possible to summarize an evolutionary history, functional role of mt-rRNA modification enzymes and an interplay of the mt-rRNA modification and mitoribosome assembly process, which is a goal of this review. Full article
(This article belongs to the Special Issue Evolution of Epigenetic Mechanisms and Signatures)
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28 pages, 2476 KiB  
Review
Diverse Defenses: A Perspective Comparing Dipteran Piwi-piRNA Pathways
by Stephanie Gamez, Satyam Srivastav, Omar S. Akbari and Nelson C. Lau
Cells 2020, 9(10), 2180; https://doi.org/10.3390/cells9102180 - 27 Sep 2020
Cited by 8 | Viewed by 4104
Abstract
Animals face the dual threat of virus infections hijacking cellular function and transposons proliferating in germline genomes. For insects, the deeply conserved RNA interference (RNAi) pathways and other chromatin regulators provide an important line of defense against both viruses and transposons. For example, [...] Read more.
Animals face the dual threat of virus infections hijacking cellular function and transposons proliferating in germline genomes. For insects, the deeply conserved RNA interference (RNAi) pathways and other chromatin regulators provide an important line of defense against both viruses and transposons. For example, this innate immune system displays adaptiveness to new invasions by generating cognate small RNAs for targeting gene silencing measures against the viral and genomic intruders. However, within the Dipteran clade of insects, Drosophilid fruit flies and Culicids mosquitoes have evolved several unique mechanistic aspects of their RNAi defenses to combat invading transposons and viruses, with the Piwi-piRNA arm of the RNAi pathways showing the greatest degree of novel evolution. Whereas central features of Piwi-piRNA pathways are conserved between Drosophilids and Culicids, multiple lineage-specific innovations have arisen that may reflect distinct genome composition differences and specific ecological and physiological features dividing these two branches of Dipterans. This perspective review focuses on the most recent findings illuminating the Piwi/piRNA pathway distinctions between fruit flies and mosquitoes, and raises open questions that need to be addressed in order to ameliorate human diseases caused by pathogenic viruses that mosquitoes transmit as vectors. Full article
(This article belongs to the Special Issue Evolution of Epigenetic Mechanisms and Signatures)
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38 pages, 1909 KiB  
Review
Evolution of Regulated Transcription
by Oleg V. Bylino, Airat N. Ibragimov and Yulii V. Shidlovskii
Cells 2020, 9(7), 1675; https://doi.org/10.3390/cells9071675 - 12 Jul 2020
Cited by 19 | Viewed by 5831
Abstract
The genomes of all organisms abound with various cis-regulatory elements, which control gene activity. Transcriptional enhancers are a key group of such elements in eukaryotes and are DNA regions that form physical contacts with gene promoters and precisely orchestrate gene expression programs. [...] Read more.
The genomes of all organisms abound with various cis-regulatory elements, which control gene activity. Transcriptional enhancers are a key group of such elements in eukaryotes and are DNA regions that form physical contacts with gene promoters and precisely orchestrate gene expression programs. Here, we follow gradual evolution of this regulatory system and discuss its features in different organisms. In eubacteria, an enhancer-like element is often a single regulatory element, is usually proximal to the core promoter, and is occupied by one or a few activators. Activation of gene expression in archaea is accompanied by the recruitment of an activator to several enhancer-like sites in the upstream promoter region. In eukaryotes, activation of expression is accompanied by the recruitment of activators to multiple enhancers, which may be distant from the core promoter, and the activators act through coactivators. The role of the general DNA architecture in transcription control increases in evolution. As a whole, it can be seen that enhancers of multicellular eukaryotes evolved from the corresponding prototypic enhancer-like regulatory elements with the gradually increasing genome size of organisms. Full article
(This article belongs to the Special Issue Evolution of Epigenetic Mechanisms and Signatures)
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27 pages, 1358 KiB  
Review
Molecular Basis of the Function of Transcriptional Enhancers
by Airat N. Ibragimov, Oleg V. Bylino and Yulii V. Shidlovskii
Cells 2020, 9(7), 1620; https://doi.org/10.3390/cells9071620 - 05 Jul 2020
Cited by 10 | Viewed by 4559
Abstract
Transcriptional enhancers are major genomic elements that control gene activity in eukaryotes. Recent studies provided deeper insight into the temporal and spatial organization of transcription in the nucleus, the role of non-coding RNAs in the process, and the epigenetic control of gene expression. [...] Read more.
Transcriptional enhancers are major genomic elements that control gene activity in eukaryotes. Recent studies provided deeper insight into the temporal and spatial organization of transcription in the nucleus, the role of non-coding RNAs in the process, and the epigenetic control of gene expression. Thus, multiple molecular details of enhancer functioning were revealed. Here, we describe the recent data and models of molecular organization of enhancer-driven transcription. Full article
(This article belongs to the Special Issue Evolution of Epigenetic Mechanisms and Signatures)
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16 pages, 1575 KiB  
Review
Transposon Reactivation in the Germline May Be Useful for Both Transposons and Their Host Genomes
by Stéphanie Maupetit-Mehouas and Chantal Vaury
Cells 2020, 9(5), 1172; https://doi.org/10.3390/cells9051172 - 08 May 2020
Cited by 16 | Viewed by 4012
Abstract
Transposable elements (TEs) are long-term residents of eukaryotic genomes that make up a large portion of these genomes. They can be considered as perfectly fine members of genomes replicating with resident genes and being transmitted vertically to the next generation. However, unlike regular [...] Read more.
Transposable elements (TEs) are long-term residents of eukaryotic genomes that make up a large portion of these genomes. They can be considered as perfectly fine members of genomes replicating with resident genes and being transmitted vertically to the next generation. However, unlike regular genes, TEs have the ability to send new copies to new sites. As such, they have been considered as parasitic members ensuring their own replication. In another view, TEs may also be considered as symbiotic sequences providing shared benefits after mutualistic interactions with their host genome. In this review, we recall the relationship between TEs and their host genome and discuss why transient relaxation of TE silencing within specific developmental windows may be useful for both. Full article
(This article belongs to the Special Issue Evolution of Epigenetic Mechanisms and Signatures)
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23 pages, 1374 KiB  
Review
Dynamic Signatures of the Epigenome: Friend or Foe?
by Marta Machnik and Urszula Oleksiewicz
Cells 2020, 9(3), 653; https://doi.org/10.3390/cells9030653 - 07 Mar 2020
Cited by 17 | Viewed by 4369
Abstract
Highly dynamic epigenetic signaling is influenced mainly by (micro)environmental stimuli and genetic factors. The exact mechanisms affecting particular epigenomic patterns differ dependently on the context. In the current review, we focus on the causes and effects of the dynamic signatures of the human [...] Read more.
Highly dynamic epigenetic signaling is influenced mainly by (micro)environmental stimuli and genetic factors. The exact mechanisms affecting particular epigenomic patterns differ dependently on the context. In the current review, we focus on the causes and effects of the dynamic signatures of the human epigenome as evaluated with the high-throughput profiling data and single-gene approaches. We will discuss three different aspects of phenotypic outcomes occurring as a consequence of epigenetics interplaying with genotype and environment. The first issue is related to the cases of environmental impacts on epigenetic profile, and its adverse and advantageous effects related to human health and evolutionary adaptation. The next topic will present a model of the interwoven co-evolution of genetic and epigenetic patterns exemplified with transposable elements (TEs) and their epigenetic repressors Krüppel-associated box zinc finger proteins (KRAB–ZNFs). The third aspect concentrates on the mitosis-based microevolution that takes place during carcinogenesis, leading to clonal diversity and expansion of tumor cells. The whole picture of epigenome plasticity and its role in distinct biological processes is still incomplete. However, accumulating data define epigenomic dynamics as an essential co-factor driving adaptation at the cellular and inter-species levels with a benefit or disadvantage to the host. Full article
(This article belongs to the Special Issue Evolution of Epigenetic Mechanisms and Signatures)
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26 pages, 943 KiB  
Review
Transgenerational Inheritance of Environmentally Induced Epigenetic Alterations during Mammalian Development
by Louis Legoff, Shereen Cynthia D’Cruz, Sergei Tevosian, Michael Primig and Fatima Smagulova
Cells 2019, 8(12), 1559; https://doi.org/10.3390/cells8121559 - 03 Dec 2019
Cited by 60 | Viewed by 9154
Abstract
Genetic studies traditionally focus on DNA as the molecule that passes information on from parents to their offspring. Changes in the DNA code alter heritable information and can more or less severely affect the progeny’s phenotype. While the idea that information can be [...] Read more.
Genetic studies traditionally focus on DNA as the molecule that passes information on from parents to their offspring. Changes in the DNA code alter heritable information and can more or less severely affect the progeny’s phenotype. While the idea that information can be inherited between generations independently of the DNA’s nucleotide sequence is not new, the outcome of recent studies provides a mechanistic foundation for the concept. In this review, we attempt to summarize our current knowledge about the transgenerational inheritance of environmentally induced epigenetic changes. We focus primarily on studies using mice but refer to other species to illustrate salient points. Some studies support the notion that there is a somatic component within the phenomenon of epigenetic inheritance. However, here, we will mostly focus on gamete-based processes and the primary molecular mechanisms that are thought to contribute to epigenetic inheritance: DNA methylation, histone modifications, and non-coding RNAs. Most of the rodent studies published in the literature suggest that transgenerational epigenetic inheritance through gametes can be modulated by environmental factors. Modification and redistribution of chromatin proteins in gametes is one of the major routes for transmitting epigenetic information from parents to the offspring. Our recent studies provide additional specific cues for this concept and help better understand environmental exposure influences fitness and fidelity in the germline. In summary, environmental cues can induce parental alterations and affect the phenotypes of offspring through gametic epigenetic inheritance. Consequently, epigenetic factors and their heritability should be considered during disease risk assessment. Full article
(This article belongs to the Special Issue Evolution of Epigenetic Mechanisms and Signatures)
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24 pages, 1817 KiB  
Review
Emerging Roles of Long Non-Coding RNAs as Drivers of Brain Evolution
by Geraldine Zimmer-Bensch
Cells 2019, 8(11), 1399; https://doi.org/10.3390/cells8111399 - 06 Nov 2019
Cited by 60 | Viewed by 5823
Abstract
Mammalian genomes encode tens of thousands of long-noncoding RNAs (lncRNAs), which are capable of interactions with DNA, RNA and protein molecules, thereby enabling a variety of transcriptional and post-transcriptional regulatory activities. Strikingly, about 40% of lncRNAs are expressed specifically in the brain with [...] Read more.
Mammalian genomes encode tens of thousands of long-noncoding RNAs (lncRNAs), which are capable of interactions with DNA, RNA and protein molecules, thereby enabling a variety of transcriptional and post-transcriptional regulatory activities. Strikingly, about 40% of lncRNAs are expressed specifically in the brain with precisely regulated temporal and spatial expression patterns. In stark contrast to the highly conserved repertoire of protein-coding genes, thousands of lncRNAs have newly appeared during primate nervous system evolution with hundreds of human-specific lncRNAs. Their evolvable nature and the myriad of potential functions make lncRNAs ideal candidates for drivers of human brain evolution. The human brain displays the largest relative volume of any animal species and the most remarkable cognitive abilities. In addition to brain size, structural reorganization and adaptive changes represent crucial hallmarks of human brain evolution. lncRNAs are increasingly reported to be involved in neurodevelopmental processes suggested to underlie human brain evolution, including proliferation, neurite outgrowth and synaptogenesis, as well as in neuroplasticity. Hence, evolutionary human brain adaptations are proposed to be essentially driven by lncRNAs, which will be discussed in this review. Full article
(This article belongs to the Special Issue Evolution of Epigenetic Mechanisms and Signatures)
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22 pages, 1839 KiB  
Review
Environmentally-Induced Transgenerational Epigenetic Inheritance: Implication of PIWI Interacting RNAs
by Karine Casier, Antoine Boivin, Clément Carré and Laure Teysset
Cells 2019, 8(9), 1108; https://doi.org/10.3390/cells8091108 - 19 Sep 2019
Cited by 19 | Viewed by 6860
Abstract
Environmentally-induced transgenerational epigenetic inheritance is an emerging field. The understanding of associated epigenetic mechanisms is currently in progress with open questions still remaining. In this review, we present an overview of the knowledge of environmentally-induced transgenerational inheritance and associated epigenetic mechanisms, mainly in [...] Read more.
Environmentally-induced transgenerational epigenetic inheritance is an emerging field. The understanding of associated epigenetic mechanisms is currently in progress with open questions still remaining. In this review, we present an overview of the knowledge of environmentally-induced transgenerational inheritance and associated epigenetic mechanisms, mainly in animals. The second part focuses on the role of PIWI-interacting RNAs (piRNAs), a class of small RNAs involved in the maintenance of the germline genome, in epigenetic memory to put into perspective cases of environmentally-induced transgenerational inheritance involving piRNA production. Finally, the last part addresses how genomes are facing production of new piRNAs, and from a broader perspective, how this process might have consequences on evolution and on sporadic disease development. Full article
(This article belongs to the Special Issue Evolution of Epigenetic Mechanisms and Signatures)
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