KDM8, a H3k36me2 Histone Demethylase That Acts in the Cyclin A1 Coding Region to Regulate Cancer Cell Proliferation
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High-Throughput Discovery of Novel Developmental Phenotypes
High-throughput discovery of novel developmental phenotypes The Harvard community has made this article openly available. Please share how this access benefits you. Your story matters Citation Dickinson, M. E., A. M. Flenniken, X. Ji, L. Teboul, M. D. Wong, J. K. White, T. F. Meehan, et al. 2016. “High-throughput discovery of novel developmental phenotypes.” Nature 537 (7621): 508-514. doi:10.1038/nature19356. http://dx.doi.org/10.1038/nature19356. Published Version doi:10.1038/nature19356 Citable link http://nrs.harvard.edu/urn-3:HUL.InstRepos:32071918 Terms of Use This article was downloaded from Harvard University’s DASH repository, and is made available under the terms and conditions applicable to Other Posted Material, as set forth at http:// nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of- use#LAA HHS Public Access Author manuscript Author ManuscriptAuthor Manuscript Author Nature. Manuscript Author Author manuscript; Manuscript Author available in PMC 2017 March 14. Published in final edited form as: Nature. 2016 September 22; 537(7621): 508–514. doi:10.1038/nature19356. High-throughput discovery of novel developmental phenotypes A full list of authors and affiliations appears at the end of the article. Abstract Approximately one third of all mammalian genes are essential for life. Phenotypes resulting from mouse knockouts of these genes have provided tremendous insight into gene function and congenital disorders. As part of the International Mouse Phenotyping Consortium effort to generate and phenotypically characterize 5000 knockout mouse lines, we have identified 410 Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms #Corresponding author: [email protected]. -
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]. -
The Box C/D Snornp Assembly Factor Bcd1 Interacts with the Histone
The box C/D snoRNP assembly factor Bcd1 interacts with the histone chaperone Rtt106 and controls its transcription dependent activity Benoît Bragantini, Christophe Charron, Maxime Bourguet, Arnaud Paul, Decebal Tiotiu, Benjamin Rothé, Hélène Marty, Guillaume Terral, Steve Hessmann, Laurence Decourty, et al. To cite this version: Benoît Bragantini, Christophe Charron, Maxime Bourguet, Arnaud Paul, Decebal Tiotiu, et al.. The box C/D snoRNP assembly factor Bcd1 interacts with the histone chaperone Rtt106 and controls its transcription dependent activity. Nature Communications, Nature Publishing Group, 2021, 12 (1), pp.1859. 10.1038/s41467-021-22077-4. hal-03181046 HAL Id: hal-03181046 https://hal.univ-lorraine.fr/hal-03181046 Submitted on 1 Apr 2021 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Distributed under a Creative Commons Attribution| 4.0 International License ARTICLE https://doi.org/10.1038/s41467-021-22077-4 OPEN The box C/D snoRNP assembly factor Bcd1 interacts with the histone chaperone Rtt106 and controls its transcription dependent -
The Complexity of the Epigenome in Cancer and Recent Clinical Advances
Published OnlineFirst August 17, 2012; DOI: 10.1158/1078-0432.CCR-12-2037 Clinical Cancer Molecular Pathways Research Molecular Pathways: The Complexity of the Epigenome in Cancer and Recent Clinical Advances Mariarosaria Conte1 and Lucia Altucci1,2 Abstract Human cancer is causally linked to genomic and epigenomic deregulations. Epigenetic abnormalities occurring within signaling pathways regulating proliferation, migration, growth, differentiation, tran- scription, and death signals may be critical in the progression of malignancies. Consequently, iden- tification of epigenetic marks and their bioimplications in tumors represents a crucial step toward defining new therapeutic strategies both in cancer treatment and prevention. Alterations of writers, readers, and erasers in cancer may affect, for example, the methylation and acetylation state of huge areas of chromatin, suggesting that epi-based treatments may require "distinct" therapeutic strategies com- pared with "canonical" targeted treatments. Whereas anticancer treatments targeting histone deacetylase and DNA methylation have entered the clinic, additional chromatin modification enzymes have not yet been pharmacologically targeted for clinical use in patients. Thus, a greater insight into alterations occurring on chromatin modifiers and their impact in tumorigenesis represents a crucial advance- ment in exploiting epigenetic targeting in cancer prevention and treatment. Here, the interplay of the best known epi-mutations and how their targeting might be optimized are addressed. Clin Cancer Res; 18 (20); 1–9. Ó2012 AACR. Background strategies both in cancer treatment and prevention (2). A number of epigenetic deregulations, such as DNA Alterations of writers, readers, and erasers in cancer may methylation, histone modifications, and microRNA-based affect the status of chromatin in vast areas of the epigenome, modulation, have been progressively reported as causally thus suggesting that epi-based treatments may require "dis- involved in tumorigenesis and progression. -
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. -
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. -
Interspecific Variation in One-Carbon Metabolism Within The
International Journal of Molecular Sciences Article Interspecific Variation in One-Carbon Metabolism within the Ovarian Follicle, Oocyte, and Preimplantation Embryo: Consequences for Epigenetic Programming of DNA Methylation Constance E. Clare 1,†, Valerie Pestinger 1,†, Wing Yee Kwong 1,†, Desmond A. R. Tutt 1, Juan Xu 1,2, Helen M. Byrne 3, David A. Barrett 2, Richard D. Emes 1 and Kevin D. Sinclair 1,* 1 Schools of Biosciences and Veterinary Medicine and Science, University of Nottingham, Sutton Bonington, Leicestershire LE12 5RD, UK; [email protected] (C.E.C.); [email protected] (V.P.); [email protected] (W.Y.K.); [email protected] (D.A.R.T.); [email protected] (J.X.); [email protected] (R.D.E.) 2 Centre for Analytical Bioscience, School of Pharmacy, University of Nottingham, Nottingham NG7 2RD, UK; [email protected] 3 Mathematical Institute, University of Oxford, Woodstock Road, Oxford OX2 6GG, UK; [email protected] * Correspondence: [email protected]; Tel.: +44-0-115-951-6053 † These authors contributed equally to this work. Abstract: One-carbon (1C) metabolism provides methyl groups for the synthesis and/or methylation Citation: Clare, C.E.; Pestinger, V.; Kwong, W.Y.; Tutt, D.A.R.; Xu, J.; of purines and pyrimidines, biogenic amines, proteins, and phospholipids. Our understanding of Byrne, H.M.; Barrett, D.A.; Emes, how 1C pathways operate, however, pertains mostly to the (rat) liver. Here we report that transcripts R.D.; Sinclair, K.D. Interspecific for all bar two genes (i.e., BHMT, MAT1A) encoding enzymes in the linked methionine-folate cycles Variation in One-Carbon Metabolism are expressed in all cell types within the ovarian follicle, oocyte, and blastocyst in the cow, sheep, within the Ovarian Follicle, Oocyte, and pig; as well as in rat granulosa cells (GCs) and human KGN cells (a granulosa-like tumor cell and Preimplantation Embryo: line). -
Mutations in the PKM2 Exon-10 Region Are Associated with Reduced Allostery and Increased Nuclear Translocation
ARTICLE https://doi.org/10.1038/s42003-019-0343-4 OPEN Mutations in the PKM2 exon-10 region are associated with reduced allostery and increased nuclear translocation Tsan-Jan Chen 1, Hung-Jung Wang2, Jai-Shin Liu1, Hsin-Hung Cheng1, Sheng-Chieh Hsu2,3, Meng-Chen Wu1, 1234567890():,; Chien-Hung Lu1, Yu-Fang Wu1, Jing-Wen Wu1, Ying-Yuan Liu1, Hsing-Jien Kung4,5 & Wen-Ching Wang1 PKM2 is a key metabolic enzyme central to glucose metabolism and energy expenditure. Multiple stimuli regulate PKM2’s activity through allosteric modulation and post-translational modifications. Furthermore, PKM2 can partner with KDM8, an oncogenic demethylase and enter the nucleus to serve as a HIF1α co-activator. Yet, the mechanistic basis of the exon-10 region in allosteric regulation and nuclear translocation remains unclear. Here, we determined the crystal structures and kinetic coupling constants of exon-10 tumor-related mutants (H391Y and R399E), showing altered structural plasticity and reduced allostery. Immunoprecipitation analysis revealed increased interaction with KDM8 for H391Y, R399E, and G415R. We also found a higher degree of HIF1α-mediated transactivation activity, particularly in the presence of KDM8. Furthermore, overexpression of PKM2 mutants significantly elevated cell growth and migration. Together, PKM2 exon-10 mutations lead to structure-allostery alterations and increased nuclear functions mediated by KDM8 in breast cancer cells. Targeting the PKM2-KDM8 complex may provide a potential therapeutic intervention. 1 Institute of Molecular and Cellular Biology and Department of Life Science, National Tsing-Hua University, Hsinchu 30013, Taiwan. 2 Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli 35053, Taiwan. -
Design, Synthesis and Biological Evaluation of Small Molecules As Modulators of Histone Methyltransferases and Demethylases
PhD School of Pharmaceutical Sciences XXVI cycle University of Naples “Federico II” DESIGN, SYNTHESIS AND BIOLOGICAL EVALUATION OF SMALL MOLECULES AS MODULATORS OF HISTONE METHYLTRANSFERASES AND DEMETHYLASES Doctoral Candidate: Supervisor: Stefano Tomassi Prof. Ettore Novellino Department of Pharmacy Faculty of Pharmacy University of Naples “Federico II” Supervisors Professor Ettore Novellino Ph.D. (tutor and main supervisor) Department of Pharmacy, University of Naples “Federico II”, Via Domenico Montesano, 49 - 80131 Naples, Italy. Adjunct Professor Antonello Mai Ph.D. (external supervisor) Department of Drug Chemistry and Technology, “Sapienza” University of Rome, P.le Aldo Moro, 5 - 00185 - Rome, Italy. 2 Table of contents 1. INTRODUCTION ................................................................................................. 5 2. EPIGENETIC AND CHROMATIN DYNAMICS ............................................ 8 3. HISTONE METHYLATION ............................................................................. 11 3.1 Protein Arginine Methyltransferases (PRMTs) .......................................... 12 3.2 Histone Lysine Methyltransferases (HKMTs) ............................................ 21 3.2.1 Enhancer of Zeste Homologue 2 (EZH2) .............................................. 27 3.2.2 EZH2 aberrations and cancer ................................................................ 36 3.3 Targeting Histone Arginine and Lysine Methyltransferases .................... 39 4. DESIGN, SYNTHESIS AND BIOLOGICAL EVALUATION OF NOVEL -
H3K36 Methylation Reprograms Gene Expression to Drive Early Gametocyte Development in Plasmodium Falciparum Jessica Connacher1, Gabrielle A
Connacher et al. Epigenetics & Chromatin (2021) 14:19 https://doi.org/10.1186/s13072-021-00393-9 Epigenetics & Chromatin RESEARCH Open Access H3K36 methylation reprograms gene expression to drive early gametocyte development in Plasmodium falciparum Jessica Connacher1, Gabrielle A. Josling2, Lindsey M. Orchard2, Janette Reader1, Manuel Llinás2,3 and Lyn‑Marié Birkholtz1* Abstract Background: The Plasmodium sexual gametocyte stages are the only transmissible form of the malaria parasite and are thus responsible for the continued transmission of the disease. Gametocytes undergo extensive functional and morphological changes from commitment to maturity, directed by an equally extensive control program. However, the processes that drive the diferentiation and development of the gametocyte post‑commitment, remain largely unexplored. A previous study reported enrichment of H3K36 di‑ and tri‑methylated (H3K36me2&3) histones in early‑ stage gametocytes. Using chromatin immunoprecipitation followed by high‑throughput sequencing, we identify a stage‑specifc association between these repressive histone modifcations and transcriptional reprogramming that defne a stage II gametocyte transition point. Results: Here, we show that H3K36me2 and H3K36me3 from stage II gametocytes are associated with repression of genes involved in asexual proliferation and sexual commitment, indicating that H3K36me2&3‑mediated repression of such genes is essential to the transition from early gametocyte diferentiation to intermediate development. Impor‑ tantly, we show that the gene encoding the transcription factor AP2‑G as commitment master regulator is enriched with H3K36me2&3 and actively repressed in stage II gametocytes, providing the frst evidence of ap2-g gene repres‑ sion in post‑commitment gametocytes. Lastly, we associate the enhanced potency of the pan‑selective Jumonji inhibitor JIB‑04 in gametocytes with the inhibition of histone demethylation including H3K36me2&3 and a disruption of normal transcriptional programs. -
New Insights Into the Role of Histone Changes in Aging
International Journal of Molecular Sciences Review New Insights into the Role of Histone Changes in Aging Sun-Ju Yi and Kyunghwan Kim * Department of Biology, School of Biological Sciences, College of Natural Sciences, Chungbuk National University, Cheongju 28644, Chungbuk, Korea; [email protected] * Correspondence: [email protected]; Tel.: +82-(43)-2612292 Received: 14 October 2020; Accepted: 2 November 2020; Published: 3 November 2020 Abstract: Aging is the progressive decline or loss of function at the cellular, tissue, and organismal levels that ultimately leads to death. A number of external and internal factors, including diet, exercise, metabolic dysfunction, genome instability, and epigenetic imbalance, affect the lifespan of an organism. These aging factors regulate transcriptome changes related to the aging process through chromatin remodeling. Many epigenetic regulators, such as histone modification, histone variants, and ATP-dependent chromatin remodeling factors, play roles in chromatin reorganization. The key to understanding the role of gene regulatory networks in aging lies in characterizing the epigenetic regulators responsible for reorganizing and potentiating particular chromatin structures. This review covers epigenetic studies on aging, discusses the impact of epigenetic modifications on gene expression, and provides future directions in this area. Keywords: aging; histone level; histone modification; histone variant; chromatin remodeling; epigenetics 1. Introduction An individual organism undergoes a series of developmental stages, including birth, growth, maturity, aging, and death. Aging is the gradual and continuous decline or loss of function at the cellular, tissue, and organismal levels with the passage of time. Aging is considered to begin in early adulthood, but is regarded as an integral part of life since other stages also affect the aging process [1]. -
JMJD-5/KDM8 Regulates H3k36me2 and Is Required for Late Steps of Homologous Recombination and Genome Integrity
JMJD-5/KDM8 regulates H3K36me2 and is required for late steps of homologous recombination and genome integrity Amendola, Pier Giorgio; Zaghet, Nico; Ramalho, João J; Johansen, Jens Vilstrup; Boxem, Mike; Salcini, Anna Elisabetta Published in: P L o S Genetics DOI: 10.1371/journal.pgen.1006632 Publication date: 2017 Document version Publisher's PDF, also known as Version of record Document license: CC BY Citation for published version (APA): Amendola, P. G., Zaghet, N., Ramalho, J. J., Johansen, J. V., Boxem, M., & Salcini, A. E. (2017). JMJD-5/KDM8 regulates H3K36me2 and is required for late steps of homologous recombination and genome integrity. P L o S Genetics, 13(2), [e1006632]. https://doi.org/10.1371/journal.pgen.1006632 Download date: 29. sep.. 2021 RESEARCH ARTICLE JMJD-5/KDM8 regulates H3K36me2 and is required for late steps of homologous recombination and genome integrity Pier Giorgio Amendola1,2, Nico Zaghet1,2, João J. Ramalho3, Jens Vilstrup Johansen1,2, Mike Boxem3, Anna Elisabetta Salcini1,2* 1 Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark, 2 Centre for Epigenetics, University of Copenhagen, Copenhagen, Denmark, 3 Developmental Biology, Department of Biology, Faculty of Science, Utrecht University, Padualaan 8, CH Utrecht, The Netherlands a1111111111 a1111111111 * [email protected] a1111111111 a1111111111 a1111111111 Abstract The eukaryotic genome is organized in a three-dimensional structure called chromatin, con- stituted by DNA and associated proteins, the majority of which are histones. Post-transla- OPEN ACCESS tional modifications of histone proteins greatly influence chromatin structure and regulate Citation: Amendola PG, Zaghet N, Ramalho JJ, many DNA-based biological processes.