Quantitative Proteomics Methods for the Analysis of Histone Post-Translational Modifications
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Functional Roles of Bromodomain Proteins in Cancer
cancers Review Functional Roles of Bromodomain Proteins in Cancer Samuel P. Boyson 1,2, Cong Gao 3, Kathleen Quinn 2,3, Joseph Boyd 3, Hana Paculova 3 , Seth Frietze 3,4,* and Karen C. Glass 1,2,4,* 1 Department of Pharmaceutical Sciences, Albany College of Pharmacy and Health Sciences, Colchester, VT 05446, USA; [email protected] 2 Department of Pharmacology, Larner College of Medicine, University of Vermont, Burlington, VT 05405, USA; [email protected] 3 Department of Biomedical and Health Sciences, University of Vermont, Burlington, VT 05405, USA; [email protected] (C.G.); [email protected] (J.B.); [email protected] (H.P.) 4 University of Vermont Cancer Center, Burlington, VT 05405, USA * Correspondence: [email protected] (S.F.); [email protected] (K.C.G.) Simple Summary: This review provides an in depth analysis of the role of bromodomain-containing proteins in cancer development. As readers of acetylated lysine on nucleosomal histones, bromod- omain proteins are poised to activate gene expression, and often promote cancer progression. We examined changes in gene expression patterns that are observed in bromodomain-containing proteins and associated with specific cancer types. We also mapped the protein–protein interaction network for the human bromodomain-containing proteins, discuss the cellular roles of these epigenetic regu- lators as part of nine different functional groups, and identify bromodomain-specific mechanisms in cancer development. Lastly, we summarize emerging strategies to target bromodomain proteins in cancer therapy, including those that may be essential for overcoming resistance. Overall, this review provides a timely discussion of the different mechanisms of bromodomain-containing pro- Citation: Boyson, S.P.; Gao, C.; teins in cancer, and an updated assessment of their utility as a therapeutic target for a variety of Quinn, K.; Boyd, J.; Paculova, H.; cancer subtypes. -
MAP3K4/CBP-Regulated H2B Acetylation Controls Epithelial-Mesenchymal Transition in Trophoblast Stem Cells
Cell Stem Cell Article MAP3K4/CBP-Regulated H2B Acetylation Controls Epithelial-Mesenchymal Transition in Trophoblast Stem Cells Amy N. Abell,1,2,7,* Nicole Vincent Jordan,1,2,7 Weichun Huang,6 Aleix Prat,2,4 Alicia A. Midland,5 Nancy L. Johnson,1,2 Deborah A. Granger,1,2 Piotr A. Mieczkowski,2,3 Charles M. Perou,2,4 Shawn M. Gomez,5 Leping Li,6 and Gary L. Johnson1,2,* 1Department of Pharmacology 2Lineberger Comprehensive Cancer Center 3Department of Genetics and Carolina Center for Genome Sciences 4Department of Genetics 5Department of Biomedical Engineering and Curriculum in Bioinformatics and Computational Biology University of North Carolina School of Medicine, Chapel Hill, NC 27599-7365, USA 6Biostatistics Branch, National Institute of Environmental Health Sciences RTP, NC 27709, USA 7These authors contributed equally to this work *Correspondence: [email protected] (A.N.A.), [email protected] (G.L.J.) DOI 10.1016/j.stem.2011.03.008 SUMMARY berg, 2008). During development, EMT is responsible for proper formation of the body plan and for differentiation of many tissues Epithelial stem cells self-renew while maintaining and organs. Examples of EMT in mammalian development multipotency, but the dependence of stem cell prop- include implantation, gastrulation, and neural crest formation erties on maintenance of the epithelial phenotype is (Thiery et al., 2009). Initiation of placenta formation regulated unclear. We previously showed that trophoblast by trophoectoderm differentiation is the first, and yet most poorly stem (TS) cells lacking the protein kinase MAP3K4 defined, developmental EMT. maintain properties of both stemness and epithelial- The commitment of stem cells to specialized cell types requires extensive reprogramming of gene expression, involving, in part, mesenchymal transition (EMT). -
EIN2 Mediates Direct Regulation of Histone Acetylation in the Ethylene Response
EIN2 mediates direct regulation of histone acetylation in the ethylene response Fan Zhanga,b,1, Likai Wanga,b,1, Bin Qic, Bo Zhaoa,b, Eun Esther Koa,b, Nathaniel D. Riggana,b, Kevin China,b, and Hong Qiaoa,b,2 aInstitute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, TX 78712; bDepartment of Molecular Biosciences, The University of Texas at Austin, Austin, TX 78712; and cDepartment of Molecular, Cellular, and Developmental Biology, University of Colorado Boulder, Boulder, CO 80309 Edited by Steven E. Jacobsen, University of California, Los Angeles, CA, and approved August 10, 2017 (received for review May 15, 2017) Ethylene gas is essential for developmental processes and stress of EBF1 and EBF2 (19, 20). In the nucleus, the EIN2-C transduces responses in plants. Although the membrane-bound protein EIN2 is signals to the transcription factors EIN3 and EIL1, which are key for critical for ethylene signaling, the mechanism by which the ethylene activation of expression of all ethylene-response genes (21, 22). We signal is transduced remains largely unknown. Here we show the recently discovered that acetylation at H3K23 and H3K14Ac is in- levels of H3K14Ac and H3K23Ac are correlated with the levels of volved in ethylene-regulated gene activation in a manner that de- EIN2 protein and demonstrate EIN2 C terminus (EIN2-C) is sufficient to pends on both EIN2 and EIN3 (23, 24). rescue the levels of H3K14/23Ac of ein2-5 at the target loci, using Here we show that the levels of H3K14/23Ac are positively CRISPR/dCas9-EIN2-C. -
Lysine Benzoylation Is a Histone Mark Regulated by SIRT2
ARTICLE DOI: 10.1038/s41467-018-05567-w OPEN Lysine benzoylation is a histone mark regulated by SIRT2 He Huang1, Di Zhang1, Yi Wang2, Mathew Perez-Neut1, Zhen Han3, Y. George Zheng3, Quan Hao2 & Yingming Zhao1 Metabolic regulation of histone marks is associated with diverse biological processes through dynamically modulating chromatin structure and functions. Here we report the identification 1234567890():,; and characterization of a histone mark, lysine benzoylation (Kbz). Our study identifies 22 Kbz sites on histones from HepG2 and RAW cells. This type of histone mark can be stimulated by sodium benzoate (SB), an FDA-approved drug and a widely used chemical food preservative, via generation of benzoyl CoA. By ChIP-seq and RNA-seq analysis, we demonstrate that histone Kbz marks are associated with gene expression and have physiological relevance distinct from histone acetylation. In addition, we demonstrate that SIRT2, a NAD+-dependent protein deacetylase, removes histone Kbz both in vitro and in vivo. This study therefore reveals a new type of histone marks with potential physiological relevance and identifies possible non-canonical functions of a widely used chemical food preservative. 1 Ben May Department for Cancer Research, The University of Chicago, Chicago, IL 60637, USA. 2 School of Biomedical Sciences, University of Hong Kong, Hong Kong, China. 3 Department of Pharmaceutical and Biomedical Sciences, University of Georgia, Athens, GA 30602, USA. Correspondence and requests for materials should be addressed to Y.Z. (email: [email protected]) NATURE COMMUNICATIONS | (2018) 9:3374 | DOI: 10.1038/s41467-018-05567-w | www.nature.com/naturecommunications 1 ARTICLE NATURE COMMUNICATIONS | DOI: 10.1038/s41467-018-05567-w hromatin structure and transcriptional activity of genes and coelution analysis were performed to compare the synthetic are regulated by diverse protein posttranslational mod- peptide with its in vivo counterpart (Fig. -
The Determinants of Nucleosome Patterns and the Impact of Phosphate Starvation on Nucleosome Patterns and Gene Expression in Rice
Louisiana State University LSU Digital Commons LSU Doctoral Dissertations Graduate School 3-14-2018 The etD erminants of Nucleosome Patterns and the Impact of Phosphate Starvation on Nucleosome Patterns and Gene Expression in Rice Qi Zhang Louisiana State University and Agricultural and Mechanical College, [email protected] Follow this and additional works at: https://digitalcommons.lsu.edu/gradschool_dissertations Part of the Agronomy and Crop Sciences Commons, Bioinformatics Commons, Genetics Commons, Genomics Commons, and the Plant Breeding and Genetics Commons Recommended Citation Zhang, Qi, "The eD terminants of Nucleosome Patterns and the Impact of Phosphate Starvation on Nucleosome Patterns and Gene Expression in Rice" (2018). LSU Doctoral Dissertations. 4502. https://digitalcommons.lsu.edu/gradschool_dissertations/4502 This Dissertation is brought to you for free and open access by the Graduate School at LSU Digital Commons. It has been accepted for inclusion in LSU Doctoral Dissertations by an authorized graduate school editor of LSU Digital Commons. For more information, please [email protected]. THE DETERMINANTS OF NUCLEOSOME PATTERNS AND THE IMPACT OF PHOSPHATE STARVATION ON NUCLEOSOME PATTERNS AND GENE EXPRESSION IN RICE A Dissertation Submitted to the Graduate Faculty of the Louisiana State University and Agricultural and Mechanical College in partial fulfillment of the requirements for the degree of Doctor of Philosophy in The Department of Biological Sciences by Qi Zhang B.S., Sichuan Agricultural University, 2012 May 2018 ACKNOWLEDGEMENTS The journey towards the completion of the degree hasn’t been easy, and I would like to express my heartfelt gratitude to everyone who has been around me, listening to me, and supporting me. -
Machine Learning & Learning Machines
A Brief History • Bootstrapping • Bagging • Boosting (Schapire 1989) • Adaboost (Schapire 1995) What’s So Good About Adaboost • Improves classification accuracy • Can be used with many different classifiers • Commonly used in many areas • Simple to implement • Not prone to over-fitting Ex. “How May I Help You?” easy to find “rules of thumb” that are “often” correct • e.g.: “IF ‘card’ occurs in utterance THEN predict ‘Calling Card’ ” • hard to find single highly accurate prediction rule Bootstrap Estimation • Repeatedly draw n samples from D • For each set of samples, estimate a statistic • The bootstrap estimate is the mean of the individual estimates • Used to estimate a statistic (parameter) and its variance Bagging - Aggregate Bootstrapping • For i = 1 .. M – Draw n*<n samples from D with replacement – Learn classifier Ci • Final classifier is a vote of C1 .. CM • Increases classifier stability/reduces variance Boosting (Schapire 1989) • Randomly select n1 < n samples from D without replacement to obtain D1 – Train weak learner C1 • Select n2 < n samples from D with half of the samples misclassified by C1 to obtain D2 – Train weak learner C2 • Select all samples from D that C1 and C2 disagree on – Train weak learner C3 • Final classifier is vote of weak learners Adaboost - Adaptive Boosting • Instead of sampling, re-weight – Previous weak learner has only 50% accuracy over new distribution • Can be used to learn weak classifiers • Final classification based on weighted vote of weak classifiers Adaboost Terms • Learner = Hypothesis = Classifier • Weak Learner: < 50% error over any distribution • Strong Classifier: thresholded linear combination of weak learner outputs Basic idea of boosting technique In general Boosting Bagging Single Tree. -
New Developments in Epigenetics and Potential Clinical Applications
NEW DEVELOPMENTS IN EPIGENETICS AND POTENTIAL CLINICAL APPLICATIONS Susan E. Bates, M.D. Columbia University Medical Center, New York, NY and J.J.P Bronx VA Medical Center, Bronx, NY TARGETING THE EPIGENOME What do we mean? “Targeting the Epigenome” - Meaning that we identify proteins that impact transcriptional controls that are important in cancer. “Epigenetics” – Meaning the right genes expressed at the right time, in the right place and in the right quantities. This process is ensured by an expanding list of genes that themselves must be expressed at the right time and right place. Think of it as a coordinated chromatin dance involving DNA, histone proteins, transcription factors, and over 700 proteins that modify them. Transcriptional Control: DNA Histone Tail Modification Nucleosomal Remodeling Non-Coding RNA HISTONE PROTEIN FAMILY 146 bp DNA wrap around an octomer of histone proteins H2A, H2B, H3, H4 are core histone families H1/H5 are linker histones >50 variants of the core histones Some with unique functions Post translational modification of “histone tails” key to gene expression Post-translational modifications include: – Acetylation – Methylation – Ubiquitination – Phosphorylation – Citrullation – SUMOylation – ADP-ribosylation THE HISTONE CODE Specific histone modifications determine function H3K9Ac, H3K27Ac, H3K36Ac H3K4Me3 – Gene activation H3K36Me2 – Inappropriate gene activation H3K27Me3 – Gene repression; Inappropriate gene repression H2AX S139Phosphorylation – associated with DNA double strand break, repair http://www.slideshare.net/jhowlin/eukaryotic-gene-regulation-part-ii-2013 KEY MODIFICATION - SPECIFIC FUNCTIONS H3K36Me: ac Active transcription, me H3K27Me: RNA elongation me Key Silencing ac ac me me Residue me me H3K4Me: H3K4 ac me Key Activating me me me Residue me H3K9 me H3K36 H3K9Ac:: H3K27 Activating Residue H3K18 H4K20 Activation me me me ac Modified from Mosammaparast N, et al. -
Transcription Shapes Genome-Wide Histone Acetylation Patterns
ARTICLE https://doi.org/10.1038/s41467-020-20543-z OPEN Transcription shapes genome-wide histone acetylation patterns Benjamin J. E. Martin 1, Julie Brind’Amour 2, Anastasia Kuzmin1, Kristoffer N. Jensen2, Zhen Cheng Liu1, ✉ Matthew Lorincz 2 & LeAnn J. Howe 1 Histone acetylation is a ubiquitous hallmark of transcription, but whether the link between histone acetylation and transcription is causal or consequential has not been addressed. 1234567890():,; Using immunoblot and chromatin immunoprecipitation-sequencing in S. cerevisiae, here we show that the majority of histone acetylation is dependent on transcription. This dependency is partially explained by the requirement of RNA polymerase II (RNAPII) for the interaction of H4 histone acetyltransferases (HATs) with gene bodies. Our data also confirms the targeting of HATs by transcription activators, but interestingly, promoter-bound HATs are unable to acetylate histones in the absence of transcription. Indeed, HAT occupancy alone poorly predicts histone acetylation genome-wide, suggesting that HAT activity is regulated post- recruitment. Consistent with this, we show that histone acetylation increases at nucleosomes predicted to stall RNAPII, supporting the hypothesis that this modification is dependent on nucleosome disruption during transcription. Collectively, these data show that histone acetylation is a consequence of RNAPII promoting both the recruitment and activity of histone acetyltransferases. 1 Department of Biochemistry and Molecular Biology, Life Sciences Institute, Molecular -
Mouse Model of Endemic Burkitt Translocations Reveals the Long-Range Boundaries of Ig-Mediated Oncogene Deregulation
Mouse model of endemic Burkitt translocations reveals the long-range boundaries of Ig-mediated oncogene deregulation Alexander L. Kovalchuka,1, Camilo Ansarah-Sobrinhob,1,Ofir Hakimc,1, Wolfgang Reschb, Helena Tolarováb, Wendy Duboisd, Arito Yamaneb, Makiko Takizawab, Isaac Kleinf, Gordon L. Hagerc, Herbert C. Morse IIIa, Michael Potterd,1, Michel C. Nussenzweige,f,2, and Rafael Casellasb,g,2 aLaboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852; bGenomics and Immunity, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892; cLaboratory of Receptor Biology and Gene Expression, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892; dLaboratory of Cancer Biology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892; eLaboratory of Molecular Immunology, and fHoward Hughes Medical Institute, The Rockefeller University, New York, NY 10065; and gCenter of Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892 Edited by Klaus Rajewsky, Max-Delbrück-Center for Molecular Medicine, Berlin, Germany, and approved May 22, 2012 (received for review January 5, 2012) Human Burkitt lymphomas are divided into two main clinical human Burkitt lymphomas (BLs), mouse plasmacytomas (PCTs), variants: the endemic form, affecting African children infected with and rat immunocytomas (15, 16). malaria and the Epstein-Barr virus, and the sporadic form, distrib- Human BLs are divided into two main clinical variants: the uted across the rest of the world. However, whereas sporadic endemic form, affecting African children infected with malaria translocations decapitate Myc from 5′ proximal regulatory ele- and the Epstein-Barr virus, and the sporadic form, distributed ments, most endemic events occur hundreds of kilobases away across the rest of the world (17). -
EIN2 Mediates Direct Regulation of Histone Acetylation in the Ethylene Response
EIN2 mediates direct regulation of histone acetylation in the ethylene response Fan Zhanga,b,1, Likai Wanga,b,1, Bin Qic, Bo Zhaoa,b, Eun Esther Koa,b, Nathaniel D. Riggana,b, Kevin China,b, and Hong Qiaoa,b,2 aInstitute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, TX 78712; bDepartment of Molecular Biosciences, The University of Texas at Austin, Austin, TX 78712; and cDepartment of Molecular, Cellular, and Developmental Biology, University of Colorado Boulder, Boulder, CO 80309 Edited by Steven E. Jacobsen, University of California, Los Angeles, CA, and approved August 10, 2017 (received for review May 15, 2017) Ethylene gas is essential for developmental processes and stress of EBF1 and EBF2 (19, 20). In the nucleus, the EIN2-C transduces responses in plants. Although the membrane-bound protein EIN2 is signals to the transcription factors EIN3 and EIL1, which are key for critical for ethylene signaling, the mechanism by which the ethylene activation of expression of all ethylene-response genes (21, 22). We signal is transduced remains largely unknown. Here we show the recently discovered that acetylation at H3K23 and H3K14Ac is in- levels of H3K14Ac and H3K23Ac are correlated with the levels of volvedinethylene-regulatedgeneactivationinamannerthatde- EIN2 protein and demonstrate EIN2 C terminus (EIN2-C) is sufficient to pends on both EIN2 and EIN3 (23, 24). rescue the levels of H3K14/23Ac of ein2-5 at the target loci, using Here we show that the levels of H3K14/23Ac are positively CRISPR/dCas9-EIN2-C. Chromatin immunoprecipitation followed by correlated with the EIN2 protein levels and demonstrate that deep sequencing (ChIP-seq) and ChIP-reChIP-seq analyses revealed that EIN2-C is sufficient to rescue the levels of H3K14Ac and EIN2-C associates with histone partially through an interaction with H3K23Ac in ein2-5 at loci targeted using CRISPR/dCas9-EIN2-C. -
Learning Chroma\N States from Chip-‐Seq Data
Learning Chroman States from ChIP-seq data Luca Pinello GC Yuan Lab Outline • Chroman structure, histone modificaons and combinatorial paerns • How to segment the genome in chroman states • How to use ChromHMM step by step • Further references 2 Epigene-cs and chroman structure • All (almost) the cells of our body share the same genome but have very different gene expression programs…. 3 h?p://jpkc.scu.edu.cn/ywwy/zbsw(E)/edetail12.htm The code over the code • The chroman structure and the accessibility are mainly controlled by: 1. Nucleosome posioning, 2. DNA methylaon, 3. Histone modificaons. 4 Histone Modificaons Specific histone modificaons or combinaons of modificaons confer unique biological func-ons to the region of the genome associated with them: • H3K4me3: promoters, gene acva.on • H3K27me3: promoters, poised enhancers, gene silencing • H2AZ: promoters • H3K4me1: enhancers • H3K36me3: transcribed regions • H3K9me3: gene silencing • H3k27ac: acve enhancers 5 Examples of *-Seq Measuring the genome genome fragmentation assembler DNA DNA reads “genome” ChIP-seq to measure histone data fragments Measuring the regulome (e.g., protein-binding of the genome) Chromatin Immunopreciptation genomic (ChIP) + intervals fragmentation Protein - peak caller bound by DNA bound DNA reads proteins REVIEWS fragments a also informative, as this ratio corresponds to the fraction ChIP–chip of nucleosomes with the particular modification at that location, averaged over all the cells assayed. One of the difficulties in conducting a ChIP–seq con- trol experiment is the large amount of sequencing that ChIP–seq may be necessary. For input DNA and bulk nucleosomes, many of the sequenced tags are spread evenly across the genome. -
Immunohistochemical Analysis of Histone H3 Modifications in Germ Cells Title During Mouse Spermatogenesis
NAOSITE: Nagasaki University's Academic Output SITE Immunohistochemical Analysis of Histone H3 Modifications in Germ Cells Title during Mouse Spermatogenesis. Song, Ning; Liu, Jie; An, Shucai; Nishino, Tomoya; Hishikawa, Yoshitaka; Author(s) Koji, Takehiko Citation Acta Histochemica et Cytochemica, 44(4), pp.183-190; 2011 Issue Date 2011-08-27 URL http://hdl.handle.net/10069/26169 Copyright (c) 2011 By the Japan Society of Histochemistry and Right Cytochemistry This document is downloaded at: 2020-09-18T06:01:32Z http://naosite.lb.nagasaki-u.ac.jp Advance Publication Acta Histochem. Cytochem. 44 (4): 183–190, 2011 doi:10.1267/ahc.11027 AHCActa0044-59911347-5800JapanTokyo,AHC1102710.1267/ahc.11027Regular Histochemica Society JapanArticle of Histochemistry et Cytochemica and Cytochemistry Immunohistochemical Analysis of Histone H3 Modifications in Germ Cells during Mouse Spermatogenesis Ning Song1, Jie Liu2, Shucai An3, Tomoya Nishino1, Yoshitaka Hishikawa1 and Takehiko Koji1 1Department of Histology and Cell Biology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan, 2Department of Prosthodontics, College of Stomatology, Jiamusi University, Jiamusi, China and 3Department of General Surgery, First Affiliated Hospital, Medical College of Jiamusi University, Jiamusi, China 00 Received June 7, 2011; accepted June 29, 2011; published online July 20, 2011 © 2011Histone The Japanmodification Society has of beenHistochemistry implicated and in the regulation of mammalian spermatogenesis. However, the association of differently modified histone H3 with a specific stage of germ cells during spermatogenesis is not fully understood. In this study, we examined the localiza- tion of variously modified histone H3 in paraffin-embedded sections of adult mouse testis immunohistochemically, focusing on acetylation at lysine 9 (H3K9ac), lysine 18 (H3K18ac), and lysine 23 (H3K23ac); tri-methylation at lysine 4 (H3K4me3) and lysine 27 (H3K27me3); and phosphorylation at serine 10 (H3S10phos).