DOCSLIB.ORG

Epigenetic Regulation of Promiscuous Gene Expression in Thymic Medullary Epithelial Cells

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Epigenetic Regulation of Promiscuous Gene Expression in Thymic Medullary Epithelial Cells Epigenetic regulation of promiscuous gene expression in thymic medullary epithelial cells Lars-Oliver Tykocinskia,1,2, Anna Sinemusa,1, Esmail Rezavandya, Yanina Weilandb, David Baddeleyb, Christoph Cremerb, Stephan Sonntagc, Klaus Willeckec, Jens Derbinskia, and Bruno Kyewskia,3 aDivision of Developmental Immunology, Tumor Immunology Program, German Cancer Research Center, D-69120 Heidelberg, Germany; bKirchhoff Institute for Physics, University of Heidelberg, D-69120 Heidelberg, Germany; and cInstitute for Genetics, University of Bonn, D-53117 Bonn, Germany Edited* by Philippa Marrack, National Jewish Health, Denver, CO, and approved September 28, 2010 (received for review July 2, 2010) Thymic central tolerance comprehensively imprints the T-cell re- ing of delimited regions allowing access of general and specific ceptor repertoire before T cells seed the periphery. Medullary transcriptional factors to act on gene-specific control elements thymic epithelial cells (mTECs) play a pivotal role in this process by (8). This scenario is clearly different from the intricate regulation virtue of promiscuous expression of tissue-restricted autoantigens. of functionally related gene families like the Hox gene locus or β The molecular regulation of this unusual gene expression, in the -globin gene locus (9). A similar phenomenon as observed in Drosophila particular the involvement of epigenetic mechanisms is only poorly has been reported for housekeeping genes but not for understood. By studying promiscuous expression of the mouse TRAs in vertebrates (10). casein locus, we report that transcription of this locus proceeds Here we analyzed the interrelationship between emerging gene expression patterns at the single cell level, promoter-associated from a delimited region (“entry site”) to increasingly complex pat- epigenetic marks, and the differentiation of mTECs in the murine terns along with mTEC maturation. Transcription of this region is casein locus. Our results argue for a role of local epigenetic preceded by promoter demethylation in immature mTECs followed control in initiating transcription of this locus. MTEC differen- upon mTEC maturation by acquisition of active histone marks and tiation goes along with increasingly complex patterns of gene local locus decontraction. Moreover, analysis of two additional expression in single cells. However, expression of certain TRAs gene loci showed that promiscuous expression is transient in single appears to be transient. The implications of these findings for the mTECs. Transient gene expression could conceivably add to the process of central tolerance will be discussed. local diversity of self-antigen display thus enhancing the efficacy IMMUNOLOGY of central tolerance. Results PGE Correlates with Gene-Specific Permissive Histone Marks in the central tolerance | locus decontraction | tissue-restricted antigens Casein Locus. To address local rather than global epigenetic mechanisms that regulate pGE in the thymus, we focused our he scope of central T-cell tolerance is to a large extent dic- analysis on the casein gene locus as a typical TRA gene cluster. Ttated by ectopic expression of numerous tissue-restricted Expression of the casein genes as well as the flanking sulfo- antigens (TRAs). This gene pool encompasses >10% of all known transferase and the UDP glycosyltransferase family members and genes and represents virtually all tissues of the body. Genes in this the family of salivary gland genes is tissue restricted. At the same pool show no obvious functional or structural commonalities. time, all of the genes within the cluster are expressed by mature but Whereas the cellular regulation and modes of tolerance induction not immature mTECs at the population level (2). This contiguous operating on this gene pool become increasingly clear, our un- expression of functionally unrelated genes within a cluster is likely derstanding of the molecular regulation of this promiscuous gene to be regulated at the epigenetic level. Hence, we analyzed the expression (pGE) has progressed slowly. To date only the auto- promoters of the casein genes as well as the promoter regions of immune regulator (Aire) has been identified as a molecular Ugt2a3, Sult1d1, Sult1e1, Smr1, and Muc10 for histone H4 acet- component, which directs the expression of a large fraction of ylation and histone H3 lysine 4 trimethylation (H3K4me3) as these genes in medullary thymic epithelial cells (mTECs). Con- marks for active chromatin and histone H3 lysine 27 trimethylation sequently, the lack of a functional Aire protein leads to a severe (H3K27me3) as a repressive mark, which is also found in bivalent multiorgan autoimmune disease—autoimmune polyendocrine chromatin domains (11, 12). Given the limited yield of ex vivo syndrome-1 (APS-1). Only 13 y after identifying the Aire gene as available mTECs, we improved the sensitivity of ChIP and rou- 5 A being responsible for APS-1, we begin to understand the molec- tinely used 10 mTECs per immunoprecipitation (IP) (Fig. S1 ). ular workings of Aire in the context of pGE (1). However, several Mammary gland epithelial cells (MECs) of lactating mice served distinctive features of pGE still seek an explanation at the mo- as a positive and thymocytes as a negative control for the casein lecular level. Promiscuously expressed genes are (i) highly en- locus. Expectedly, the casein gene promoters in MECs and the riched in tissue-restricted genes (2, 3) and (ii) preferentially lo- CD45 gene promoter in thymocytes were highly H4 acetylated and calize to genomic clusters in mice and man (2, 4). In particular the H3K4 trimethylated (Fig. 1). In MECs, the promoter regions of the nonexpressed genes flanking the casein genes as well as the segregation into gene clusters may offer clues as to how genes of fi different ontology and without obvious functional relatedness are CD45 promoter showed no signi cant acetylation of histone H4. targeted for coexpression in a single cell type. On the basis of our Thymocytes as well as immature mTECs showed none of the previous studies on the mouse casein locus (2, 5), we proposed that pGE might target genes via epigenetic marks rather than common sequence motives in their cis-acting regulatory elements Author contributions: L.-O.T., A.S., J.D., and B.K. designed research; L.-O.T., A.S., E.R., and (6). Thus, we found that epithelial cells of the lactating mammary J.D. performed research; Y.W., D.B., C.C., S.S., and K.W. contributed new reagents/analytic gland selectively coexpressed milk protein genes but not other tools; L.-O.T., A.S., and J.D. analyzed data; and L.-O.T., A.S., and B.K. wrote the paper. genes of the extended casein locus, whereas in mTECs all genes The authors declare no conflict of interest. within this locus were expressed at similar frequencies (with *This Direct Submission article had a prearranged editor. one exception) in an apparently stochastic manner irrespective of 1L.-O.T. and A.S. contributed equally to this work. their tissue affiliation (5). Such coexpression neighborhoods 2Present address: Department of Medicine V, Division of Rheumatology, University of of functionally unrelated genes have been described for the Heidelberg, INF 410, D-69120 Heidelberg, Germany. Drosophila genome and estimated to encompass up to 20% of all 3To whom correspondence should be addressed. E-mail: [email protected]. genes analyzed (7). Several mechanisms have been suggested to This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. account for this observation, one of which is the epigenetic open- 1073/pnas.1009265107/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1009265107 PNAS Early Edition | 1of6 Downloaded by guest on September 28, 2021 positive histone marks within the casein gene cluster. In mature acetylation was around 10–20% of expressing cells within a mixed mTECs, only the Csnb promoter was strongly acetylated at histone cell population (Fig. S1B), we cannot at present exclude that his- H4 and trimethylated at H3K4, whereas all other gene promoters tone modifications within a minor mTEC population escaped showed only background levels for these histone marks. The re- detection in our ChIP assay (see below). pressive H3K27me3 mark could not be detected to a significant degree in any promoter within the casein cluster in mTECs, MECs, PGE Correlates with Gene-Specific Promoter DNA Demethylation in or thymocytes. In contrast, the Hoxc10 promoter, known to be the Casein Cluster. The chromatin structure that determines the targeted by polycomb group complexes (13) and used in this study accessibility of a gene promoter depends on histone modifications as a positive control for H3K27me3, was highly trimethylated at as well as on the DNA methylation status. Both epigenetic H3K27 in all four cell types. The casein cluster is thus character- modifications can influence each other and the relationship can ized neither by a state of facultative heterochromatin nor by bi- work in both directions (14). We analyzed the DNA methylation valent chromatin (carrying both H3K4me3 and H3K27me3 marks status of the 5′ regions of all casein genes and of the neighboring simultaneously) in any of the four cell populations analyzed. Re- Sult1e1 gene in immature and mature mTECs, MECs, and thy- markably, Csnb is the only gene in the casein cluster carrying active mocytes. As expected, all gene promoters were highly methylated histone modifications at its promoter region in mature mTECs, in thymocytes, which do not express any of the analyzed genes yet all genes in the casein cluster are expressed in mature mTECs (Fig. 2). In MECs, all casein gene promoters were highly deme- at the population level. Gene expression analysis at the single cell thylated. In immature as well as in mature mTECs, the Sult1e1 as level, however, showed that only 2–15% of the mature mTECs well as the Csna and Csnk promoter were highly methylated, express a particular gene of the casein cluster. Csnb is an exception whereas the 5′ regions of the Csng and Csnd genes were partially being expressed in more than 80% of mature mTECs (5).
Load more

Recommended publications
  • DNA Methylation Regulates Discrimination of Enhancers From
    Sharifi-Zarchi et al. BMC Genomics (2017) 18:964 DOI 10.1186/s12864-017-4353-7 RESEARCHARTICLE Open Access DNA methylation regulates discrimination of enhancers from promoters through a H3K4me1-H3K4me3 seesaw mechanism Ali Sharifi-Zarchi1,2,3,4†, Daniela Gerovska5†, Kenjiro Adachi6, Mehdi Totonchi3, Hamid Pezeshk7,8, Ryan J. Taft9, Hans R. Schöler6,10, Hamidreza Chitsaz2, Mehdi Sadeghi8,11, Hossein Baharvand3,12* and Marcos J. Araúzo-Bravo5,13,14* Abstract Background: DNA methylation at promoters is largely correlated with inhibition of gene expression. However, the role of DNA methylation at enhancers is not fully understood, although a crosstalk with chromatin marks is expected. Actually, there exist contradictory reports about positive and negative correlations between DNA methylation and H3K4me1, a chromatin hallmark of enhancers. Results: We investigated the relationship between DNA methylation and active chromatin marks through genome- wide correlations, and found anti-correlation between H3K4me1 and H3K4me3 enrichment at low and intermediate DNA methylation loci. We hypothesized “seesaw” dynamics between H3K4me1 and H3K4me3 in the low and intermediate DNA methylation range, in which DNA methylation discriminates between enhancers and promoters, marked by H3K4me1 and H3K4me3, respectively. Low methylated regions are H3K4me3 enriched, while those with intermediate DNA methylation levels are progressively H3K4me1 enriched. Additionally, the enrichment of H3K27ac, distinguishing active from primed enhancers, follows a plateau in the lower range of the intermediate DNA methylation level, corresponding to active enhancers, and decreases linearly in the higher range of the intermediate DNA methylation. Thus, the decrease of the DNA methylation switches smoothly the state of the enhancers from a primed to an active state.
    [Show full text]
  • Modes of Interaction of KMT2 Histone H3 Lysine 4 Methyltransferase/COMPASS Complexes with Chromatin
    cells Review Modes of Interaction of KMT2 Histone H3 Lysine 4 Methyltransferase/COMPASS Complexes with Chromatin Agnieszka Bochy ´nska,Juliane Lüscher-Firzlaff and Bernhard Lüscher * ID Institute of Biochemistry and Molecular Biology, Medical School, RWTH Aachen University, Pauwelsstrasse 30, 52057 Aachen, Germany; [email protected] (A.B.); jluescher-fi[email protected] (J.L.-F.) * Correspondence: [email protected]; Tel.: +49-241-8088850; Fax: +49-241-8082427 Received: 18 January 2018; Accepted: 27 February 2018; Published: 2 March 2018 Abstract: Regulation of gene expression is achieved by sequence-specific transcriptional regulators, which convey the information that is contained in the sequence of DNA into RNA polymerase activity. This is achieved by the recruitment of transcriptional co-factors. One of the consequences of co-factor recruitment is the control of specific properties of nucleosomes, the basic units of chromatin, and their protein components, the core histones. The main principles are to regulate the position and the characteristics of nucleosomes. The latter includes modulating the composition of core histones and their variants that are integrated into nucleosomes, and the post-translational modification of these histones referred to as histone marks. One of these marks is the methylation of lysine 4 of the core histone H3 (H3K4). While mono-methylation of H3K4 (H3K4me1) is located preferentially at active enhancers, tri-methylation (H3K4me3) is a mark found at open and potentially active promoters. Thus, H3K4 methylation is typically associated with gene transcription. The class 2 lysine methyltransferases (KMTs) are the main enzymes that methylate H3K4. KMT2 enzymes function in complexes that contain a necessary core complex composed of WDR5, RBBP5, ASH2L, and DPY30, the so-called WRAD complex.
    [Show full text]
  • Modeling of Histone Modifications Reveals Formation Mechanism and Function of Bivalent Chromatin
    bioRxiv preprint doi: https://doi.org/10.1101/2021.02.03.429504; this version posted February 3, 2021. 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. Modeling of histone modifications reveals formation mechanism and function of bivalent chromatin Wei Zhao1,2, Lingxia Qiao1, Shiyu Yan2, Qing Nie3,*, Lei Zhang1,2,* 1 Beijing International Center for Mathematical Research, Peking University, Beijing 100871, China 2 Center for Quantitative Biology, Peking University, Beijing 100871, China 3 Department of Mathematics and Department of Developmental and Cell Biology, University of California Irvine, Irvine, CA 92697, USA. *Corresponding authors: Qing Nie, email: [email protected]; Lei Zhang, email: [email protected] Abstract Bivalent chromatin is characterized by occupation of both activating histone modifications and repressive histone modifications. While bivalent chromatin is known to link with many biological processes, the mechanisms responsible for its multiple functions remain unclear. Here, we develop a mathematical model that involves antagonistic histone modifications H3K4me3 and H3K27me3 to capture the key features of bivalent chromatin. Three necessary conditions for the emergence of bivalent chromatin are identified, including advantageous methylating activity over demethylating activity, frequent noise conversions of modifications, and sufficient nonlinearity. The first condition is further confirmed by analyzing the
    [Show full text]
  • H3k4me3 Is Neither Instructive For, Nor Informed By, Transcription
    bioRxiv preprint first posted online Jul. 19, 2019; doi: http://dx.doi.org/10.1101/709014. The copyright holder for this preprint (which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license. H3K4me3 is neither instructive for, nor informed by, transcription. Struan C Murray1, Philipp Lorenz1, Françoise S Howe1, Meredith Wouters1, Thomas Brown1, Shidong Xi1, Harry Fischl1, Walaa Khushaim1, Joseph Regish Rayappu1, Andrew Angel1 & Jane Mellor1* 1Department of Biochemistry, University of Oxford, Oxford, OX1 3QU, UK. *Corresponding author. Tel: +44 1865 613241; E-mail: [email protected] Key words histone modification; gene regulation; H3K4me3; chromatin; RNA polymerase Abstract H3K4me3 is a near-universal histone modification found predominantly at the 5’ region of genes, with a well-documented association with gene activity. H3K4me3 has been ascribed roles as both an instructor of gene expression and also a downstream consequence of expression, yet neither has been convincingly proven on a genome-wide scale. Here we test these relationships using a combination of bioinformatics, modelling and experimental data from budding yeast in which the levels of H3K4me3 have been massively ablated. We find that loss of H3K4me3 has no effect on the levels of nascent transcription or transcript in the population. Moreover, we observe no change in the rates of transcription initiation, elongation, mRNA export or turnover, or in protein levels, or cell-to-cell variation of mRNA. Loss of H3K4me3 also has no effect on the large changes in gene expression patterns that follow galactose induction.
    [Show full text]
  • Histone H3k27me3 Demethylases Regulate Human Th17 Cell Development and Effector Functions by Impacting on Metabolism
    Histone H3K27me3 demethylases regulate human Th17 cell development and effector functions by impacting on metabolism Adam P. Cribbsa,1, Stefan Terlecki-Zaniewicza, Martin Philpotta, Jeroen Baardmanb, David Ahernc, Morten Lindowd, Susanna Obadd, Henrik Oerumd, Brante Sampeye, Palwinder K. Manderf, Henry Penng, Paul Wordswortha, Paul Bownessa, Menno de Wintherh, Rab K. Prinjhaf, Marc Feldmanna,c,1, and Udo Oppermanna,i,j,k,1 aBotnar Research Center, Nuffield Department of Orthopedics, Rheumatology and Musculoskeletal Sciences, National Institute for Health Research Oxford Biomedical Research Unit, University of Oxford, OX3 7LD Oxford, United Kingdom; bExperimental Vascular Biology, Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centres, University of Amsterdam, 1105AZ Amsterdam, The Netherlands; cKennedy Institute of Rheumatology, Nuffield Department of Orthopedics, Rheumatology and Musculoskeletal Sciences, National Institute for Health Research Oxford Biomedical Research Unit, University of Oxford, OX3 7FY Oxford, United Kingdom; dRoche Innovation Center Copenhagen A/S, DK 2970 Hørsholm, Denmark; eMetabolon Inc., Durham, NC 27713; fEpinova Discovery Performance Unit, Medicines Research Centre, GlaxoSmithKline R&D, SG1 2NY Stevenage, United Kingdom; gArthritis Centre, Northwick Park Hospital, HA13UJ Harrow, United Kingdom; hInstitute for Cardiovascular Prevention, Ludwig Maximilians University, 80336 Munich, Germany; iStructural Genomics Consortium, University of Oxford, OX3 7DQ Oxford,
    [Show full text]
  • Dual Recognition of H3k4me3 and H3k27me3 by a Plant Histone Reader SHL
    ARTICLE DOI: 10.1038/s41467-018-04836-y OPEN Dual recognition of H3K4me3 and H3K27me3 by a plant histone reader SHL Shuiming Qian1,2, Xinchen Lv3,4, Ray N. Scheid1,2,LiLu1,2, Zhenlin Yang3,4, Wei Chen3, Rui Liu3, Melissa D. Boersma2, John M. Denu2,5,6, Xuehua Zhong 1,2 & Jiamu Du 3 The ability of a cell to dynamically switch its chromatin between different functional states constitutes a key mechanism regulating gene expression. Histone mark “readers” display 1234567890():,; distinct binding specificity to different histone modifications and play critical roles in reg- ulating chromatin states. Here, we show a plant-specific histone reader SHORT LIFE (SHL) capable of recognizing both H3K27me3 and H3K4me3 via its bromo-adjacent homology (BAH) and plant homeodomain (PHD) domains, respectively. Detailed biochemical and structural studies suggest a binding mechanism that is mutually exclusive for either H3K4me3 or H3K27me3. Furthermore, we show a genome-wide co-localization of SHL with H3K27me3 and H3K4me3, and that BAH-H3K27me3 and PHD-H3K4me3 interactions are important for SHL-mediated floral repression. Together, our study establishes BAH-PHD cassette as a dual histone methyl-lysine binding module that is distinct from others in recognizing both active and repressive histone marks. 1 Laboratory of Genetics, University of Wisconsin-Madison, Madison, WI 53706, USA. 2 Wisconsin Institute for Discovery, University of Wisconsin-Madison, Madison, WI 53706, USA. 3 National Key Laboratory of Plant Molecular Genetics, CAS Center for Excellence in Molecular Plant Sciences, Shanghai Center for Plant Stress Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 201602, China.
    [Show full text]
  • The Importance of Epigenetics in Diagnostics and Treatment of Major Depressive Disorder
    Journal of Personalized Medicine Review The Importance of Epigenetics in Diagnostics and Treatment of Major Depressive Disorder Piotr Czarny 1,† , Katarzyna Białek 2,†, Sylwia Ziółkowska 1,†, Justyna Strycharz 1 , Gabriela Barszczewska 2 and Tomasz Sliwinski 2,* 1 Department of Medical Biochemistry, Medical University of Lodz, 92-216 Lodz, Poland; [email protected] (P.C.); [email protected] (S.Z.); [email protected] (J.S.) 2 Laboratory of Medical Genetics, Faculty of Biology and Environmental Protection, University of Lodz, 90-236 Lodz, Poland; [email protected] (K.B.); [email protected] (G.B.) * Correspondence: [email protected] † Equal contribution. Abstract: Recent studies imply that there is a tight association between epigenetics and a molecular mechanism of major depressive disorder (MDD). Epigenetic modifications, i.e., DNA methylation, post-translational histone modification and interference of microRNA (miRNA) or long non-coding RNA (lncRNA), are able to influence the severity of the disease and the outcome of the therapy. This article summarizes the most recent literature data on this topic, i.e., usage of histone deacetylases as therapeutic agents with an antidepressant effect and miRNAs or lncRNAs as markers of depression. Due to the noteworthy potential of the role of epigenetics in MDD diagnostics and therapy, we have gathered the most relevant data in this area. Citation: Czarny, P.; Białek, K.; Ziółkowska, S.; Strycharz, J.; Keywords: depression; epigenetics; personalized medicine; histones; histone modifications; DNA Barszczewska, G.; Sliwinski, T. The methylation; microRNA; long non-coding RNA Importance of Epigenetics in Diagnostics and Treatment of Major Depressive Disorder.
    [Show full text]
  • 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.
    [Show full text]
  • Early Life Stress Induces Age-Dependent Epigenetic Changes
    www.nature.com/scientificreports OPEN Early life stress induces age‑dependent epigenetic changes in p11 gene expression in male mice Mi Kyoung Seo1, Jung Goo Lee1,2* & Sung Woo Park1,3* Early life stress (ELS) causes long‑lasting changes in gene expression through epigenetic mechanisms. However, little is known about the efects of ELS in adulthood, specifcally across diferent age groups. In this study, the epigenetic modifcations of p11 expression in adult mice subjected to ELS were investigated in diferent stages of adulthood. Pups experienced maternal separation (MS) for 3 h daily from postnatal day 1 to 21. At young and middle adulthood, behavioral test, hippocampal p11 expression levels, and levels of histone acetylation and methylation and DNA methylation at the hippocampal p11 promoter were measured. Middle‑aged, but not young adult, MS mice exhibited increased immobility time in the forced swimming test. Concurrent with reduced hippocampal p11 levels, mice in both age groups showed a decrease in histone acetylation (AcH3) and permissive histone methylation (H3K4me3) at the p11 promoter, as well as an increase in repressive histone methylation (H3K27me3). Moreover, our results showed that the expression, AcH3 and H3Kme3 levels of p11 gene in response to MS were reduced with age. DNA methylation analysis of the p11 promoter revealed increased CpG methylation in middle‑aged MS mice only. The results highlight the age‑ dependent deleterious efects of ELS on the epigenetic modifcations of p11 transcription. Children exposed to early life stress (ELS) such as neglect and abuse have a signifcantly increased risk of devel- oping depression1,2. In human and animal studies, ELS has been reported to induce a depression-like phenotype in adulthood3,4.
    [Show full text]
  • Chromatin Dynamics During DNA Replication Raz Bar-Ziv*, Yoav Voichek* and Naama Barkai†
    Downloaded from genome.cshlp.org on October 5, 2021 - Published by Cold Spring Harbor Laboratory Press Chromatin Dynamics during DNA Replication Raz Bar-Ziv*, Yoav Voichek* and Naama Barkai† Affiliations: Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel. *these authors contributed equally to the manuscript †Correspondence to: [email protected] Keywords: Chromatin; Replication; Summary: Chromatin is composed of DNA and histones, which provide a unified platform for regulating DNA-related processes, mostly through their post translational modification. During DNA replication, histone arrangement is perturbed, to first allow progression of DNA polymerase and then during repackaging of the replicated DNA. To study how DNA replication influences the pattern of histone modification, we followed the cell-cycle dynamics of ten histone marks in budding yeast. We find that histones deposited on newly replicated DNA are modified at different rates; while some marks appear immediately upon replication (e.g. H4K16ac, H3K4me1), others increase with transcription-dependent delays (e.g. H3K4me3, H3K36me3). Notably, H3K9ac was deposited as a wave preceding the replication fork by ~5-6 kb. This replication-guided H3K9ac was fully dependent on the acetyltransferase Rtt109, while expression-guided H3K9ac was deposited by Gcn5. Further, topoisomerase depletion intensified H3K9ac in front of the replication fork, and in sites where RNA polymerase II was trapped, suggesting supercoiling stresses trigger H3K9 acetylation. Our results assign complementary roles for DNA replication and gene expression in defining the pattern of histone modification. Introduction: In eukaryotic cells, DNA is wrapped around histone octamers to form nucleosomes, the basic building blocks of the chromatin structure.
    [Show full text]
  • Deciphering the Histone Code to Build the Genome Structure
    bioRxiv preprint doi: https://doi.org/10.1101/217190; this version posted November 13, 2017. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC 4.0 International license. Deciphering the histone code to build the genome structure Kirti Prakasha,b,c,* and David Fournierd,* aPhysico-Chimie Curie, Institut Curie, CNRS UMR 168, 75005 Paris, France; bOxford Nanoimaging Ltd, OX1 1JD Oxford, UK; cMicron Advanced Bioimaging Unit, Department of Biochemistry, University of Oxford, Oxford, UK; dFaculty of Biology and Center for Computational Sciences, Johannes Gutenberg University Mainz, 55128 Mainz, Germany; *Correspondence: [email protected], [email protected] Histones are punctuated with small chemical modifications that alter their interaction with DNA. One attractive hypothesis stipulates that certain combinations of these histone modifications may function, alone or together, as a part of a predictive histone code to provide ground rules for chromatin folding. We consider four features that relate histone modifications to chromatin folding: charge neutrali- sation, molecular specificity, robustness and evolvability. Next, we present evidence for the association among different histone modi- fications at various levels of chromatin organisation and show how these relationships relate to function such as transcription, replica- tion and cell division. Finally, we propose a model where the histone code can set critical checkpoints for chromatin to fold reversibly be- tween different orders of the organisation in response to a biological stimulus. DNA | nucleosomes | histone modifications | chromatin domains | chro- mosomes | histone code | chromatin folding | genome structure Introduction The genetic information within chromosomes of eukaryotes is packaged into chromatin, a long and folded polymer of double-stranded DNA, histones and other structural and non- structural proteins.
    [Show full text]
  • Histone H3Q5 Serotonylation Stabilizes H3K4 Methylation and Potentiates Its Readout
    Histone H3Q5 serotonylation stabilizes H3K4 methylation and potentiates its readout Shuai Zhaoa,1, Kelly N. Chuhb,1, Baichao Zhanga,1, Barbara E. Dulb, Robert E. Thompsonb, Lorna A. Farrellyc,d, Xiaohui Liue, Ning Xue, Yi Xuee, Robert G. Roederf, Ian Mazec,d,2, Tom W. Muirb,2, and Haitao Lia,g,2 aMinistry of Education Key Laboratory of Protein Sciences, Beijing Advanced Innovation Center for Structural Biology, Beijing Frontier Research Center for Biological Structure, Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing 100084, China; bDepartment of Chemistry, Princeton University, Princeton, NJ 08540; cNash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029; dDepartment of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029; eNational Protein Science Technology Center, School of Life Sciences, Tsinghua University, Beijing 100084, China; fLaboratory of Biochemistry and Molecular Biology, The Rockefeller University, New York, NY 10065; and gTsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China Edited by Peter Cheung, York University, Toronto, ON, Canada, and accepted by Editorial Board Member Karolin Luger November 12, 2020 (received for review August 7, 2020) Serotonylation of glutamine 5 on histone H3 (H3Q5ser) was recently established that H3K4me3 regulates gene expression through re- identified as a permissive posttranslational modification that coexists cruitment of nuclear factors that contain reader domains specific with adjacent lysine 4 trimethylation (H3K4me3). While the resulting for the mark. These include ATP-dependent chromatin remod- dual modification, H3K4me3Q5ser, is enriched at regions of active eling enzymes, as well as several transcription factors (13).
    [Show full text]