DOCSLIB.ORG

The Histone Methyltransferase SETDB1 Represses Endogenous and Exogenous Retroviruses in B Lymphocytes

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
The Histone Methyltransferase SETDB1 Represses Endogenous and Exogenous Retroviruses in B Lymphocytes The histone methyltransferase SETDB1 represses endogenous and exogenous retroviruses in B lymphocytes Patrick L. Collinsa, Katherine E. Kylea, Takeshi Egawaa, Yoichi Shinkaib, and Eugene M. Oltza,1 aDepartment of Pathology, Washington University School of Medicine, St. Louis, MO 63110; and bCellular Memory Laboratory, RIKEN, Saitama 351-0198, Japan Edited by John V. Moran, University of Michigan, Ann Arbor, MI, and accepted by the Editorial Board May 21, 2015 (received for review November 19, 2014) Genome stability relies on epigenetic mechanisms that enforce tumor viruses (MMTVs). Reintegration of these expressed viruses repression of endogenous retroviruses (ERVs). Current evidence can generate mutations with potential oncogenic consequences suggests that distinct chromatin-based mechanisms repress ERVs (7). Thus, suppression of ERVs via epigenetic mechanisms is es- in cells of embryonic origin (histone methylation dominant) vs. pecially important in adult tissues that harbor cells with a high more differentiated cells (DNA methylation dominant). However, proliferative capacity. the latter aspect of this model has not been tested. Remarkably, Recent studies suggest that the mechanisms of ERV re- and in contrast to the prevailing model, we find that repressive pression in differentiated adult tissues are distinct from those histone methylation catalyzed by the enzyme SETDB1 is critical for in embryonic stem cells (ESCs) or early lineage progenitors (3). In fully differentiated cells, such as fibroblasts, DNA methylation suppression of specific ERV families and exogenous retroviruses in appears to be particularly important for ERV suppression, committed B-lineage cells from adult mice. The profile of ERV whereas HMTs responsible for H3K9me3 are largely dispens- activation in SETDB1-deficient B cells is distinct from that observed able (3, 4). In contrast, ESC and primordial germ cells rely on in corresponding embryonic tissues, despite the loss of repressive H3K9me3 for ERV repression, a process that is independent of chromatin modifications at all ERVs. We provide evidence that, on CpG methylation by DNMTs (8). For LTR-containing ERVs, loss of SETDB1, ERVs are activated in a lineage-specific manner the repressive H3K9me3 modification is mediated by SETDB1, depending on the set of transcription factors available to target which is targeted by its interactions with KAP1 and sequence- proviral regulatory elements. These findings have important im- specific zinc finger proteins (ZFPs). Depletion of either SETDB1 plications for genome stability in somatic cells, as well as the in- or KAP1 activates expression of IAPs, ETns, and other ERV terface between epigenetic repression and viral latency. families in ESCs (4, 9). However, suppression of these ERV families is maintained in differentiated cells lacking KAP1 or epigenetics | histone methylation | repression | transposable elements | SETDB1 (9). Thus, available evidence suggests that KAP1:SETDB1 retroviruses complexes are important for initial repression of ERVs in em- bryonic cells, whereas DNA methylation is critical for their si- lencing in differentiated tissues. However, a definitive test that epressive chromatin is a biochemical platform for many ERV repression is HMT independent in any adult differentiated Rcellular processes (1), including gene silencing during devel- cell types is lacking. Here, we test this model via conditional opment and the suppression of potentially mutagenic repetitive deletion of SETDB1 in developing B lymphocytes. We find that elements, such as endogenous retroviruses (ERVs). The forma- SETDB1 functions as an epigenetic repressor of all ERVs in tion and maintenance of repressive chromatin rely on epigenetic modification of its DNA and nucleosome components, including Significance hypermethylation of CpG dinucleotides by DNA methyltransferases (DNMTs). DNA methylation patterns are conserved during rep- lication, and this modification is thought to provide the most stable Mammalian genomes are replete with silent endogenous ret- roviruses (ERVs). Inappropriate ERV activation in dividing cells is form of repression (1). An important modification for initiating particularly dangerous because it can produce oncogenic muta- repressive chromatin formation is trimethylation of histone H3 at tions via new ERV insertions. Here, we show that endogenous the lysine 9 position (H3K9me3) by two major histone methyl- and exogenous retroviruses are repressed in B lymphocytes from transferases (HMTs). Suppressor Of Variegation 3-9 Homolog adult mice by methylation of histones that package viral DNA (SUV39H)1/2 complexes maintain this modification at constitutive into repressive chromatin. These findings contrast with current GENETICS heterochromatin and most long interspersed nuclear elements models, which posit that histone methylation is dispensable for (LINEs), which together encompass the vast majority of H3K9me3 ERV repression in postembryonic tissues. We also show that ERV in chromatin (2, 3). In contrast, the HMT called SET Domain, activation upon loss of histone methylation relies on specific sets Bifurcated 1 (SETDB1 a.k.a. ESET) is targeted primarily to ERVs, of transcription factors in a given cell type. Our findings uncover which must be silenced to maintain genome and transcriptome new mechanisms of genome stability and viral repression in integrity (4). mammalian cells of adult origin. Long terminal repeat (LTR)-containing ERVs represent ∼10% of human and mouse genomes (5). Although most are defunct Author contributions: P.L.C., Y.S., and E.M.O. designed research; P.L.C., K.E.K., and T.E. genomic artifacts, many species contain a substantial number of performed research; P.L.C. and Y.S. contributed new reagents/analytic tools; P.L.C. and active ERVs (6). In mice, ERV expression is tissue and strain E.M.O. analyzed data; and P.L.C., Y.S., and E.M.O. wrote the paper. specific. The intracisternal A particle (IAP) and early transposon/ The authors declare no conflict of interest. Mus musculus type D (ETn/MusD) families of ERVs are ex- This article is a PNAS Direct Submission. J.V.M. is a guest editor invited by the pressed predominantly in early embyronic tissues. One con- Editorial Board. sequence of this de-repression is the acquisition of spontaneous Data deposition: The data reported in this paper have been deposited in the Gene Ex- germ-line mutations, with IAP and ETn retrotransposition ac- pression Omnibus (GEO) database, www.ncbi.nlm.nih.gov/geo (accession no. GSE69504). counting for nearly 15% of these genomic alterations in mice (5). 1To whom correspondence should be addressed. Email: [email protected]. Likewise, B lymphocytes from leukemia-prone strains activate This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. endogenous murine leukemia viruses (MLVs) or mouse mammary 1073/pnas.1422187112/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1422187112 PNAS | July 7, 2015 | vol. 112 | no. 27 | 8367–8372 Downloaded by guest on September 25, 2021 Δ Δ these lineage-committed cells, but that transcriptional activation pro-B to pre-B transition is not rescued in Setdb1 / animals by of specific ERVs relies on the regulatory architecture of their provision of a preassembled Igh transgene, suggesting that V(D)J LTRs and the availability of corresponding transcription factors. recombination is not the primary defect (Fig. S1D). IgH protein expression facilitates pro-B-cell differentiation by providing both Results proliferative and survival signals. Indeed, previous studies have SETDB1 Is Required for B-Cell Development. An outstanding ques- implicated SETDB1 in viability programs for many cell types, tion is whether HMTs are required to maintain ERV repression either through regulation of P53 or caspases (13, 14). Although Δ/Δ in the more physiologic setting of differentiated cells from an P53 deficiency fails to rescue B-cell development in the Setdb1 adult animal. For this purpose, we selectively removed Setdb1 in background (Fig. S1D), suppression of caspase pathways, via the B-lymphocyte lineage, which offers a well-defined develop- expression of the anti-apoptotic BCL2 protein, restores pro-B mental pathway characterized in great molecular detail. and pre-B-cell compartments, but not those corresponding to Genetic ablation of Setdb1 (Δ/Δ) was achieved by crossing later stages of B-cell development in the bone marrow and mice harboring published conditional alleles (Setdb1 C/C) (4) spleen (Fig. 1A and Fig. S1D). Thus, SETDB1 is essential for with an Mb1-Cre driver (10), which efficiently deletes floxed exons B-cell development beginning at its earliest stages, likely pro- and abrogates SETDB1 protein expression at the earliest stages of viding a prosurvival function. B-cell development (pro-B cells; Fig. S1 A and B). Consistent with Cellular and Molecular Defects in B Lymphocytes Lacking SETDB1. prior findings (4), SETDB1 depletion only modestly reduces Δ/Δ global H3K9me3 levels (Fig. S1B). Despite these modest meth- The rescue of Setdb1 B-cell precursors by BCL2 allowed us ylation defects, SETDB1 deficiency significantly impacts the pro- to examine the molecular and cellular pathways under SETDB1 B-cell compartment and nearly abolishes bone marrow and splenic control. Consistent with the inability of an Igh transgene to rescue the pro-B to pre-B transition, rearrangement of the endogenous B-cell populations corresponding to later stages of development Δ/Δ (Fig. 1A and Fig. S1 C and D). Prior studies,
Load more

Recommended publications
  • Structure of the Tripartite Motif of KAP1/TRIM28 Identifies Molecular Interfaces Required for Transcriptional Silencing of Retrotransposons
    bioRxiv preprint doi: https://doi.org/10.1101/505677; this version posted December 25, 2018. 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. Structure of the tripartite motif of KAP1/TRIM28 identifies molecular interfaces required for transcriptional silencing of retrotransposons Guido A. Stoll1, Shun-ichiro Oda1, Zheng-Shan Chong1, Minmin Yu2, Stephen H. McLaughlin2 and Yorgo Modis1,* 1 Molecular Immunity Unit, Department of Medicine, University of Cambridge, MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Cambridge, CB2 0QH, UK 2 MRC Laboratory oF Molecular Biology, Cambridge Biomedical Campus, Cambridge, CB2 0QH, UK * Correspondence: [email protected] (Y.M.) Abstract Transcription oF transposable elements is tightly regulated to prevent damage to the genome. The family of KRAB domain-containing zinc Finger proteins (KRAB-ZFPs) and KRAB-associated protein 1 (KAP1/TRIM28) play a key role in regulating retrotransposons. KRAB-ZFPs recognize speciFic retrotransposon sequences and recruit KAP1, which controls the assembly of an epigenetic silencing complex including histone H3K9 methyltransferase SETDB1. The chromatin remodeling activities of this complex repress transcription of the targeted transposable element and any adjacent genes. Here, we use biophysical and structural approaches to show that the tripartite motif (TRIM) of KAP1 Forms antiparallel dimers, which Further assemble into tetramers and higher-order oligomers in a concentration-dependent manner. Structure-based mutations in the B-box 1 domain prevented higher-order oligomerization without a signiFicant loss oF retrotransposon silencing activity in a cell-based assay, indicating that, in contrast to other TRIM family members, selF-assembly is not essential For the function of KAP1.
    [Show full text]
  • A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus
    Page 1 of 781 Diabetes A Computational Approach for Defining a Signature of β-Cell Golgi Stress in Diabetes Mellitus Robert N. Bone1,6,7, Olufunmilola Oyebamiji2, Sayali Talware2, Sharmila Selvaraj2, Preethi Krishnan3,6, Farooq Syed1,6,7, Huanmei Wu2, Carmella Evans-Molina 1,3,4,5,6,7,8* Departments of 1Pediatrics, 3Medicine, 4Anatomy, Cell Biology & Physiology, 5Biochemistry & Molecular Biology, the 6Center for Diabetes & Metabolic Diseases, and the 7Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; 2Department of BioHealth Informatics, Indiana University-Purdue University Indianapolis, Indianapolis, IN, 46202; 8Roudebush VA Medical Center, Indianapolis, IN 46202. *Corresponding Author(s): Carmella Evans-Molina, MD, PhD ([email protected]) Indiana University School of Medicine, 635 Barnhill Drive, MS 2031A, Indianapolis, IN 46202, Telephone: (317) 274-4145, Fax (317) 274-4107 Running Title: Golgi Stress Response in Diabetes Word Count: 4358 Number of Figures: 6 Keywords: Golgi apparatus stress, Islets, β cell, Type 1 diabetes, Type 2 diabetes 1 Diabetes Publish Ahead of Print, published online August 20, 2020 Diabetes Page 2 of 781 ABSTRACT The Golgi apparatus (GA) is an important site of insulin processing and granule maturation, but whether GA organelle dysfunction and GA stress are present in the diabetic β-cell has not been tested. We utilized an informatics-based approach to develop a transcriptional signature of β-cell GA stress using existing RNA sequencing and microarray datasets generated using human islets from donors with diabetes and islets where type 1(T1D) and type 2 diabetes (T2D) had been modeled ex vivo. To narrow our results to GA-specific genes, we applied a filter set of 1,030 genes accepted as GA associated.
    [Show full text]
  • A KAP1 Phosphorylation Switch Controls Myod Function During Skeletal Muscle Differentiation
    Downloaded from genesdev.cshlp.org on October 2, 2021 - Published by Cold Spring Harbor Laboratory Press A KAP1 phosphorylation switch controls MyoD function during skeletal muscle differentiation Kulwant Singh,1,5 Marco Cassano,2,5 Evarist Planet,2 Soji Sebastian,1 Suk Min Jang,2 Gurjeev Sohi,1 Herve Faralli,1 Jinmi Choi,3 Hong-Duk Youn,3 F. Jeffrey Dilworth,1,4 and Didier Trono2 1Sprott Center for Stem Cell Research, Ottawa Hospital Research Institute, Ottawa, Ontario K1H 8L6, Canada; 2School of Life Sciences, Ecole Polytechnique Fed erale de Lausanne (EPFL), 1015 Lausanne, Switzerland; 3Department of Biomedical Sciences and Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul 110-799, Korea; 4Department of Cellular and Molecular Medicine, University of Ottawa, Ontario K1H 8L6, Canada The transcriptional activator MyoD serves as a master controller of myogenesis. Often in partnership with Mef2 (myocyte enhancer factor 2), MyoD binds to the promoters of hundreds of muscle genes in proliferating myoblasts yet activates these targets only upon receiving cues that launch differentiation. What regulates this off/on switch of MyoD function has been incompletely understood, although it is known to reflect the action of chromatin modifiers. Here, we identify KAP1 (KRAB [Kruppel-like€ associated box]-associated protein 1)/TRIM28 (tripartite motif protein 28) as a key regulator of MyoD function. In myoblasts, KAP1 is present with MyoD and Mef2 at many muscle genes, where it acts as a scaffold to recruit not only coactivators such as p300 and LSD1 but also corepressors such as G9a and HDAC1 (histone deacetylase 1), with promoter silencing as the net outcome.
    [Show full text]
  • Hippocampal Dysfunction in the Euchromatin Histone Methyltransferase 1 Heterozygous Knockout Mouse Model for Kleefstra Syndrome
    Human Molecular Genetics, 2013, Vol. 22, No. 5 852–866 doi:10.1093/hmg/dds490 Advance Access published on November 21, 2012 Hippocampal dysfunction in the Euchromatin histone methyltransferase 1 heterozygous knockout mouse model for Kleefstra syndrome Monique C.M. Balemans1,2, Nael Nadif Kasri3, Maksym V. Kopanitsa5, Nurudeen O. Afinowi5, Ger Ramakers6, Theo A. Peters4, Andy J. Beynon4, Sanne M. Janssen1, Rik C.J. van Summeren1,2, Jorine M. Eeftens1, Nathalie Eikelenboom1, Marco Benevento3, Makoto Tachibana7, Yoichi Shinkai7, Tjitske Kleefstra1, Hans van Bokhoven1,3,∗,{ and Catharina E.E.M. Van der Zee2,∗,{ 1Department of Human Genetics, 2Department of Cell Biology, Nijmegen Centre for Molecular Life Sciences, 3Department of Cognitive Neurosciences, and 4Department of Otorhinolaryngology, Donders Institute for Brain, Downloaded from Cognition and Behavior, Radboud University, Nijmegen Medical Centre, P.O. Box 9101, 6500 HB Nijmegen, the Netherlands 5Synome Ltd, Moneta Building, Babraham Research Campus, Cambridge CB22 3AT, UK, 6Department of Developmental Psychology, University of Amsterdam, Roetersstraat 15, 1018 WB Amsterdam, the Netherlands and 7Experimental Research Center for Infectious Diseases, Institute for Virus Research, Kyoto, University, 53 Shogoin, http://hmg.oxfordjournals.org/ Kawara-cho, Sakyo-ku, Kyoto, Japan Received October 21, 2012; Revised October 21, 2012; Accepted November 15, 2012 Euchromatin histone methyltransferase 1 (EHMT1) is a highly conserved protein that catalyzes mono- and dimethylation of histone H3 lysine 9, thereby epigenetically regulating transcription. Kleefstra syndrome (KS), is caused by haploinsufficiency of the EHMT1 gene, and is an example of an emerging group of intel- lectual disability (ID) disorders caused by genes encoding epigenetic regulators of neuronal gene activity. by guest on March 24, 2016 Little is known about the mechanisms underlying this disorder, prompting us to study the Euchromatin his- tone methyltransferase 1 heterozygous knockout (Ehmt11/2) mice as a model for KS.
    [Show full text]
  • Functional Dependency Analysis Identifies Potential Druggable
    cancers Article Functional Dependency Analysis Identifies Potential Druggable Targets in Acute Myeloid Leukemia 1, 1, 2 3 Yujia Zhou y , Gregory P. Takacs y , Jatinder K. Lamba , Christopher Vulpe and Christopher R. Cogle 1,* 1 Division of Hematology and Oncology, Department of Medicine, College of Medicine, University of Florida, Gainesville, FL 32610-0278, USA; yzhou1996@ufl.edu (Y.Z.); gtakacs@ufl.edu (G.P.T.) 2 Department of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, Gainesville, FL 32610-0278, USA; [email protected]fl.edu 3 Department of Physiological Sciences, College of Veterinary Medicine, University of Florida, Gainesville, FL 32610-0278, USA; cvulpe@ufl.edu * Correspondence: [email protected]fl.edu; Tel.: +1-(352)-273-7493; Fax: +1-(352)-273-5006 Authors contributed equally. y Received: 3 November 2020; Accepted: 7 December 2020; Published: 10 December 2020 Simple Summary: New drugs are needed for treating acute myeloid leukemia (AML). We analyzed data from genome-edited leukemia cells to identify druggable targets. These targets were necessary for AML cell survival and had favorable binding sites for drug development. Two lists of genes are provided for target validation, drug discovery, and drug development. The deKO list contains gene-targets with existing compounds in development. The disKO list contains gene-targets without existing compounds yet and represent novel targets for drug discovery. Abstract: Refractory disease is a major challenge in treating patients with acute myeloid leukemia (AML). Whereas the armamentarium has expanded in the past few years for treating AML, long-term survival outcomes have yet to be proven. To further expand the arsenal for treating AML, we searched for druggable gene targets in AML by analyzing screening data from a lentiviral-based genome-wide pooled CRISPR-Cas9 library and gene knockout (KO) dependency scores in 15 AML cell lines (HEL, MV411, OCIAML2, THP1, NOMO1, EOL1, KASUMI1, NB4, OCIAML3, MOLM13, TF1, U937, F36P, AML193, P31FUJ).
    [Show full text]
  • Network Inference Analysis Identifies SETDB1 As a Key Regulator for Reverting Colorectal Cancer Cells Into Differentiated Normal-Like Cells
    MOLECULAR CANCER RESEARCH | NEW HORIZONS IN CANCER BIOLOGY Network Inference Analysis Identifies SETDB1 as a Key Regulator for Reverting Colorectal Cancer Cells into Differentiated Normal-Like Cells Soobeom Lee1, Chansu Lee2, Chae Young Hwang1, Dongsan Kim1, Younghyun Han1, Sung Noh Hong2, Seok-Hyung Kim3, and Kwang-Hyun Cho1 ABSTRACT ◥ Cancer cells exhibit properties of cells in a less differentiated state methyltransferase, hinders the function of the identified TFs. than the adjacent normal cells in the tissue. We explored whether SETDB1 depletion effectively converts stem-like colorectal cancer cancer cells can be converted to a differentiated normal-like state by cells into postmitotic cells and restores normal morphology in restoring the gene regulatory network (GRN) of normal cells. Here, patient-derived colorectal cancer organoids. RNA-sequencing anal- we report that colorectal cancer cells exhibit a range of develop- yses revealed that SETDB1 depletion recapitulates global gene mental states from embryonic and intestinal stem-like cells to expression profiles of normal differentiated cells by restoring the differentiated normal-like cells. To identify the transcription factors transcriptional activity of core TFs on their target genes. (TF) that commit stem-like colorectal cancer cells into a differen- tiated normal-like state, we reconstructed GRNs of normal colon Implications: Our study provides insights into the molecular mucosa and identified core TFs (CDX2, ELF3, HNF4G, PPARG, regulatory mechanism underlying the developmental hierarchy of and VDR) that govern the cellular state. We further found that SET colorectal cancer and suggests that induction of a postmitotic state Domain Bifurcated 1 (SETDB1), a histone H3 lysine 9–specific may be a therapeutic alternative to destruction of cancer cells.
    [Show full text]
  • SETDB1 Regulates Microtubule Dynamics
    bioRxiv preprint doi: https://doi.org/10.1101/2021.05.15.444210; this version posted May 16, 2021. 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-ND 4.0 International license. SETDB1 regulates microtubule dynamics Rosari Hernandez-Vicens1, Nomi Pernicone1,2, Tamar Listovsky1,2 and Gabi Gerlitz1,* 1 Department of Molecular Biology, Faculty of Life Sciences and Ariel Center for Applied Cancer Research, Ariel University, Ariel 40700, Israel. 2 Adelson School of Medicine, Ariel University, Ariel 40700, Israel *Correspondence to: Department of Molecular Biology, Faculty of Natural Sciences, Ariel University, Kiryat Hamada, Ariel 40700, Israel. E-mail addresses: [email protected] bioRxiv preprint doi: https://doi.org/10.1101/2021.05.15.444210; this version posted May 16, 2021. 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-ND 4.0 International license. Summary SETDB1 is a methyltransferase responsible for the methylation of histone H3-lysine-9, which is mainly related to heterochromatin formation. SETDB1 is overexpressed in various cancer types and is associated with an aggressive phenotype. In agreement with its activity, it mainly exhibits a nuclear localization; however, in several cell types a cytoplasmic localization was reported. Here we show that a substantial cytoplasmic pool of SETDB1 is colocalized with microtubules.
    [Show full text]
  • Fetal Alcohol Spectrum Disorder (FASD) Associated Neural Defects: Complex Mechanisms and Potential Therapeutic Targets
    Brain Sci. 2013, 3, 964-991; doi:10.3390/brainsci3020964 OPEN ACCESS brain sciences ISSN 2076-3425 www.mdpi.com/journal/brainsci/ Review Fetal Alcohol Spectrum Disorder (FASD) Associated Neural Defects: Complex Mechanisms and Potential Therapeutic Targets Pooja Muralidharan 1,†, Swapnalee Sarmah 1,†, Feng C. Zhou 2 and James A. Marrs 1,* 1 Department of Biology, Indiana University-Purdue University Indianapolis, Indianapolis, IN 46202, USA; E-Mails: [email protected] (P.M.); [email protected] (S.S.) 2 Department of Anatomy and Cell Biology, Stark Neuroscience Research Institute, Indiana University School of Medicine, Indianapolis, IN 46202, USA; E-Mail: [email protected] † These authors contributed equally to this work. * Author to whom correspondence should be addressed; E-Mail: [email protected]; Tel.: +1-317-278-0031; Fax: +1-317-274-2846. Received: 1 April 2013; in revised form: 3 June 2013 / Accepted: 4 June 2013 / Published: 19 June 2013 Abstract: Fetal alcohol spectrum disorder (FASD), caused by prenatal alcohol exposure, can result in craniofacial dysmorphism, cognitive impairment, sensory and motor disabilities among other defects. FASD incidences are as high as 2% to 5 % children born in the US, and prevalence is higher in low socioeconomic populations. Despite various mechanisms being proposed to explain the etiology of FASD, the molecular targets of ethanol toxicity during development are unknown. Proposed mechanisms include cell death, cell signaling defects and gene expression changes. More recently, the involvement of several other molecular pathways was explored, including non-coding RNA, epigenetic changes and specific vitamin deficiencies. These various pathways may interact, producing a wide spectrum of consequences.
    [Show full text]
  • Discovery of Potential Epigenetic Inhibitors Against Histone Methyltransferases Through Molecular Docking and Molecular Dynamics Simulations
    bioRxiv preprint doi: https://doi.org/10.1101/2020.04.13.040030; this version posted April 14, 2020. 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. Discovery of potential epigenetic inhibitors against histone methyltransferases through molecular docking and molecular dynamics simulations Tirumalasetty Muni Chandra Babua,#, Zaiping Zhangb,#, Danian Qina,*, Chengyang Huanga,b,c,* a Department of Physiology, Shantou University Medical College, Shantou 515041, China b Center for Neurobiology, Shantou University Medical College, Shantou 515041, China c Department of Biological Chemistry, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles California (UCLA) 90095, USA. # Equal contribution, T.M.C.B. and Z.P.Z. contributed equally in this work. *Corresponding author: Danian Qin ([email protected]) and Chengyang Huang ([email protected]) bioRxiv preprint doi: https://doi.org/10.1101/2020.04.13.040030; this version posted April 14, 2020. 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. Abstract Histone methyltransferases (HMTases) catalyze histone methylations that are the important epigenetic marks regulating gene expression, cell fate, and disease progression. In this study, we investigated potential epigenetic inhibitors against HMTases through in silico approaches, including ensembled molecular docking and molecular dynamics simulations (MDS).We identified three candidate compounds, including echinomycin, emetine, and streptonigrin, which showed interactions with HMTases. Echinomycin showed similar binding affinity with H3K4-HMTase NSD3 and H3K9-HMTase SETDB1 but streptonigrin and emetine had preferential binding affinity with NSD3 and SETDB1, respectively.
    [Show full text]
  • STAT3 Targets Suggest Mechanisms of Aggressive Tumorigenesis in Diffuse Large B Cell Lymphoma
    STAT3 Targets Suggest Mechanisms of Aggressive Tumorigenesis in Diffuse Large B Cell Lymphoma Jennifer Hardee*,§, Zhengqing Ouyang*,1,2,3, Yuping Zhang*,4 , Anshul Kundaje*,†, Philippe Lacroute*, Michael Snyder*,5 *Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305; §Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, CT 06520; and †Department of Computer Science, Stanford University School of Engineering, Stanford, CA 94305 1The Jackson Laboratory for Genomic Medicine, Farmington, CT 06030 2Department of Biomedical Engineering, University of Connecticut, Storrs, CT 06269 3Department of Genetics and Developmental Biology, University of Connecticut Health Center, Farmington, CT 06030 4Department of Biostatistics, Yale School of Public Health, Yale University, New Haven, CT 06520 5Corresponding author: Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305. Email: [email protected] DOI: 10.1534/g3.113.007674 Figure S1 STAT3 immunoblotting and immunoprecipitation with sc-482. Western blot and IPs show a band consistent with expected size (88 kDa) of STAT3. (A) Western blot using antibody sc-482 versus nuclear lysates. Lanes contain (from left to right) lysate from K562 cells, GM12878 cells, HeLa S3 cells, and HepG2 cells. (B) IP of STAT3 using sc-482 in HeLa S3 cells. Lane 1: input nuclear lysate; lane 2: unbound material from IP with sc-482; lane 3: material IP’d with sc-482; lane 4: material IP’d using control rabbit IgG. Arrow indicates the band of interest. (C) IP of STAT3 using sc-482 in K562 cells. Lane 1: input nuclear lysate; lane 2: material IP’d using control rabbit IgG; lane 3: material IP’d with sc-482.
    [Show full text]
  • Histone Methyltransferase SETDB1 Promotes Cells Proliferation And
    Zhang et al. BMC Cancer (2018) 18:539 https://doi.org/10.1186/s12885-018-4464-9 RESEARCH ARTICLE Open Access Histone methyltransferase SETDB1 promotes cells proliferation and migration by interacting withTiam1 in hepatocellular carcinoma Yuqin Zhang†, Jing Huang†, Qisheng Li, Keli Chen, Yonghao Liang, Zetao Zhan, Feng Ye, Wen Ni, Longhua Chen* and Yi Ding* Abstract Background: SETDB1 is a histone H3K9 methyltransferase, which plays a significant role in the occurrence and progression of tumors. Previous studies have confirmed that T-lymphom invasion and metastasis gene (Tiam1) is a protein associated with the metastasis of hepatocellular carcinoma (HCC); however, we have not yet been successful in elucidating the specific mechanism of HCC. Methods: Yeast two-hybrid test was conducted to screen proteins that interacted with Tiam1 gene. Glutathione-S-transferase (GST) pull-down and crosslinking-immunoprecipitation (CLIP) assays were performed to determine whether SETDB1 can interact with Tiam1 gene. A series of related experiments were performed to explore role of SETDB1 on cell proliferation, migration, and invasion in HCC. Recovery experiment was performedtoinvestigatetheeffectofTiam1knockdownoncellproliferationandmigration,whichwas caused by SETDB1 overexpression in HCC cells. The expression of SETDB1 was frequently upregulated in HCC tissues and positively correlated with Tiam1. Results: GST pull-down and CLIP assays were performed to elucidate the interaction between SETDB1 and Tiam1. Cell proliferation, migration, and epithelial mesenchymal transformation (EMT) in HCC cells was promoted with the overexpression of SETDB1. Following the knockdown of Tiam1 gene, the effect of SETDB1 on cell proliferation and migration was reversed in HCC cells. The expression of SETDB1 was frequently up-regulated in HCC tissues, and it was positively correlated with Tiam1 gene.
    [Show full text]
  • A Mutation in the Tuft Mouse Disrupts TET1 Activity and Alters the Expression of Genes That Are Crucial for Neural Tube Closure Keith S
    © 2016. Published by The Company of Biologists Ltd | Disease Models & Mechanisms (2016) 9, 585-596 doi:10.1242/dmm.024109 RESEARCH ARTICLE A mutation in the tuft mouse disrupts TET1 activity and alters the expression of genes that are crucial for neural tube closure Keith S. K. Fong1,*, Robert B. Hufnagel2,3, Vedbar S. Khadka4, Michael J. Corley5, Alika K. Maunakea5, Ben Fogelgren1, Zubair M. Ahmed2,6 and Scott Lozanoff1 ABSTRACT INTRODUCTION Genetic variations affecting neural tube closure along the head result Neural tube defects (NTDs), such as anencephaly, encephalocele in malformations of the face and brain. Neural tube defects (NTDs) and spina bifida, are among the most common birth defects in are among the most common birth defects in humans. We previously humans, with estimates of over 2650 annual cases in the United reported a mouse mutant called tuft that arose spontaneously in our States (Centers for Disease Control; www.cdc.gov). Despite wild-type 3H1 colony. Adult tuft mice present midline craniofacial significant reductions, largely owing to prenatal supplementation malformations with or without an anterior cephalocele. In addition, of folic acid (FA) over the past 18 years in the United States affected embryos presented neural tube closure defects resulting in (mandatory fortification authorized in 1996, but not fully insufficient closure of the anterior neuropore or exencephaly. Here, implemented until 1998), NTDs remain among the most common through whole-genome sequencing, we identified a nonsense serious birth defect. Furthermore, we still do not understand how FA mutation in the Tet1 gene, which encodes a methylcytosine prevents NTDs (reviewed in Copp et al., 2013).
    [Show full text]