Genome-Wide Profiling of Active Enhancers in Colorectal Cancer
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MOZ and MORF, Two Large Mystic Hats in Normal and Cancer Stem Cells
Oncogene (2007) 26, 5408–5419 & 2007 Nature Publishing Group All rights reserved 0950-9232/07 $30.00 www.nature.com/onc REVIEW MOZ and MORF, two large MYSTic HATs in normal and cancer stem cells X-J Yang and M Ullah Molecular Oncology Group, Department of Medicine, McGill University Health Center, Montre´al, Que´bec, Canada Genes of the human monocytic leukemia zinc-finger protein pattern. For cancer biology, it is thus important to MOZ (HUGO symbol, MYST3) and its paralog MORF understand the fundamental mechanisms whereby chro- (MYST4) are rearranged in chromosome translocations matin structure and function are regulated. In the associated withacute myeloid leukemia and/or benign past two decades, our knowledge about regulation in uterine leiomyomata. Both proteins have intrinsic histone this field has exploded. Known regulatory mechanisms acetyltransferase activity and are components of quartet include chromatin assembly, ATP-dependent remodeling, complexes withnoncatalytic subunits containing thebromo- covalent modification, condensin-mediated condensation, domain, plant homeodomain-linked (PHD) finger and replacement with histone variants, and association of proline-tryptophan-tryptophan-proline (PWWP)-containing noncoding RNA (reviewed by Horn and Peterson, 2002; domain, three types of structural modules characteristic of Khorasanizadeh, 2004; Li et al., 2007). Covalent chromatin regulators. Although leukemia-derived fusion pro- modification can occur at both the DNA and histone teins suchas MOZ-TIF2 promote self-renewal of leukemic levels. With histones, modifications include acetylation, stem cells, recent studies indicate that murine MOZ and phosphorylation, methylation, ubiquitination, and many MORF are important for proper development of hema- others (for reviews, see Spencer and Davie, 1999; Strahl topoietic and neurogenic progenitors, respectively, thereby and Allis, 2000; Berger, 2002; Jason et al., 2002; highlighting the importance of epigenetic integrity in Kouzarides, 2007). -
The Basic Region and Leucine Zipper Transcription Factor Mafk Is a New Nerve Growth Factor-Responsive Immediate Early Gene That Regulates Neurite Outgrowth
The Journal of Neuroscience, October 15, 2002, 22(20):8971–8980 The Basic Region and Leucine Zipper Transcription Factor MafK Is a New Nerve Growth Factor-Responsive Immediate Early Gene That Regulates Neurite Outgrowth Be´ ata To¨ro¨ csik, James M. Angelastro, and Lloyd A. Greene Department of Pathology and Center for Neurobiology and Behavior, Columbia University College of Physicians and Surgeons, New York, New York 10032 We used serial analysis of gene expression to identify new mediated by an atypical isoform of PKC but not by mitogen- NGF-responsive immediate early genes (IEGs) with potential activated kinase kinase, phospholipase C␥, or phosphoinositide roles in neuronal differentiation. Among those identified was 3Ј-kinase. Interference with MafK expression or activity by small MafK, a small Maf family basic region and leucine zipper tran- interfering RNA and dominant negative strategies, respectively, scriptional repressor and coactivator expressed in immature suppresses NGF-promoted outgrowth and maintenance of neu- neurons. NGF treatment elevates the levels of both MafK tran- rites by PC12 cells and neurite outgrowth by immature telence- scripts and protein. In contrast, there is no effect on expression phalic neurons. Our findings support a role for MafK as a novel of the closely related MafG. Unlike many other NGF-responsive regulator of neuronal differentiation. IEGs, MafK regulation shows selectivity and is unresponsive to epidermal growth factor, depolarization, or cAMP derivatives. Key words: MafK; NGF; immediate early -
Recognition of Histone Acetylation by the GAS41 YEATS Domain Promotes H2A.Z Deposition in Non-Small Cell Lung Cancer
Downloaded from genesdev.cshlp.org on October 5, 2021 - Published by Cold Spring Harbor Laboratory Press Recognition of histone acetylation by the GAS41 YEATS domain promotes H2A.Z deposition in non-small cell lung cancer Chih-Chao Hsu,1,2,8 Jiejun Shi,3,8 Chao Yuan,1,2,7,8 Dan Zhao,4,5,8 Shiming Jiang,1,2 Jie Lyu,3 Xiaolu Wang,1,2 Haitao Li,4,5 Hong Wen,1,2 Wei Li,3 and Xiaobing Shi1,2,6 1Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA; 2Center for Cancer Epigenetics, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA; 3Dan L. Duncan Cancer Center, Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA; 4MOE Key Laboratory of Protein Sciences, Beijing Advanced Innovation Center for Structural Biology, Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing 100084, China; 5Tsinghua-Peking Joint Center for Life Sciences, Tsinghua University, Beijing 100084, China; 6Genetics and Epigenetics Graduate Program, The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, Texas 77030, USA Histone acetylation is associated with active transcription in eukaryotic cells. It helps to open up the chromatin by neutralizing the positive charge of histone lysine residues and providing binding platforms for “reader” proteins. The bromodomain (BRD) has long been thought to be the sole protein module that recognizes acetylated histones. Re- cently, we identified the YEATS domain of AF9 (ALL1 fused gene from chromosome 9) as a novel acetyl-lysine- binding module and showed that the ENL (eleven-nineteen leukemia) YEATS domain is an essential acetyl-histone reader in acute myeloid leukemias. -
Human Small Maf Proteins Form Heterodimers with CNC Family Transcription Factors and Recognize the NF-E2 Motif
Oncogene (1997) 14, 1901 ± 1910 1997 Stockton Press All rights reserved 0950 ± 9232/97 $12.00 Human small Maf proteins form heterodimers with CNC family transcription factors and recognize the NF-E2 motif Tsutomu Toki1, Jugou Itoh2, Jun'ichi Kitazawa1, Koji Arai1, Koki Hatakeyama3, Jun-itsu Akasaka4, Kazuhiko Igarashi5, Nobuo Nomura6, Masaru Yokoyama1, Masayuki Yamamoto5 and Etsuro Ito1 1Department of Pediatrics, 2Medicine, School of Medicine; 3Department of Biology, Faculty of Sciences, Hirosaki University, Hirosaki 036; 4Department of Biochemistry, Tohoku University School of Medicine, Sendai 980-77; 5Center for TARA and Institute of Basic Medical Sciences, University of Tsukuba, Tsukuba 305; 6Kazusa DNA Institute, Kisarazu 292, Japan The transcription factor NF-E2, a heterodimeric protein Talbot et al., 1990; Talbot and Grosveld, 1991; complex composed of p45 and small Maf family Kotkow and Orkin, 1995). Recent analyses demon- proteins, is considered crucial for the regulation of strated that NF-E2 is composed of two subunits erythroid gene expression and platelet formation. To (Andrews et al., 1993a,b; Igarashi et al., 1994). The facilitate the characterization of NF-E2 functions in large p45 subunit belongs to a family of basic leucine- human cells, we isolated cDNAs encoding two members zipper (bZip) proteins that is closely related to the of the small Maf family, MafK and MafG. The human Drosophila Cap`n'colar (the CNC family) factor mafK and mafG genes encode proteins of 156 and 162 (Mohler et al., 1991). It cannot bind to the NF-E2 amino acid residues, respectively, whose deduced amino sequence as a homodimer, but does do after forming acid sequences show approximately 95% identity to their heterodimers with chicken small Maf family proteins, respective chicken counterparts. -
Heterogeneous Nuclear Ribonucleoprotein C1 C2, Mecp1
Heterogeneous nuclear ribonucleoprotein C1͞C2, MeCP1, and SWI͞SNF form a chromatin remodeling complex at the -globin locus control region Milind C. Mahajan*, Geeta J. Narlikar†, Gokul Boyapaty*, Robert E. Kingston‡, and Sherman M. Weissman*§ *Department of Genetics, The Anlyan Center, Yale University School of Medicine, New Haven, CT 06511; †Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94143; and ‡Department of Molecular Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114 Contributed by Sherman M. Weissman, August 31, 2005 Locus control regions (LCRs) are regulatory DNA sequences that are promoter (20–23). These studies suggest the possible association situated many kilobases away from their cognate promoters. LCRs of the LCR with specific chromatin remodeling activities, al- protect transgenes from position effect variegation and hetero- though such a LCR-specific chromatin remodeling activity has chromatinization and also promote copy-number dependence of not been isolated. In the present work, we describe the biochem- the levels of transgene expression. In this work, we describe the ical purification and properties of a previously undescribed biochemical purification of a previously undescribed LCR-associ- chromatin-remodeling complex that binds to the human -globin ated remodeling complex (LARC) that consists of heterogeneous LCR HS2 in a sequence-specific manner. nuclear ribonucleoprotein C1͞C2, nucleosome remodeling SWI͞ SNF, and nucleosome remodeling and deacetylating (NuRD)͞ Materials and Methods MeCP1 as a single homogeneous complex. LARC binds to the Cell Culture and Preparation of Nuclear Extracts. Growth of the K562 hypersensitive 2 (HS2)-Maf recognition element (MARE) DNA in a cells and preparation of the nuclear extract is described in ref. -
H3K27 Acetylation and Gene Expression Analysis Reveals Differences in Placental Chromatin Activity in Fetal Growth Restriction N
Paauw et al. Clinical Epigenetics (2018) 10:85 https://doi.org/10.1186/s13148-018-0508-x RESEARCH Open Access H3K27 acetylation and gene expression analysis reveals differences in placental chromatin activity in fetal growth restriction N. D. Paauw1,6*, A. T. Lely1, J. A. Joles2, A. Franx1, P. G. Nikkels3, M. Mokry4 and B. B. van Rijn1,5,6* Abstract Background: Posttranslational modification of histone tails such as histone 3 lysine 27 acetylation (H3K27ac) is tightly coupled to epigenetic regulation of gene expression. To explore whether this is involved in placenta pathology, we probed genome-wide H3K27ac occupancy by chromatin immunoprecipitation sequencing (ChIP- seq) in healthy placentas and placentas from pathological pregnancies with fetal growth restriction (FGR). Furthermore, we related specific acetylation profiles of FGR placentas to gene expression changes. Results: Analysis of H3K27ac occupancy in FGR compared to healthy placentas showed 970 differentially acetylated regions distributed throughout the genome. Principal component analysis and hierarchical clustering revealed complete segregation of the FGR and control group. Next, we identified 569 upregulated genes and 521 downregulated genes in FGR placentas by RNA sequencing. Differential gene transcription largely corresponded to expected direction based on H3K27ac status. Pathway analysis on upregulated transcripts originating from hyperacetylated sites revealed genes related to the HIF-1-alpha transcription factor network and several other genes with known involvement in placental pathology (LEP, FLT1, HK2, ENG, FOS). Downregulated transcripts in the vicinity of hypoacetylated sites were related to the immune system and growth hormone receptor signaling. Additionally, we found enrichment of 141 transcription factor binding motifs within differentially acetylated regions. -
Investigation of KRAS Dependency Bypass and Functional Characterization of All Possible KRAS Missense Variants
Investigation of KRAS Dependency Bypass and Functional Characterization of All Possible KRAS Missense Variants The Harvard community has made this article openly available. Please share how this access benefits you. Your story matters Citable link http://nrs.harvard.edu/urn-3:HUL.InstRepos:40050098 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 Investigation of KRAS Dependency Bypass and Functional Characterization of All Possible KRAS Missense Variants A dissertation presented by Seav Huong Ly to The Division of Medical Sciences in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the subject of Biological and Biomedical Sciences Harvard University Cambridge, Massachusetts April 2018 © 2018 Seav Huong Ly All rights reserved. Dissertation Advisor: William C. Hahn Seav Huong Ly Investigation of KRAS Dependency Bypass and Functional Characterization of All Possible KRAS Missense Variants Abstract The importance of oncogenic KRAS in human cancers have prompted intense efforts to target KRAS and its effectors. To anticipate the development of resistance to these strategies, we previously performed a genome-scale expression screen to identify genes that bypass KRAS oncogenic dependency. Here we test thirty-seven genes that scored over five standard deviations and find that overexpression of LIM homeobox 9 (LHX9), a transcription factor involved in embryonic development, robustly rescues the suppression of KRAS in vitro and xenograft models. Furthermore, LHX9 substantially decreases cell sensitivity to KRASG12C and MEK1/2 inhibitors in KRAS-dependent cells. -
The Chemical Defensome of Five Model Teleost Fish
www.nature.com/scientificreports OPEN The chemical defensome of fve model teleost fsh Marta Eide1,5, Xiaokang Zhang2,3,5, Odd André Karlsen1, Jared V. Goldstone4, John Stegeman4, Inge Jonassen2 & Anders Goksøyr1* How an organism copes with chemicals is largely determined by the genes and proteins that collectively function to defend against, detoxify and eliminate chemical stressors. This integrative network includes receptors and transcription factors, biotransformation enzymes, transporters, antioxidants, and metal- and heat-responsive genes, and is collectively known as the chemical defensome. Teleost fsh is the largest group of vertebrate species and can provide valuable insights into the evolution and functional diversity of defensome genes. We have previously shown that the xenosensing pregnane x receptor (pxr, nr1i2) is lost in many teleost species, including Atlantic cod (Gadus morhua) and three-spined stickleback (Gasterosteus aculeatus), but it is not known if compensatory mechanisms or signaling pathways have evolved in its absence. In this study, we compared the genes comprising the chemical defensome of fve fsh species that span the teleosteii evolutionary branch often used as model species in toxicological studies and environmental monitoring programs: zebrafsh (Danio rerio), medaka (Oryzias latipes), Atlantic killifsh (Fundulus heteroclitus), Atlantic cod, and three-spined stickleback. Genome mining revealed evolved diferences in the number and composition of defensome genes that can have implication for how these species sense and respond to environmental pollutants, but we did not observe any candidates of compensatory mechanisms or pathways in cod and stickleback in the absence of pxr. The results indicate that knowledge regarding the diversity and function of the defensome will be important for toxicological testing and risk assessment studies. -
NF-E2p18/Mafk Is Required in DMSO-Induced Differentiation Of
Leukemia (1997) 11, 273–280 1997 Stockton Press All rights reserved 0887-6924/97 $12.00 NF-E2p18/mafK is required in DMSO-induced differentiation of Friend erythroleukemia cells by enhancing NF-E2 activity C Francastel, V Poindessous-Jazat, Y Augery-Bourget and J Robert-Le´ze´ne`s INSERM U268, Hoˆpital Paul Brousse, 94800 Villejuif, France When Friend murine erythroleukemia (F-MEL) cells are induced (LCR).6 The b-globin complex LCR (b-LCR) include four to differentiate by dimethylsulfoxide (DMSO), erythroid-specific erythroid-specific DNasel hypersensitive sites (designated HS- genes are transcriptionally activated. The erythroid transcrip- 1 to HS-4) and acts as a powerful enhancer of transcription tion factor NF-E2 is essential for enhancer activity of the globin 7,8 locus control regions. NF-E2 functions as a heterocomplex of globin promoters. While all four HS have LCR activity in consisting of a 45-kDa subunit (NF-E2p45) and a 18-kDa sub- transgenic mice, only one region (HS-2) is crucial for unit (NF-E2p18). The larger subunit NF-E2p45 is tissue-restric- enhancer activity when assayed in transient transfection ted and is believed to play a role in globin gene expression in systems.9–11 Within HS-2, the enhancer activity for globin F-MEL cells. The expression of the smaller subunit NF-E2p18, expression requires a tandem repeat of AP-1-like which is a Maf family member (MafK), is cell type- and develop- 12,13 mental stage-specific. We have investigated the possible role elements. This tandem motif was shown to bind two tran- of NF-E2p18 in Friend erythroid differentiation by stably trans- scription factors: the ubiquitous AP-1 protein and the lineage fecting either sense and antisense p18 constructs into differen- limited NF-E2 protein.14,15 The NF-E2 complex is a hetero- tiation-sensitive 745A and partially defective-differentiation dimer of two b-Zip proteins of 45 and 18 kDa.16,17 While NF- TFP10 cell lines. -
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. -
EZH2 in Normal Hematopoiesis and Hematological Malignancies
www.impactjournals.com/oncotarget/ Oncotarget, Vol. 7, No. 3 EZH2 in normal hematopoiesis and hematological malignancies Laurie Herviou2, Giacomo Cavalli2, Guillaume Cartron3,4, Bernard Klein1,2,3 and Jérôme Moreaux1,2,3 1 Department of Biological Hematology, CHU Montpellier, Montpellier, France 2 Institute of Human Genetics, CNRS UPR1142, Montpellier, France 3 University of Montpellier 1, UFR de Médecine, Montpellier, France 4 Department of Clinical Hematology, CHU Montpellier, Montpellier, France Correspondence to: Jérôme Moreaux, email: [email protected] Keywords: hematological malignancies, EZH2, Polycomb complex, therapeutic target Received: August 07, 2015 Accepted: October 14, 2015 Published: October 20, 2015 This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT Enhancer of zeste homolog 2 (EZH2), the catalytic subunit of the Polycomb repressive complex 2, inhibits gene expression through methylation on lysine 27 of histone H3. EZH2 regulates normal hematopoietic stem cell self-renewal and differentiation. EZH2 also controls normal B cell differentiation. EZH2 deregulation has been described in many cancer types including hematological malignancies. Specific small molecules have been recently developed to exploit the oncogenic addiction of tumor cells to EZH2. Their therapeutic potential is currently under evaluation. This review summarizes the roles of EZH2 in normal and pathologic hematological processes and recent advances in the development of EZH2 inhibitors for the personalized treatment of patients with hematological malignancies. PHYSIOLOGICAL FUNCTIONS OF EZH2 state through tri-methylation of lysine 27 on histone H3 (H3K27me3) [6]. -
JDP2, a Novel Molecular Key in Heart Failure and Atrial Fibrillation?
International Journal of Molecular Sciences Review JDP2, a Novel Molecular Key in Heart Failure and Atrial Fibrillation? Gerhild Euler 1,* , Jens Kockskämper 2, Rainer Schulz 1 and Mariana S. Parahuleva 3 1 Institute of Physiology, Justus Liebig University, 35392 Giessen, Germany; [email protected] 2 Biochemical-Pharmacological Centre (BPC) Marburg, Institute of Pharmacology and Clinical Pharmacy, University of Marburg, 35043 Marburg, Germany; [email protected] 3 Internal Medicine/Cardiology and Angiology, University Hospital of Giessen and Marburg, 35033 Marburg, Germany; [email protected] * Correspondence: [email protected]; Tel.: +49-0641-9947246; Fax: +49-0641-9947219 Abstract: Heart failure (HF) and atrial fibrillation (AF) are two major life-threatening diseases worldwide. Causes and mechanisms are incompletely understood, yet current therapies are unable to stop disease progression. In this review, we focus on the contribution of the transcriptional modulator, Jun dimerization protein 2 (JDP2), and on HF and AF development. In recent years, JDP2 has been identified as a potential prognostic marker for HF development after myocardial infarction. This close correlation to the disease development suggests that JDP2 may be involved in initiation and progression of HF as well as in cardiac dysfunction. Although no studies have been done in humans yet, studies on genetically modified mice impressively show involvement of JDP2 in HF and AF, making it an interesting therapeutic target. Citation: Euler, G.; Kockskämper, J.; Keywords: heart failure; atrial fibrillation; transcription factor; remodeling Schulz, R.; Parahuleva, M.S. JDP2, a Novel Molecular Key in Heart Failure and Atrial Fibrillation? Int.