Non-canonical functions of the DNA methylome in gene regulation

2013 ◽  
Vol 451 (1) ◽  
pp. 13-23 ◽  
Author(s):  
James P. Reddington ◽  
Sari Pennings ◽  
Richard R. Meehan
Keyword(s):  
Dna Methylation ◽  
Gene Regulation ◽  
Transcriptional Regulation ◽  
Polycomb Group ◽  
Epigenetic Mark ◽  
Regulation Of Transcription ◽  
Gene Promoters ◽  
Dna Modification ◽  
Dna Methylome ◽  
Genomic Regions

Methylation of the cytosine base in DNA, DNA methylation, is an essential epigenetic mark in mammals that contributes to the regulation of transcription. Several advances have been made in this area in recent years, leading to a leap forward in our understanding of how this pathway contributes to gene regulation during embryonic development, and the functional consequences of its perturbation in human disease. Critical to these advances is a comprehension of the genomic distribution of modified cytosine bases in unprecedented detail, drawing attention to genomic regions beyond gene promoters. In addition, we have a more complete understanding of the multifactorial manner by which DNA methylation influences gene regulation at the molecular level, and which genes rely directly on the DNA methylome for their normal transcriptional regulation. It is becoming apparent that a major role of DNA modification is to act as a relatively stable, and mitotically heritable, template that contributes to the establishment and maintenance of chromatin states. In this regard, interplay is emerging between DNA methylation and the PcG (Polycomb group) proteins, which act as evolutionarily conserved mediators of cell identity. In the present paper we review these aspects of DNA methylation, and discuss how a multifunctional view of DNA modification as an integral part of chromatin organization is influencing our understanding of this epigenetic mark's contribution to transcriptional regulation.

scholarly journals A DNS-metiláció szerepe és megváltozása az öregedés és a daganatos betegségek kialakulása során

2018 ◽  
Vol 159 (1) ◽  
pp. 3-15 ◽  
Author(s):  
Krisztina Andrea Szigeti ◽  
Orsolya Galamb ◽  
Alexandra Kalmár ◽  
Barbara Kinga Barták ◽  
Zsófia Brigitta Nagy ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Current Knowledge ◽  
Genetic Research ◽  
Regulation Of Transcription ◽  
Gene Promoters ◽  
Defence Mechanisms ◽  
Dna Mutation ◽  
Expression Of Genes ◽  
Initiation Of Replication ◽  
Disease Diagnostics

Abstract: Besides the genetic research, increasing number of scientific studies focus on epigenetic phenomena – such as DNA methylation – regulating the expression of genes behind the phenotype, thus can be related to the pathomechanism of several diseases. In this review, we aim to summarize the current knowledge about the evolutionary appearance and functional diversity of DNA methylation as one of the epigenetic mechanisms and to demonstrate its role in aging and cancerous diseases. DNA methylation is also characteristic/also appear to prokaryotes, eukaryotes and viruses. In prokaryotes and viruses, it provides defence mechanisms against extragenous DNA. DNA methylation in prokaryotes plays a significant role in the regulation of transcription, the initiation of replication and in Dam-directed mismatch repair. In viruses, it participates not only in defence mechanisms, but in the assembly of capsids as well which is necessary for spreading. In eukaryotes, DNA methylation is involved in recombination, replication, X chromosome inactivation, transposon control, regulation of chromatin structure and transcription, and it also contributes to the imprinting phenomenon. Besides the above-mentioned aspects, DNA methylation also has an evolutionary role as it can change DNA mutation rate. Global hypomethylation appearing during aging and in cancerous diseases can lead to genetic instablility and spontaneous mutations through its role in the regulation of transposable elements. Local hypermethylated alterations such as hypermethylation of SFRP1, SFRP2, DKK1 and APC gene promoters can cause protein expression changes, thus contribute to development of cancer phenotype. DNA methylation alterations during aging in cancerous diseases support the importance of epigenetic research focusing on disease diagnostics and prognostics. Orv Hetil. 2018; 159(1): 3–15.

scholarly journals Transcriptional overlap links DNA hypomethylation with DNA hypermethylation at adjacent promoters in cancer

2021 ◽  
Author(s):  
Jean S Fain ◽  
Axelle Loriot ◽  
Anna Diacofotaki ◽  
Aurelie Van Tongelen ◽  
Charles De Smet
Keyword(s):  
Dna Methylation ◽  
Dna Methyltransferase ◽  
De Novo ◽  
Tumor Development ◽  
Epigenetic Mark ◽  
Dna Hypomethylation ◽  
Dna Hypermethylation ◽  
Bioinformatics Analyses ◽  
Genomic Regions ◽  
Methylation Patterns

DNA methylation is an epigenetic mark associated with gene repression. It is now well established that tumor development involves alterations in DNA methylation patterns, which include both gains (hypermethylation) and losses (hypomethylation) of methylation marks in different genomic regions. The mechanisms underlying these two opposite, yet co-existing, alterations in tumors remain unclear. While studying the human MAGEA6/GABRA3 gene locus, we observed that DNA hypomethylation in tumor cells can lead to the activation of a long transcript (CT-GABRA3) that overlaps downstream promoters (GABRQ and GABRA3) and triggers their hypermethylation. Overlapped promoters displayed increases in H3K36me3, a histone mark known to be deposited during progression of the transcription machinery and to stimulate de novo DNA methylation. Consistent with such a processive mechanism, increases in H3K36me3 and DNA methylation were observed over the entire region covered by the CT-GABRA3 overlapping transcript. Importantly, experimental induction of CT-GABRA3 by depletion of DNMT1 DNA methyltransferase, resulted in a similar pattern of increased DNA methylation in the MAGEA6/GABRA3 locus. Bioinformatics analyses in lung cancer datasets identified other genomic loci displaying this process of coupled DNA hypo- and hypermethylation. In several of these loci, DNA hypermethylation affected tumor suppressor genes, e.g. RERG and PTPRO. Together, our work reveals that focal DNA hypomethylation in tumors can indirectly contribute to hypermethylation of nearby promoters through activation of overlapping transcription, and establishes therefore an unsuspected connection between these two opposite epigenetic alterations.

scholarly journals Methylation by multiple type I restriction modification systems avoids influencing gene regulation in uropathogenic Escherichia coli

2021 ◽  
Author(s):  
Kurosh S Mehershahi ◽  
Swaine Chen
Keyword(s):  
Gene Expression ◽  
Escherichia Coli ◽  
Dna Methylation ◽  
Gene Regulation ◽  
Detectable Effect ◽  
Epigenetic Mark ◽  
Type I ◽  
E Coli ◽  
Restriction Modification ◽  
Restriction Modification Systems

DNA methylation is a common epigenetic mark that influences transcriptional regulation, and therefore cellular phenotype, across all domains of life, extending also to bacterial virulence. Both orphan methyltransferases and those from restriction modification systems (RMSs) have been co-opted to regulate virulence epigenetically in many bacteria. However, the potential regulatory role of DNA methylation mediated by archetypal Type I systems in Escherichia coli has never been studied. We demonstrated that removal of DNA methylated mediated by three different Escherichia coli Type I RMSs in three distinct E. coli strains had no detectable effect on gene expression or growth in a screen of 1190 conditions. Additionally, deletion of the Type I RMS EcoUTI in UTI89, a prototypical cystitis strain of E. coli , which led to loss of methylation at >750 sites across the genome, had no detectable effect on virulence in a murine model of ascending urinary tract infection (UTI). Finally, introduction of two heterologous Type I RMSs into UTI89 also resulted in no detectable change in gene expression or growth phenotypes. These results stand in sharp contrast with many reports of RMSs regulating gene expression in other bacteria, leading us to propose the concept of “regulation avoidance” for these E. coli Type I RMSs. We hypothesize that regulation avoidance is a consequence of evolutionary adaptation of both the RMSs and the E. coli genome. Our results provide a clear and (currently) rare example of regulation avoidance for Type I RMSs in multiple strains of E. coli , further study of which may provide deeper insights into the evolution of gene regulation and horizontal gene transfer.

scholarly journals Editing DNA Methylation in Mammalian Embryos

2020 ◽  
Vol 21 (2) ◽  
pp. 637 ◽  
Author(s):  
Taiga Yamazaki ◽  
Yu Hatano ◽  
Ryoya Taniguchi ◽  
Noritada Kobayashi ◽  
Kazuo Yamagata
Keyword(s):  
Dna Methylation ◽  
Transcriptional Regulation ◽  
Gene Knockout ◽  
Methylation Status ◽  
Dna Methyltransferases ◽  
Biological Functions ◽  
Epigenome Editing ◽  
Early Embryos ◽  
Mammalian Embryos ◽  
Genomic Regions

DNA methylation in mammals is essential for numerous biological functions, such as ensuring chromosomal stability, genomic imprinting, and X-chromosome inactivation through transcriptional regulation. Gene knockout of DNA methyltransferases and demethylation enzymes has made significant contributions to analyzing the functions of DNA methylation in development. By applying epigenome editing, it is now possible to manipulate DNA methylation in specific genomic regions and to understand the functions of these modifications. In this review, we first describe recent DNA methylation editing technology. We then focused on changes in DNA methylation status during mammalian gametogenesis and preimplantation development, and have discussed the implications of applying this technology to early embryos.

scholarly journals Loss of SETD1B results in the redistribution of genomic H3K4me3 in the oocyte

2021 ◽  
Author(s):  
Courtney W. Hanna ◽  
Jiahao Huang ◽  
Christian Belton ◽  
Susanne Reinhardt ◽  
Andreas Dahl ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Gene Expression Analysis ◽  
Cpg Islands ◽  
Conditional Knockout ◽  
Epigenetic Mark ◽  
Gene Promoters ◽  
Downregulated Gene ◽  
Mammalian Development ◽  
Histone 3

SummaryHistone 3 lysine 4 trimethylation (H3K4me3) is an epigenetic mark found at gene promoters and CpG islands. H3K4me3 is essential for mammalian development, yet mechanisms underlying its genomic targeting are poorly understood. H3K4me3 methyltransferases SETD1B and MLL2 are essential for oogenesis. We investigated changes in H3K4me3 in Setd1b conditional knockout (cKO) GV oocytes using ultra-low input ChIP-seq, in conjunction with DNA methylation and gene expression analysis. Setd1b cKO oocytes showed a redistribution of H3K4me3, with a marked loss at active gene promoters associated with downregulated gene expression. Remarkably, many regions gained H3K4me3 in Setd1b cKOs, in particular those that were DNA hypomethylated, transcriptionally inactive and CpG-rich - hallmarks of MLL2 targets. Thus, loss of SETD1B appears to enable enhanced MLL2 activity. Our work reveals two distinct, complementary mechanisms of genomic targeting of H3K4me3 in oogenesis, with SETD1B linked to gene expression in the oogenic program and MLL2 to CpG content.

scholarly journals Distinct chromatin signatures of DNA hypomethylation in aging and cancer

2017 ◽  
Author(s):  
Raúl F. Pérez ◽  
Juan Ramón Tejedor ◽  
Gustavo F. Bayón ◽  
Agustín F. Fernández ◽  
Mario F. Fraga
Keyword(s):  
Dna Methylation ◽  
Dna Sequences ◽  
Es Cells ◽  
Gene Promoters ◽  
Dna Hypomethylation ◽  
Chromatin Signature ◽  
Unknown Gene ◽  
Genomic Regions ◽  
Nih Roadmap

AbstractBackgroundCancer is an aging-associated disease but the underlying molecular links between these processes are still largely unknown. Gene promoters that become hypermethylated in aging and cancer share a common chromatin signature in ES cells. In addition, there is also global DNA hypomethylation in both processes. However, any similarities of the regions where this loss of DNA methylation occurs is currently not well characterized, nor is it known whether such regions also share a common chromatin signature in aging and cancer.ResultsTo address this issue we analysed TCGA DNA methylation data from a total of 2,311 samples, including control and cancer cases from patients with breast, kidney, thyroid, skin, brain and lung tumors and healthy blood, and integrated the results with histone, chromatin state and transcription factor binding site data from the NIH Roadmap Epigenomics and ENCODE projects. We identified 98,857 CpG sites differentially methylated in aging, and 286,746 in cancer. Hyper- and hypomethylated changes in both processes each had a similar genomic distribution across tissues and displayed tissue-independent alterations. The identified hypermethylated regions in aging and cancer shared a similar bivalent chromatin signature. In contrast, hypomethylated DNA sequences occurred in very different chromatin contexts. DNA hypomethylated sequences were enriched at genomic regions marked with the activating histone posttranslational modification H3K4me1 in aging, whilst in cancer, loss of DNA methylation was primarily associated with the repressive H3K9me3 mark.ConclusionsOur results suggest that the role of DNA methylation as a molecular link between aging and cancer is more complex than previously thought.

scholarly journals A model for the aberrant DNA methylomes in aging cells and cancer cells

2019 ◽  
Vol 47 (4) ◽  
pp. 997-1003 ◽  
Author(s):  
Huiming Zhang ◽  
Kang Zhang ◽  
Jian-Kang Zhu
Keyword(s):  
Dna Methylation ◽  
Cancer Cells ◽  
Developmental Stages ◽  
Methylation Pattern ◽  
Epigenetic Mark ◽  
Dna Hypomethylation ◽  
Genome Wide ◽  
Abnormal Cells ◽  
Genomic Regions ◽  
Methylation Patterns

Abstract DNA methylation at the fifth position of cytosine is a major epigenetic mark conserved in plants and mammals. Genome-wide DNA methylation patterns are dynamically controlled by integrated activities of establishment, maintenance, and removal. In both plants and mammals, a pattern of global DNA hypomethylation coupled with increased methylation levels at some specific genomic regions arises at specific developmental stages and in certain abnormal cells, such as mammalian aging cells and cancer cells as well as some plant epigenetic mutants. Here we provide an overview of this distinct DNA methylation pattern in mammals and plants, and propose that a methylstat, which is a cis-element responsive to both DNA methylation and active demethylation activities and controlling the transcriptional activity of a key DNA methylation regulator, can help to explain the enigmatic DNA methylation patterns in aging cells and cancer cells.

scholarly journals The exploration of N6-deoxyadenosine methylation in mammalian genomes

2021 ◽  
Author(s):  
Xuwen Li ◽  
Zijian Zhang ◽  
Xinlong Luo ◽  
Jacob Schrier ◽  
Andrew D. Yang ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Regulatory Mechanism ◽  
Epigenetic Mark ◽  
Dna Modification ◽  
Biological Processes ◽  
Environmental Stress Response ◽  
Mammalian Genomes ◽  
Higher Eukaryotes ◽  
And Function ◽  
Major Progress

AbstractN6-methyladenine (N6-mA, m6dA, or 6mA), a prevalent DNA modification in prokaryotes, has recently been identified in higher eukaryotes, including mammals. Although 6mA has been well-studied in prokaryotes, the function and regulatory mechanism of 6mA in eukaryotes are still poorly understood. Recent studies indicate that 6mA can serve as an epigenetic mark and play critical roles in various biological processes, from transposable-element suppression to environmental stress response. Here, we review the significant advances in methodology for 6mA detection and major progress in understanding the regulation and function of this non-canonical DNA methylation in eukaryotes, predominantly mammals.

Exploring and exploiting epigenetic variation in cropsThis article is one of a selection of papers from the conference “Exploiting Genome-wide Association in Oilseed Brassicas: a model for genetic improvement of major OECD crops for sustainable farming”.

Genome ◽  
2010 ◽  
Vol 53 (11) ◽  
pp. 856-868 ◽  
Author(s):  
Graham J King ◽  
Stephen Amoah ◽  
Smita Kurup
Keyword(s):  
Dna Methylation ◽  
Gene Regulation ◽  
Genetic Improvement ◽  
Developmental Stages ◽  
De Novo ◽  
Methylation Status ◽  
Intervention Strategy ◽  
Morphological Plasticity ◽  
Epigenetic Mark ◽  
Epigenetic Variation

This review addresses the mechanisms by which epigenetic variation modulates plant gene regulation and phenotype. In particular we explore the scope for harnessing such processes within the context of crop genetic improvement. We focus on the role of DNA methylation as an epigenetic mark that contributes to epiallelic diversity and modulation of gene regulation. We outline the prevalence and distribution of epigenetic marks in relation to eukaryote developmental processes, and in particular identify where this may be relevant to crop traits both in terms of specific developmental stages and in relation to physiological responses to environmental change. Recent whole genome surveys have identified specific characteristics of the distribution of DNA methylation within plant genomes. Together with greater understanding of the mode of action of different maintenance and de novo methyltransferases, this provides an opportunity to modulate DNA methylation status at specific loci as an intervention strategy in crop genetic improvement. We discuss alternative approaches that may be suitable for harnessing such induced epiallelic variation. Most of the discussion is associated with Brassica crops, which demonstrate considerable morphological plasticity, segmental chromosomal duplication, and polyploidy.

scholarly journals DNA Methylation in Cancer and Development: An Evolving Paradigm

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. SCI-50-SCI-50
Author(s):  
Maria E. Figueroa
Keyword(s):  
Dna Methylation ◽  
Gene Regulation ◽  
Cytosine Methylation ◽  
Conflicts Of Interest ◽  
Cpg Islands ◽  
Dna Methyltransferases ◽  
Dna Demethylation ◽  
Epigenetic Mark ◽  
Cpg Dinucleotides ◽  
Promoter Dna

DNA methylation is an epigenetic mark which, in mammals, occurs primarily on position 5 of cytosines, especially at those found in the context of CpG dinucleotides. This CpG methylation is known to play a major role in gene regulation. Cytosine methylation is regulated by the DNA methyltransferases, responsible for adding the methyl group to unmethylated CpGs, and the TET dioxygenases, involved in the DNA demethylation pathway. Initially, DNA methylation was believed to be important mainly for gene silencing through promoter DNA methylation, especially at CpG-rich promoters containing CpG islands. However, our understanding of the role that DNA methylation plays in gene regulation during normal development and how this process becomes deregulated in cancer, has evolved in recent years. Moreover, the discovery of frequent mutations in DNMT3A and TET2 both in clonal hematopoiesis of indeterminate significance as well as in many hematological malignancies has brought new interest into understanding what role DNA methylation plays in normal HSC function as well as how it contributes to malignant transformation. In this session, we will review the current understanding in the field of DNA methylation and gene regulation, and present data on DNA methylation in normal HSCs as well as the role that this epigenetic mark plays during leukemic transformation in acute myeloid leukemia. Disclosures No relevant conflicts of interest to declare.

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