Specific Or Not Specific Recruitment of Dnmts for DNA Methylation, an Epigenetic Dilemma
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Insights Into Hp1a-Chromatin Interactions
cells Review Insights into HP1a-Chromatin Interactions Silvia Meyer-Nava , Victor E. Nieto-Caballero, Mario Zurita and Viviana Valadez-Graham * Instituto de Biotecnología, Departamento de Genética del Desarrollo y Fisiología Molecular, Universidad Nacional Autónoma de México, Cuernavaca Morelos 62210, Mexico; [email protected] (S.M.-N.); [email protected] (V.E.N.-C.); [email protected] (M.Z.) * Correspondence: [email protected]; Tel.: +527773291631 Received: 26 June 2020; Accepted: 21 July 2020; Published: 9 August 2020 Abstract: Understanding the packaging of DNA into chromatin has become a crucial aspect in the study of gene regulatory mechanisms. Heterochromatin establishment and maintenance dynamics have emerged as some of the main features involved in genome stability, cellular development, and diseases. The most extensively studied heterochromatin protein is HP1a. This protein has two main domains, namely the chromoshadow and the chromodomain, separated by a hinge region. Over the years, several works have taken on the task of identifying HP1a partners using different strategies. In this review, we focus on describing these interactions and the possible complexes and subcomplexes associated with this critical protein. Characterization of these complexes will help us to clearly understand the implications of the interactions of HP1a in heterochromatin maintenance, heterochromatin dynamics, and heterochromatin’s direct relationship to gene regulation and chromatin organization. Keywords: heterochromatin; HP1a; genome stability 1. Introduction Chromatin is a complex of DNA and associated proteins in which the genetic material is packed in the interior of the nucleus of eukaryotic cells [1]. To organize this highly compact structure, two categories of proteins are needed: histones [2] and accessory proteins, such as chromatin regulators and histone-modifying proteins. -
Mouse Germ Line Mutations Due to Retrotransposon Insertions Liane Gagnier1, Victoria P
Gagnier et al. Mobile DNA (2019) 10:15 https://doi.org/10.1186/s13100-019-0157-4 REVIEW Open Access Mouse germ line mutations due to retrotransposon insertions Liane Gagnier1, Victoria P. Belancio2 and Dixie L. Mager1* Abstract Transposable element (TE) insertions are responsible for a significant fraction of spontaneous germ line mutations reported in inbred mouse strains. This major contribution of TEs to the mutational landscape in mouse contrasts with the situation in human, where their relative contribution as germ line insertional mutagens is much lower. In this focussed review, we provide comprehensive lists of TE-induced mouse mutations, discuss the different TE types involved in these insertional mutations and elaborate on particularly interesting cases. We also discuss differences and similarities between the mutational role of TEs in mice and humans. Keywords: Endogenous retroviruses, Long terminal repeats, Long interspersed elements, Short interspersed elements, Germ line mutation, Inbred mice, Insertional mutagenesis, Transcriptional interference Background promoter and polyadenylation motifs and often a splice The mouse and human genomes harbor similar types of donor site [10, 11]. Sequences of full-length ERVs can TEs that have been discussed in many reviews, to which encode gag, pol and sometimes env, although groups of we refer the reader for more in depth and general infor- LTR retrotransposons with little or no retroviral hom- mation [1–9]. In general, both human and mouse con- ology also exist [6–9]. While not the subject of this re- tain ancient families of DNA transposons, none view, ERV LTRs can often act as cellular enhancers or currently active, which comprise 1–3% of these genomes promoters, creating chimeric transcripts with genes, and as well as many families or groups of retrotransposons, have been implicated in other regulatory functions [11– which have caused all the TE insertional mutations in 13]. -
Euchromatin Histone Methyltransferase II (EHMT2) Regulates the Expression of Ras-Related GTP Binding C (RRAGC) Protein
BMB Rep. 2020; 53(11): 576-581 BMB www.bmbreports.org Reports Euchromatin histone methyltransferase II (EHMT2) regulates the expression of ras-related GTP binding C (RRAGC) protein Supyong Hwang1, Soyoung Kim1, Kyungkon Kim1,2,3, Jeonghun Yeom2, Sojung Park1 & Inki Kim1,2,3,* 1Biomedical Research Center, ASAN Institute for Life Sciences, ASAN Medical Center, Seoul 05505, 2Convergence Medicine Research Center (CREDIT), ASAN Institute for Life Sciences, ASAN Medical Center, Seoul 05505, 3Department of Convergence Medicine, University of Ulsan College of Medicine, Seoul 05505, Korea Dimethylation of the histone H3 protein at lysine residue 9 INTRODUCTION (H3K9) is mediated by euchromatin histone methyltransferase II (EHMT2) and results in transcriptional repression of target Epigenetic modifications are gene regulatory mechanisms that genes. Recently, chemical inhibition of EHMT2 was shown to are independent of changes in DNA sequences (1). This mode induce various physiological outcomes, including endoplasmic of gene regulation can be achieved by means of histone and reticulum stress-associated genes transcription in cancer cells. DNA modifications, such as methylation and acetylation (1). To identify genes that are transcriptionally repressed by EHMT2 Among these, methylation at lysine residues 4 (H3K4) and 36 during apoptosis, and cell stress responses, we screened genes (H3K36) of histone H3 are hallmarks of transcriptional acti- that are upregulated by BIX-01294, a chemical inhibitor of vation, whereas methylation of histone H3 residues at lysines EHMT2. RNA sequencing analyses revealed 77 genes that were 9 (H3K9) and 27 (H3K27) leads to repression (2). Methylation upregulated by BIX-01294 in all four hepatic cell carcinoma of histones is accomplished by histone methyltransferases (HMTs) (HCC) cell lines. -
DNMT1 Gene DNA Methyltransferase 1
DNMT1 gene DNA methyltransferase 1 Normal Function The DNMT1 gene provides instructions for making an enzyme called DNA methyltransferase 1. This enzyme is involved in DNA methylation, which is the addition of methyl groups, consisting of one carbon atom and three hydrogen atoms, to DNA molecules. In particular, the enzyme helps add methyl groups to DNA building blocks ( nucleotides) called cytosines. DNA methylation is important in many cellular functions. These include determining whether the instructions in a particular segment of DNA are carried out or suppressed ( gene silencing), regulating reactions involving proteins and fats (lipids), and controlling the processing of chemicals that relay signals in the nervous system (neurotransmitters). DNA methyltransferase 1 is active in the adult nervous system. Although its specific function is not well understood, the enzyme may help regulate nerve cell (neuron) maturation and specialization (differentiation), the ability of neurons to move (migrate) and connect with each other, and neuron survival. Health Conditions Related to Genetic Changes Autosomal dominant cerebellar ataxia, deafness, and narcolepsy At least four DNMT1 gene mutations have been identified in people with a nervous system disorder called autosomal dominant cerebellar ataxia, deafness, and narcolepsy (ADCADN). Features of this disorder include difficulty coordinating movements (ataxia), hearing loss caused by abnormalities of the inner ear (sensorineural deafness), and excessive daytime sleepiness (narcolepsy). Cognitive decline occurs as the disorder progresses. Numbness, tingling, or pain in the arms and legs (sensory neuropathy) can also occur. Affected individuals usually survive into their forties or fifties. The DNMT1 gene mutations associated with this disorder affect a region of the DNA methyltransferase 1 enzyme, known as the targeting sequence, that helps direct the methylation process to the correct segments of DNA. -
Recognition of Cancer Mutations in Histone H3K36 by Epigenetic Writers and Readers Brianna J
EPIGENETICS https://doi.org/10.1080/15592294.2018.1503491 REVIEW Recognition of cancer mutations in histone H3K36 by epigenetic writers and readers Brianna J. Kleina, Krzysztof Krajewski b, Susana Restrepoa, Peter W. Lewis c, Brian D. Strahlb, and Tatiana G. Kutateladzea aDepartment of Pharmacology, University of Colorado School of Medicine, Aurora, CO, USA; bDepartment of Biochemistry & Biophysics, The University of North Carolina School of Medicine, Chapel Hill, NC, USA; cWisconsin Institute for Discovery, University of Wisconsin, Madison, WI, USA ABSTRACT ARTICLE HISTORY Histone posttranslational modifications control the organization and function of chromatin. In Received 30 May 2018 particular, methylation of lysine 36 in histone H3 (H3K36me) has been shown to mediate gene Revised 1 July 2018 transcription, DNA repair, cell cycle regulation, and pre-mRNA splicing. Notably, mutations at or Accepted 12 July 2018 near this residue have been causally linked to the development of several human cancers. These KEYWORDS observations have helped to illuminate the role of histones themselves in disease and to clarify Histone; H3K36M; cancer; the mechanisms by which they acquire oncogenic properties. This perspective focuses on recent PTM; methylation advances in discovery and characterization of histone H3 mutations that impact H3K36 methyla- tion. We also highlight findings that the common cancer-related substitution of H3K36 to methionine (H3K36M) disturbs functions of not only H3K36me-writing enzymes but also H3K36me-specific readers. The latter case suggests that the oncogenic effects could also be linked to the inability of readers to engage H3K36M. Introduction from yeast to humans and has been shown to have a variety of functions that range from the control Histone proteins are main components of the of gene transcription and DNA repair, to cell cycle nucleosome, the fundamental building block of regulation and nutrient stress response [8]. -
Physical and Functional Interactions Between the Human DNMT3L Protein and Members of the De Novo Methyltransferase Family
Journal of Cellular Biochemistry 95:902–917 (2005) Physical and Functional Interactions Between the Human DNMT3L Protein and Members of the De Novo Methyltransferase Family Zhao-Xia Chen,1,2 Jeffrey R. Mann,1,2 Chih-Lin Hsieh,3 Arthur D. Riggs,1,2 and Fre´de´ric Che´din1* 1Division of Biology, Beckman Research Institute of the City of Hope, Duarte, California 91010 2Graduate School of Biological Sciences, Beckman Research Institute of the City of Hope, Duarte, California 91010 3Departments of Urology and of Biochemistry and Molecular Biology, University of Southern California, Keck School of Medicine, Norris Comprehensive Cancer Center, Los Angeles, California 90033 Abstract The de novo methyltransferase-like protein, DNMT3L, is required for methylation of imprinted genes in germ cells. Although enzymatically inactive, human DNMT3L was shown to act as a general stimulatory factor for de novo methylation by murine Dnmt3a. Several isoforms of DNMT3A and DNMT3B with development-stage and tissue-specific expression patterns have been described in mouse and human, thus bringing into question the identity of the physiological partner(s) for stimulation by DNMT3L. Here, we used an episome-based in vivo methyltransferase assay to systematically analyze five isoforms of human DNMT3A and DNMT3B for activity and stimulation by human DNMT3L. Our results show that human DNMT3A, DNMT3A2, DNMT3B1, and DNMT3B2 are catalytically competent, while DNMT3B3 is inactive in our assay. We also report that the activity of all four active isoforms is significantly increased upon co-expression with DNMT3L, albeit to varying extents. This is the first comprehensive description of the in vivo activities of the poorly characterized human DNMT3A and DNMT3B isoforms and of their functional interactions with DNMT3L. -
Screening for Genes That Accelerate the Epigenetic Aging Clock in Humans Reveals a Role for the H3K36 Methyltransferase NSD1 Daniel E
Martin-Herranz et al. Genome Biology (2019) 20:146 https://doi.org/10.1186/s13059-019-1753-9 RESEARCH Open Access Screening for genes that accelerate the epigenetic aging clock in humans reveals a role for the H3K36 methyltransferase NSD1 Daniel E. Martin-Herranz1,2* , Erfan Aref-Eshghi3,4, Marc Jan Bonder1,5, Thomas M. Stubbs2, Sanaa Choufani6, Rosanna Weksberg6, Oliver Stegle1,5,7, Bekim Sadikovic3,4, Wolf Reik8,9,10*† and Janet M. Thornton1*† Abstract Background: Epigenetic clocks are mathematical models that predict the biological age of an individual using DNA methylation data and have emerged in the last few years as the most accurate biomarkers of the aging process. However, little is known about the molecular mechanisms that control the rate of such clocks. Here, we have examined the human epigenetic clock in patients with a variety of developmental disorders, harboring mutations in proteins of the epigenetic machinery. Results: Using the Horvath epigenetic clock, we perform an unbiased screen for epigenetic age acceleration in the blood of these patients. We demonstrate that loss-of-function mutations in the H3K36 histone methyltransferase NSD1, which cause Sotos syndrome, substantially accelerate epigenetic aging. Furthermore, we show that the normal aging process and Sotos syndrome share methylation changes and the genomic context in which they occur. Finally, we found that the Horvath clock CpG sites are characterized by a higher Shannon methylation entropy when compared with the rest of the genome, which is dramatically decreased in Sotos syndrome patients. Conclusions: These results suggest that the H3K36 methylation machinery is a key component of the epigenetic maintenance system in humans, which controls the rate of epigenetic aging, and this role seems to be conserved in model organisms. -
H19 Lncrna Controls Gene Expression of the Imprinted Gene Network by Recruiting MBD1
H19 lncRNA controls gene expression of the Imprinted Gene Network by recruiting MBD1 Paul Monniera,b, Clémence Martineta, Julien Pontisc, Irina Stanchevad, Slimane Ait-Si-Alic, and Luisa Dandoloa,1 aGenetics and Development Department, Institut National de la Santé et de la Recherche Médicale U1016, Centre National de la Recherche Scientifique (CNRS) Unité Mixte de Recherche (UMR) 8104, University Paris Descartes, Institut Cochin, Paris 75014, France; bUniversity Paris Pierre and Marie Curie, Paris 75005, France; cUniversity Paris Diderot, Sorbonne Paris Cité, Laboratoire Epigénétique et Destin Cellulaire, CNRS UMR 7216, Paris 75013, France; and dWellcome Trust Centre for Cell Biology, University of Edinburgh, Edinburgh EH9 3JR, United Kingdom Edited by Marisa Bartolomei, University of Pennsylvania, Philadelphia, PA, and accepted by the Editorial Board November 11, 2013 (received for review May 30, 2013) The H19 gene controls the expression of several genes within the this control is transcriptional or posttranscriptional and whether Imprinted Gene Network (IGN), involved in growth control of the these nine targets are direct or indirect targets remain elusive. embryo. However, the underlying mechanisms of this control re- Several lncRNAs interact with chromatin-modifying com- main elusive. Here, we identified the methyl-CpG–binding domain plexes and appear to exert a transcriptional control by targeting fi protein 1 MBD1 as a physical and functional partner of the H19 local chromatin modi cations at discrete genomic regions (8, 9). long noncoding RNA (lncRNA). The H19 lncRNA–MBD1 complex is In the case of imprinted clusters, the DMRs controlling the ex- fi pression of imprinted genes exhibit parent-of-origin epigenetic required for the control of ve genes of the IGN. -
Histone H3 Lysine 36 Methylation Affects Temperature-Induced Alternative Splicing and Flowering in Plants A
Pajoro et al. Genome Biology (2017) 18:102 DOI 10.1186/s13059-017-1235-x RESEARCH Open Access Histone H3 lysine 36 methylation affects temperature-induced alternative splicing and flowering in plants A. Pajoro1,2, E. Severing3,4, G. C. Angenent1,2 and R. G. H. Immink1,2* Abstract Background: Global warming severely affects flowering time and reproductive success of plants. Alternative splicing of pre-messenger RNA (mRNA) is an important mechanism underlying ambient temperature-controlled responses in plants, yet its regulation is poorly understood. An increase in temperature promotes changes in plant morphology as well as the transition from the vegetative to the reproductive phase in Arabidopsis thaliana via changes in splicing of key regulatory genes. Here we investigate whether a particular histone modification affects ambient temperature-induced alternative splicing and flowering time. Results: We use a genome-wide approach and perform RNA-sequencing (RNA-seq) analyses and histone H3 lysine 36 tri-methylation (H3K36me3) chromatin immunoprecipitation sequencing (ChIP-seq) in plants exposed to different ambient temperatures. Analysis and comparison of these datasets reveal that temperature-induced differentially spliced genes are enriched in H3K36me3. Moreover, we find that reduction of H3K36me3 deposition causes alteration in temperature-induced alternative splicing. We also show that plants with mutations in H3K36me3 writers, eraser, or readers have altered high ambient temperature-induced flowering. Conclusions: Our results show a key role for the histone mark H3K36me3 in splicing regulation and plant plasticity to fluctuating ambient temperature. Our findings open new perspectives for the breeding of crops that can better cope with environmental changes due to climate change. -
Regulation of DNMT1 Stability Through SET7-Mediated Lysine Methylation in Mammalian Cells
Regulation of DNMT1 stability through SET7-mediated lysine methylation in mammalian cells Pierre-Olivier Este` vea,1, Hang Gyeong China,1, Jack Bennera, George R. Feeherya, Mala Samaranayakea, Gregory A. Horwitzb, Steven E. Jacobsenb, and Sriharsa Pradhana,2 aNew England Biolabs Incorporated, 240 County Road, Ipswich, MA 01938; and bHoward Hughes Medical Institute and Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, CA 90095-1606 Edited by Jasper Rine, University of California, Berkeley, CA, and approved February 10, 2009 (received for review October 15, 2008) Inheritance of epigenetic information encoded by cytosine DNA A D methylation patterns is crucial for mammalian cell survival, in large ET7 S part through the activity of the maintenance DNA methyltrans- : IP: IgG IP IP: DNMT1 449 kDa ferase (DNMT1). Here, we show that SET7, a known histone 159 kDa Anti- methyltransferase, is involved in the regulation of protein stability DNMT1 Anti- of DNMT1. SET7 colocalizes and directly interacts with DNMT1 and DNMT1 Anti- specifically monomethylates Lys-142 of DNMT1. Methylated SET7 DNMT1 peaks during the S and G2 phases of the cell cycle and is DsRed- Merged/ prone to proteasome-mediated degradation. Overexpression of B C Time Nucleus DNMT1 SET7 Merged Nucleus SET7 leads to decreased DNMT1 levels, and siRNA-mediated knock- (hrs) down of SET7 stabilizes DNMT1. These results demonstrate that 2-4 SET7 PRMT1 signaling through SET7 represents a means of DNMT1 enzyme G9a DNMT1 turnover. [3H] 4-8 DNA methyltransferase ͉ methylated lysine ͉ proteasome ͉ protein degradation 8-12 H3 H4 ammalian DNA methylation is essential for development Mand is controlled by a variety of factors including 3 active >15 DNA cytosine methyltransferases (DNMT1, DNMT3A, and DNMT3B) and a methyltransferase-like protein, DNMT3L (1– 4). -
Dynamics of Transcription-Dependent H3k36me3 Marking by the SETD2:IWS1:SPT6 Ternary Complex
bioRxiv preprint doi: https://doi.org/10.1101/636084; this version posted May 14, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Dynamics of transcription-dependent H3K36me3 marking by the SETD2:IWS1:SPT6 ternary complex Katerina Cermakova1, Eric A. Smith1, Vaclav Veverka2, H. Courtney Hodges1,3,4,* 1 Department of Molecular & Cellular Biology, Center for Precision Environmental Health, and Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, 77030, USA 2 Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Prague, Czech Republic 3 Center for Cancer Epigenetics, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA 4 Department of Bioengineering, Rice University, Houston, TX, 77005, USA * Lead contact; Correspondence to: [email protected] Abstract The genome-wide distribution of H3K36me3 is maintained SETD2 contributes to gene expression by marking gene through various mechanisms. In human cells, H3K36 is bodies with H3K36me3, which is thought to assist in the mono- and di-methylated by eight distinct histone concentration of transcription machinery at the small portion methyltransferases; however, the predominant writer of the of the coding genome. Despite extensive genome-wide data trimethyl mark on H3K36 is SETD21,11,12. Interestingly, revealing the precise localization of H3K36me3 over gene SETD2 is a major tumor suppressor in clear cell renal cell bodies, the physical basis for the accumulation, carcinoma13, breast cancer14, bladder cancer15, and acute maintenance, and sharp borders of H3K36me3 over these lymphoblastic leukemias16–18. In these settings, mutations sites remains rudimentary. -
The Rb/Chromatin Connection and Epigenetic Control: Opinion
Oncogene (2001) 20, 3128 ± 3133 ã 2001 Nature Publishing Group All rights reserved 0950 ± 9232/01 $15.00 www.nature.com/onc The Rb/chromatin connection and epigenetic control: opinion Roger Ferreira1, Irina Naguibneva1, Linda L Pritchard1, Slimane Ait-Si-Ali1 and Annick Harel-Bellan*,1 1Laboratoire `OncogeneÁse, DieÂrenciation et Transduction du Signal', CNRS UPR 9079, Institut Andre Lwo, 7 rue Guy Moquet, Villejuif, France The balance between cell dierentiation and proliferation proteins' family that also includes p130 and p107 (for is regulated at the transcriptional level. In the cell cycle, reviews see Grana et al., 1998; Mulligan and Jacks, the transition from G1 to S phase (G1/S transition) is of 1998). Rb exerts its anti-proliferative activity, at least paramount importance in this regard. Indeed, it is only in part, by inhibiting the E2F transcription factor. Rb before this point that cells can be oriented toward the is regulated by phosphorylation: in non-cycling cells, or dierentiation pathway: beyond, cells progress into the in early G1, Rb is hypophosphorylated and inhibits cycle in an autonomous manner. The G1/S transition is E2F activity; during G1, Rb is progressively phos- orchestrated by the transcription factor E2F. E2F controls phorylated by cyclin-CDK complexes (for review see the expression of a group of checkpoint genes whose Harbour and Dean, 2000) and, as a consequence, loses products are required either for the G1-to-S transition its anity for E2F. The release of Rb triggers the itself or for DNA replication (e.g. DNA polymerase a). activation of E2F target genes, which allows the cells E2F activity is repressed in growth-arrested cells and in to proceed through the G1/S transition.