DOCSLIB.ORG

Autism and Cancer Share Risk Genes, Pathways, and Drug Targets

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Autism and Cancer Share Risk Genes, Pathways, and Drug Targets TIGS 1255 No. of Pages 8 Forum Table 1 summarizes the characteristics of unclear whether this is related to its signal- Autism and Cancer risk genes for ASD that are also risk genes ing function or a consequence of a second for cancers, extending the original finding independent PTEN activity, but this dual Share Risk Genes, that the PI3K-Akt-mTOR signaling axis function may provide the rationale for the (involving PTEN, FMR1, NF1, TSC1, and dominant role of PTEN in cancer and Pathways, and Drug TSC2) was associated with inherited risk autism. Other genes encoding common Targets for both cancer and ASD [6–9]. Recent tumor signaling pathways include MET8[1_TD$IF],[2_TD$IF] genome-wide exome-sequencing studies PTK7, and HRAS, while p53, AKT, mTOR, Jacqueline N. Crawley,1,2,* of de novo variants in ASD and cancer WNT, NOTCH, and MAPK are compo- Wolf-Dietrich Heyer,3,4 and have begun to uncover considerable addi- nents of signaling pathways regulating Janine M. LaSalle1,4,5 tional overlap. What is surprising about the the nuclear factors described above. genes in Table 1 is not necessarily the Autism is a neurodevelopmental number of risk genes found in both autism Autism is comorbid with several mono- and cancer, but the shared functions of genic neurodevelopmental disorders, disorder, diagnosed behaviorally genes in chromatin remodeling and including Fragile X (FMR1), Rett syndrome by social and communication genome maintenance, transcription fac- (MECP2), Phelan-McDermid (SHANK3), fi de cits, repetitive behaviors, tors, and signal transduction pathways 15q duplication syndrome (UBE3A), and restricted interests. Recent leading to nuclear changes [7,8]. Chroma- neurofibromatosis (NF1), tuberous sclero- genome-wide exome sequencing tin remodeling factors important in altering sis (TSC1 and TSC2), and Cornelia de has revealed extensive overlap in nucleosome accessibility for transcription Lange syndrome (NIPBL and SMC1A) risk genes for autism and for can- and genome maintenance mechanisms (Table 1). Neurofibromatosis and tuberous cer. Understanding the genetic include CHD8, CHD7, CHD2, ARID1B, sclerosis are directly associated with commonalities of autism(s) and and ATRX. ATRX may exert a more spe- tumors, but such tumors are benign and cancer(s), with a focus on mecha- cific function in telomere maintenance, rarely associated, if at all, with malignan- nistic pathways, could lead to analogous to other Swi2/Snf2 family fac- cies. However, mutations in NF1, TSC1, repurposed therapeutics. tors, such as ERCC6, RAD54, HTLF, or TSC2 enhance the risk for developing SHPRH,orRAD16, which function in ded- cancer [6]. Notably, NF1, TSC1, and icated DNA repair pathways. Proteins TSC2 function like PTEN in the AKT path- Autism is a neurodevelopmental disor- involved in histone methyltransferase way of mTOR control. Mutations in tran- der, diagnosed by behavioral symptoms reactions important in setting the histone scriptional factor genes also mediate including impaired social interactions and code include ASHL1, EHMT1, EHMT2, downstream signaling pathways that communication, repetitive behaviors, and KMT2C, KMT2D, and SUV420H1. include key proteins implicated in cell pro- restricted interests [1]. Extraordinarily PHF2, KDM5B, and KDM6B are histone liferation or differentiation pathways impli- high heritability for autism spectrum dis- demethylases, and MACROD2 encodes a cated in cancer and autism, such as order (ASD) has been detected in twin nuclear factor regulated by a metabolite of mTOR, RAS GTPases, MAP kinases, studies, with a range of 50–90% concor- histone deacetylation. Ubiquitin modifica- AKT, EIF4E, WNT, ERK, PI3K, and dance between monozygotic twins, tions to histones and other proteins are CHD8. A risk gene originally identified in compared with 0–30% between dizy- implicated by the risk genes CUL3, individuals with cancer may present as a gotic twins and siblings, and approxi- HERC2, MIB1, TBL1XR1, TRIP12, de novo mutation in a small number of mately 1% prevalence in the general UBE3A, and WAC. Transcription factors individuals with ASD, or may be implicated population, along with a high male:female genetically implicated in both autism and in ASD through interactome analysis of ratio [2]. International consortia searching cancer include ADNP, PAX5, FOXP1, interrelated genes and interacting pro- for the genetic causes of ASD quickly TCF7L2, and TBLXR1. Interestingly, these teins, such as within a signaling pathway recognized that autism is not a mono- nuclear factors are downstream of several (Table 1). genic disorder. Hundreds of de novo key signal transduction pathways also and familial risk genes, copy number var- genetically implicated in ASD and cancer, What does tumor cell proliferation have in iants, and epigenetic modifiers have been including PTEN [7].PTENfunctions in the common with brain development and identified through linkage analysis, AKT signaling pathway, where its phospha- neuronal synapse formation? Similar to genome wide-association studies, and tase activity is needed for AKT downregu- cancers, ‘autisms’ are best conceptual- exon and whole-genome sequencing of lation. Nuclear PTEN also regulates ized in the plural. ASD encompasses a individuals with ASD over the past 2 years recombinational DNA repair, a key genome broad range of putative causes, symptom [2–5]. maintenance pathway (see below). It is presentations, and outcomes, including Trends in Genetics, Month Year, Vol. xx, No. yy 1 2 TIGS 1255 No. of Pages 8 Trends in Genetics, Month Year, Vol. xx, No. yy Table 1. Characteristics of Risk Genes Implicated in Both Autism and Cancer[3_TD$IF] a Gene Symbol Gene Name[5_TD$IF] Human Protein Function Interacting Autism-Related Neu- Cancer Susceptibility Refs (PMID) Chromosome Proteins rodevelopmental or Pathway Location Syndrome ADNP Activity-dependent 20q13.13 Potential transcription factor. May SMARCA4, Helsmoortel-Van[6_TD$IF] der p53, WNT 25891009 neuroprotector mediate some neuroprotective SMARCC2, Aa syndrome homeobox peptide VIP-associated effects ARID1A ANK2 Ankyrin 2, Neuronal 4q25 Attaches integral membrane DMD, DCTN4, Long Proteoglycans 25863124 proteins to cytoskeletal elements ACTF1 (Electrocardiographic) and regulates cell motility, QT Syndrome 4 activation, proliferation, and contact ARID1B AT Rich Interacting 6q25.3 Subunit of SWI/SNF chromatin ARID1A, Coffin[7_TD$IF]–Siris syndrome ESR1, WNT; prostate 25891009 Domain 1B (SWI1- remodeling complex SMARCA2, cancer like), BRG1-Binding RELB, SMAD9, protein ASF1A ASH1L Lysine 1q22 Histone methyltransferase SMAD7, Autism, susceptibility Lysine degradation 26402605 N-Methyltransferase specifically methylating Lys-36 of HIST1H3A 2H histone H3 (H3K36me) ATRX RAD54, Alpha Xq21.1 SWI/SNF ATP-dependent DNA CBX5, DAXX, Alpha-thalassemia/ Breast cancer, 24779060 Thalassemia/Mental motor protein that acts in HDAC1, mental retardation telomeres Retardation heterochromatin and at[8_TD$IF] telomeres SMC1A, SMC3 syndrome Syndrome X-linked CHD2 Chromodomain 15q26.1 SWI/SNF ATP-dependent DNA SUMO1, PARK7 Epileptic Chromatin regulation 25891009 Helicase DNA motor protein that acts as a encephalopathy, Binding Protein 2, chromatin remodeling factor and childhood-onset ATP-dependent transcriptional regulator, and also helicase in DNA repair CHD7 Chromodomain 8q12.2 SWI/SNF ATP-dependent DNA CHD8, PBRM1, CHARGE syndrome WNT signaling, 24768552 Helicase DNA motor protein that acts as a SMARCC1, chromatin regulation Binding Protein 7, chromatin remodeling factor and SMARCC2, ATP-dependent transcriptional regulator SMARCE1 helicase CHD8 Chromodomain 14q11.2 SWI/SNF ATP-dependent DNA RBBP5, WDR5, Autism, susceptibility WNT signaling, 25891009 Helicase DNA motor protein that acts as a CTNNB1, USF1, chromatin regulation Binding Protein 8, chromatin remodeling factor and CTCF HELSNF1, AUTS18 transcriptional regulator CUL3 Cullin 3 2q36.2 Core component of multiple cullin- KLHL3, NEDD8, Autism, susceptibility WNT signaling, 25363768 RING-based BCR (BTB-CUL3- KEAP1, RBX1, chromatin regulation RBX1) E3 ubiquitin–protein ligase CASP8 complex DNMT3A DNA (5-cytosine)- 2p23.3 Required for genome-wide de DNMT3L, Autism, susceptibility Chromatin regulation 26402605 methyltransferase novo methylation; essential for DNMT3B, 3A establishment of DNA methylation UHRF1 patterns during development Table 1. (continued) TIGS 1255 No. of Pages 8 Gene Symbol Gene Name[5_TD$IF] Human Protein Function Interacting Autism-Related Neu- Cancer Susceptibility Refs (PMID) Chromosome Proteins rodevelopmental or Pathway Location Syndrome DYRK1A Dual-specificity 21q22.13 Serine/threonine kinase implicated HIPK2, SFN, Down syndrome, NOTCH signaling, 17583556 tyrosine in cell survival, proliferation, and YWHAB, mental retardation, translation regulation phosphorylation- differentiation YWHAE, DCAF autosomal dominant 7 regulated kinase 1A EHMT1 Euchromatic 9q34.3 Histone methyltransferase of MDM2, p53, Kleefstra syndrome Cellular senescence, 24779060 Histone-Lysine H3K9me and H3K9me2 in SUV39H1, NOTCH, lysine N- euchromatin HIST1H3A, degradation Methyltransferase, CTBP1, KMT1D, CLP SUV39H1 ERBB2IP ERBB2 Interacting 5q12.3 Acts as adapter for ERBB2 ERBB2, SMAD2, Autism, susceptibility TGFb signaling, cervical 26402605 protein receptor, inhibits NOD2- SMAD3, NRG2, and colon cancer dependent NF-k-B signaling and PKP4 proinflammatory cytokine secretion ERCC6 Cockayne's 10q11.23 SWI/SNF ATP-dependent DNA Cockayne's High confidence ASD Transcription-coupled 24768552 Syndrome B motor protein that acts in Syndrome-A/ candidate
Load more

Recommended publications
  • Aberrant Methylation Underlies Insulin Gene Expression in Human Insulinoma
    ARTICLE https://doi.org/10.1038/s41467-020-18839-1 OPEN Aberrant methylation underlies insulin gene expression in human insulinoma Esra Karakose1,6, Huan Wang 2,6, William Inabnet1, Rajesh V. Thakker 3, Steven Libutti4, Gustavo Fernandez-Ranvier 1, Hyunsuk Suh1, Mark Stevenson 3, Yayoi Kinoshita1, Michael Donovan1, Yevgeniy Antipin1,2, Yan Li5, Xiaoxiao Liu 5, Fulai Jin 5, Peng Wang 1, Andrew Uzilov 1,2, ✉ Carmen Argmann 1, Eric E. Schadt 1,2, Andrew F. Stewart 1,7 , Donald K. Scott 1,7 & Luca Lambertini 1,6 1234567890():,; Human insulinomas are rare, benign, slowly proliferating, insulin-producing beta cell tumors that provide a molecular “recipe” or “roadmap” for pathways that control human beta cell regeneration. An earlier study revealed abnormal methylation in the imprinted p15.5-p15.4 region of chromosome 11, known to be abnormally methylated in another disorder of expanded beta cell mass and function: the focal variant of congenital hyperinsulinism. Here, we compare deep DNA methylome sequencing on 19 human insulinomas, and five sets of normal beta cells. We find a remarkably consistent, abnormal methylation pattern in insu- linomas. The findings suggest that abnormal insulin (INS) promoter methylation and altered transcription factor expression create alternative drivers of INS expression, replacing cano- nical PDX1-driven beta cell specification with a pathological, looping, distal enhancer-based form of transcriptional regulation. Finally, NFaT transcription factors, rather than the cano- nical PDX1 enhancer complex, are predicted to drive INS transactivation. 1 From the Diabetes Obesity and Metabolism Institute, The Department of Surgery, The Department of Pathology, The Department of Genetics and Genomics Sciences and The Institute for Genomics and Multiscale Biology, The Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
    [Show full text]
  • Nucleoporin 107, 62 and 153 Mediate Kcnq1ot1 Imprinted Domain Regulation in Extraembryonic Endoderm Stem Cells
    ARTICLE DOI: 10.1038/s41467-018-05208-2 OPEN Nucleoporin 107, 62 and 153 mediate Kcnq1ot1 imprinted domain regulation in extraembryonic endoderm stem cells Saqib S. Sachani 1,2,3,4, Lauren S. Landschoot1,2, Liyue Zhang1,2, Carlee R. White1,2, William A. MacDonald3,4, Michael C. Golding 5 & Mellissa R.W. Mann 3,4 1234567890():,; Genomic imprinting is a phenomenon that restricts transcription to predominantly one par- ental allele. How this transcriptional duality is regulated is poorly understood. Here we perform an RNA interference screen for epigenetic factors involved in paternal allelic silen- cing at the Kcnq1ot1 imprinted domain in mouse extraembryonic endoderm stem cells. Multiple factors are identified, including nucleoporin 107 (NUP107). To determine NUP107’s role and specificity in Kcnq1ot1 imprinted domain regulation, we deplete Nup107, as well as Nup62, Nup98/96 and Nup153. Nup107, Nup62 and Nup153, but not Nup98/96 depletion, reduce Kcnq1ot1 noncoding RNA volume, displace the Kcnq1ot1 domain from the nuclear periphery, reactivate a subset of normally silent paternal alleles in the domain, alter histone modifications with concomitant changes in KMT2A, EZH2 and EHMT2 occupancy, as well as reduce cohesin interactions at the Kcnq1ot1 imprinting control region. Our results establish an important role for specific nucleoporins in mediating Kcnq1ot1 imprinted domain regulation. 1 Departments of Obstetrics & Gynaecology, and Biochemistry, Western University, Schulich School of Medicine and Dentistry, London, ON N6A 5W9, Canada. 2 Children’s Health Research Institute, London, ON N6C 2V5, Canada. 3 Departments of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA. 4 Magee-Womens Research Institute, Pittsburgh, PA 15213, USA.
    [Show full text]
  • Integrase Interactor 1 (INI-1) Deficient Renal Cell Carcinoma
    Open Access Case Report DOI: 10.7759/cureus.13082 Integrase Interactor 1 (INI-1) Deficient Renal Cell Carcinoma Manpreet Singh 1 , Harkirat Singh 1 , Benjamin Hambro 1 , Jasleen Kaur 1 , Ravi Rao 2 1. Internal Medicine, St Agnes Medical Center, Fresno, USA 2. Hematology and Oncology, St Agnes Medical Center, Fresno, USA Corresponding author: Manpreet Singh, [email protected] Abstract Members of the SWItch/sucrose nonfermentable (SWI-SNF) family, including SWI/SNF related, matrix- associated, actin-dependent regulator of chromatin, subfamily A, member 4 (SMARCA4), SWI/SNF related, matrix‐associated, actin‐dependent regulator of chromatin, subfamily B member 1 (SMARCB1)/integrase interactor 1 (INI-1) are known tumor suppressor genes. Interactions between SMARCB1/INI-1 and key protein components in various cellular pathways are related to tumor progression and proliferation. SMARCB1/INI-1 protein was undetectable in rhabdoid tumor cells, whereas non-tumorous cells express the SMARCB1/INI-1 genes. Germline and sporadic mutations of several genes encoding for proteins in this complex are known to cause a spectrum of cancers, usually with sarcomatoid features which include a very aggressive renal medullary carcinoma. We report a case of a 29-year-old male who presented with SMARCA4 deficient renal tumor with a very aggressive clinical behavior which ultimately led to his death. Categories: Nephrology, Oncology Keywords: renal medullary carcinoma, ini-1, renal cell carcinoma, swi/snf, smarcb1, integrase interactor 1 Introduction Renal medullary carcinoma is a rare and very aggressive malignancy affecting young adults with rare cases in patients with sickle cell disease or trait [1]. The tumor arises predominantly in the renal medulla and exhibits a variety of growth patterns including reticular, solid, tubular, trabecular, cribriform, sarcomatoid, and micropapillary [1].
    [Show full text]
  • Molecular Profile of Tumor-Specific CD8+ T Cell Hypofunction in a Transplantable Murine Cancer Model
    Downloaded from http://www.jimmunol.org/ by guest on September 25, 2021 T + is online at: average * The Journal of Immunology , 34 of which you can access for free at: 2016; 197:1477-1488; Prepublished online 1 July from submission to initial decision 4 weeks from acceptance to publication 2016; doi: 10.4049/jimmunol.1600589 http://www.jimmunol.org/content/197/4/1477 Molecular Profile of Tumor-Specific CD8 Cell Hypofunction in a Transplantable Murine Cancer Model Katherine A. Waugh, Sonia M. Leach, Brandon L. Moore, Tullia C. Bruno, Jonathan D. Buhrman and Jill E. Slansky J Immunol cites 95 articles Submit online. Every submission reviewed by practicing scientists ? is published twice each month by Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts http://jimmunol.org/subscription Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html http://www.jimmunol.org/content/suppl/2016/07/01/jimmunol.160058 9.DCSupplemental This article http://www.jimmunol.org/content/197/4/1477.full#ref-list-1 Information about subscribing to The JI No Triage! Fast Publication! Rapid Reviews! 30 days* Why • • • Material References Permissions Email Alerts Subscription Supplementary The Journal of Immunology The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2016 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. This information is current as of September 25, 2021. The Journal of Immunology Molecular Profile of Tumor-Specific CD8+ T Cell Hypofunction in a Transplantable Murine Cancer Model Katherine A.
    [Show full text]
  • Molecular and Physiological Basis for Hair Loss in Near Naked Hairless and Oak Ridge Rhino-Like Mouse Models: Tracking the Role of the Hairless Gene
    University of Tennessee, Knoxville TRACE: Tennessee Research and Creative Exchange Doctoral Dissertations Graduate School 5-2006 Molecular and Physiological Basis for Hair Loss in Near Naked Hairless and Oak Ridge Rhino-like Mouse Models: Tracking the Role of the Hairless Gene Yutao Liu University of Tennessee - Knoxville Follow this and additional works at: https://trace.tennessee.edu/utk_graddiss Part of the Life Sciences Commons Recommended Citation Liu, Yutao, "Molecular and Physiological Basis for Hair Loss in Near Naked Hairless and Oak Ridge Rhino- like Mouse Models: Tracking the Role of the Hairless Gene. " PhD diss., University of Tennessee, 2006. https://trace.tennessee.edu/utk_graddiss/1824 This Dissertation is brought to you for free and open access by the Graduate School at TRACE: Tennessee Research and Creative Exchange. It has been accepted for inclusion in Doctoral Dissertations by an authorized administrator of TRACE: Tennessee Research and Creative Exchange. For more information, please contact [email protected]. To the Graduate Council: I am submitting herewith a dissertation written by Yutao Liu entitled "Molecular and Physiological Basis for Hair Loss in Near Naked Hairless and Oak Ridge Rhino-like Mouse Models: Tracking the Role of the Hairless Gene." I have examined the final electronic copy of this dissertation for form and content and recommend that it be accepted in partial fulfillment of the requirements for the degree of Doctor of Philosophy, with a major in Life Sciences. Brynn H. Voy, Major Professor We have read this dissertation and recommend its acceptance: Naima Moustaid-Moussa, Yisong Wang, Rogert Hettich Accepted for the Council: Carolyn R.
    [Show full text]
  • PHF2 Histone Demethylase Prevents DNA Damage and Genome Instability by Controlling Cell Cycle Progression of Neural Progenitors
    PHF2 histone demethylase prevents DNA damage and genome instability by controlling cell cycle progression of neural progenitors Stella Pappaa, Natalia Padillab,c,1, Simona Iacobuccia,1, Marta Viciosoa, Elena Álvarez de la Campab,c, Claudia Navarroa, Elia Marcosa, Xavier de la Cruzb,c,2, and Marian A. Martínez-Balbása,2 aDepartment of Molecular Genomics, Instituto de Biología Molecular de Barcelona, Consejo Superior de Investigaciones Científicas, 08028 Barcelona, Spain; bClinical and Translational Bioinformatics, Vall d’Hebron Institute of Research, E-08035 Barcelona, Spain; and cInstitut Català per la Recerca i Estudis Avançats, 08018 Barcelona, Spain Edited by Robert E. Kingston, Massachusetts General Hospital/Harvard Medical School, Boston, MA, and approved August 6, 2019 (received for review February 25, 2019) Histone H3 lysine 9 methylation (H3K9me) is essential for cellular terestingly, PHF2 mutations have been found in patients with homeostasis; however, its contribution to development is not well autism spectrum disorder (ASD) (22–24). Despite PHF2 high established. Here, we demonstrate that the H3K9me2 demethy- expression in the neural tube and its implication on mental dis- lase PHF2 is essential for neural progenitor proliferation in vitro eases, PHF2 involvement in neural development has not yet and for early neurogenesis in the chicken spinal cord. Using genome- been explored. wide analyses and biochemical assays we show that PHF2 controls In this study, we analyzed the role of PHF2 in neural stem cell the expression of critical cell cycle progression genes, particularly (NSC) biology. We found that PHF2 is essential for progenitor those related to DNA replication, by keeping low levels of H3K9me3 proliferation in vitro and in vivo, in the chicken spinal cord.
    [Show full text]
  • Bioinformatics Applications Through Visualization of Variations on Protein
    1 Bioinformatics applications through visualization of variations on protein structures, comparative functional genomics, and comparative modeling for protein structure studies A dissertation presented by Alper Uzun to The Department of Biology In partial fulfillment of the requirements for the degree of Doctor of Philosophy in the field of Biology Northeastern University Boston, Massachusetts July 2009 2 ©2009 Alper Uzun ALL RIGHTS RESERVED 3 Bioinformatics applications through visualization of variations on protein structures, comparative functional genomics, and comparative modeling for protein structure studies by Alper Uzun ABSTRACT OF DISSERTATION Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Biology in the Graduate School of Arts and Sciences of Northeastern University, July, 2009 4 Abstract The three-dimensional structure of a protein provides important information for understanding and answering many biological questions in molecular detail. The rapidly growing number of sequenced genes and related genomic information is intensively accumulating in the biological databases. It is significantly important to combine biological data and developing bioinformatics tools while information of protein sequences, structures and DNA sequences are exponentially growing. On the other hand, especially the number of known protein sequences is much larger than the number of experimentally solved protein structures. However the experimental methods cannot always be applied or protein structures
    [Show full text]
  • Modes of Interaction of KMT2 Histone H3 Lysine 4 Methyltransferase/COMPASS Complexes with Chromatin
    cells Review Modes of Interaction of KMT2 Histone H3 Lysine 4 Methyltransferase/COMPASS Complexes with Chromatin Agnieszka Bochy ´nska,Juliane Lüscher-Firzlaff and Bernhard Lüscher * ID Institute of Biochemistry and Molecular Biology, Medical School, RWTH Aachen University, Pauwelsstrasse 30, 52057 Aachen, Germany; [email protected] (A.B.); jluescher-fi[email protected] (J.L.-F.) * Correspondence: [email protected]; Tel.: +49-241-8088850; Fax: +49-241-8082427 Received: 18 January 2018; Accepted: 27 February 2018; Published: 2 March 2018 Abstract: Regulation of gene expression is achieved by sequence-specific transcriptional regulators, which convey the information that is contained in the sequence of DNA into RNA polymerase activity. This is achieved by the recruitment of transcriptional co-factors. One of the consequences of co-factor recruitment is the control of specific properties of nucleosomes, the basic units of chromatin, and their protein components, the core histones. The main principles are to regulate the position and the characteristics of nucleosomes. The latter includes modulating the composition of core histones and their variants that are integrated into nucleosomes, and the post-translational modification of these histones referred to as histone marks. One of these marks is the methylation of lysine 4 of the core histone H3 (H3K4). While mono-methylation of H3K4 (H3K4me1) is located preferentially at active enhancers, tri-methylation (H3K4me3) is a mark found at open and potentially active promoters. Thus, H3K4 methylation is typically associated with gene transcription. The class 2 lysine methyltransferases (KMTs) are the main enzymes that methylate H3K4. KMT2 enzymes function in complexes that contain a necessary core complex composed of WDR5, RBBP5, ASH2L, and DPY30, the so-called WRAD complex.
    [Show full text]
  • Autism Ontario Genetics Webinar EN.Pdf
    Autism Ontario Genetics Webinar Thursday October 29, 2020 12:00 – 1:00 pm Panelist Stephen Scherer, PhD - Scientist Ny Hoang, MS, CGC – Genetic Counsellor Ryan Yuen, PhD - Scientist Evdokia Anagnostou, MD - Child Neurologist Autism Spectrum Disorders weak genetic factor Complex Multifactorial Condition strong genetic factor environmental factors Genetic contribution is highly variable Strong genetic Moderate genetic Weaker genetic factor factor factor Examples of genetic factors: SHANK3, NRXN1, CHD8, ARID1B, 16p13.11, 22q11 Genetic contribution is a biological difference chromosome Cell DNA sequence Protein Genetic contribution is a biological difference chromosome Cell DNA sequence genetic variant Protein not working Protein Protein not working DNA sequence genetic variant Deletions & Duplications Single Nucleotide Variations 1q21.1 deletions/ duplications CHD8, ARID1B, SCN2A, SYNGAP1, 16p13.11 deletions/ duplications SHANK3, ANK2, GRIN2B, CHD2 NRXN3, ASTN2, MBD5, PTCHD1 DNA sequence genetic variant Repeat Expansions Example: Fragile X syndrome (FMR1) CGGCGGCGGCGGCGG Normal repeat size: 5-40 CGGCGGCGGCGGCGGCGGCGGCGGCGG Syndrome repeat size: >200 DNA sequence genetic variant Repeat Expansions Fragile X syndrome (FMR1), repeat >200 • Disorders linked to well- CGG defined repeat pattern (motif) Friedreich Ataxia (FXN), repeat >100 • Only one pattern per disorder GAA • Myotonic dystrophy Type 1 (DMPK), repeat >50 Normal repeat size range CTG known Huntington’s Disease (HTT), repeat >35 CAG Spinocerebellar Ataxia Type 10 (ATXN10), repeat >800
    [Show full text]
  • C/EBP Creates Elite Cells for Ipsc Reprogramming by Upregulating
    ARTICLES C/EBPα creates elite cells for iPSC reprogramming by upregulating Klf4 and increasing the levels of Lsd1 and Brd4 Bruno Di Stefano1,2,8,9,10, Samuel Collombet3,8, Janus Schou Jakobsen4,5,6,8, Michael Wierer7, Jose Luis Sardina1,2, Andreas Lackner1,2,9, Ralph Stadhouders1,2, Carolina Segura-Morales1,2, Mirko Francesconi1,2, Francesco Limone1,2, Matthias Mann7, Bo Porse4,5,6, Denis Thieffry3 and Thomas Graf1,2,10 Reprogramming somatic cells into induced pluripotent stem cells (iPSCs) is typically inefficient and has been explained by elite-cell and stochastic models. We recently reported that B cells exposed to a pulse of C/EBPα (Bα0 cells) behave as elite cells, in that they can be rapidly and efficiently reprogrammed into iPSCs by the Yamanaka factors OSKM. Here we show that C/EBPα post-transcriptionally increases the abundance of several hundred proteins, including Lsd1, Hdac1, Brd4, Med1 and Cdk9, components of chromatin-modifying complexes present at super-enhancers. Lsd1 was found to be required for B cell gene silencing and Brd4 for the activation of the pluripotency program. C/EBPα also promotes chromatin accessibility in pluripotent cells and upregulates Klf4 by binding to two haematopoietic enhancers. Bα0 cells share many properties with granulocyte/macrophage progenitors, naturally occurring elite cells that are obligate targets for leukaemic transformation, whose formation strictly requires C/EBPα. The ability to reprogram somatic into pluripotent cells has revolu- complex process, where multiple players synergistically establish new tionized stem cell research with major implications for almost all transcriptional networks and remove epigenetic barriers14. Among the fields of modern biology.
    [Show full text]
  • Case-Control Analysis Identifies Shared Properties of Rare Germline Variation in Cancer Predisposing Genes
    Case-control analysis identifies shared properties of rare germline variation in cancer predisposing genes Mykyta Artomov1,2, Vijai Joseph3, Grace Tiao1,2, Tinu Thomas3, Kasmintan Schrader3, Robert J. Klein3, Adam Kiezun2, Namrata Gupta2, Lauren MarGolin2, Alexander J. StratiGos4, Ivana Kim5, Kristen Shannon6, Leif W. Ellisen6,7, Daniel Haber6,7,8, Gad Getz2, Hensin Tsao9,10, Steven M. Lipkin11, David Altshuler2, Kenneth Offit*3,12 and Mark J. Daly*1,2 1Analytic and Translational Genetics Unit, MGH, Boston, MA, USA 2Broad Institute, CambridGe, MA, USA 3 Clinical Genetics Research Laboratory, Department of Medicine, Memorial Sloan KetterinG Cancer Center, New York, NY, USA 41st Department of DermatoloGy-VenereoloGy, National and Kapodistrian University of Athens School of Medicine, Andreas SyGros Hospital, Athens, Greece 5 Retina Service, Massachusetts Eye and Ear Infirmary, Boston, MA, USA 6 Massachusetts General Hospital Cancer Center, Boston, MA, USA 7 Harvard Medical School, Boston, MA, USA 8 Howard HuGhes Medical Institute, Chevy Chase, Maryland 20815, USA 9 Department of DermatoloGy, Wellman Center for Photomedicine, MGH, Boston, MA, USA 10 Melanoma Genetics ProGram, MGH Cancer Center, MGH, Boston, MA, USA 11 Department of Medicine, ProGram in Mendelian Genetics, Weill-Cornell Medicine, New York, NY, USA 12 Cancer BioloGy and Genetics ProGram, Sloan KetterinG Institute, New York, NY, USA Correspondence: Mark J. Daly, 185 CambridGe St, CPZN-6823A, Boston, MA, 02114, USA; [email protected]; phone: (617)-726-5936 Kenneth Offit, Memorial Sloan KetterinG Cancer Center, 1275 York Avenue, New York, NY, 10065; [email protected]; phone: (212)-639-2000 Authors declare no conflict of interests SUPPLEMENTARY INFORMATION Patient cohorts .........................................................................................................................................
    [Show full text]
  • Increased ACTL6A Occupancy Within Mswi/SNF Chromatin Remodelers
    bioRxiv preprint doi: https://doi.org/10.1101/2021.03.22.435873; this version posted March 22, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Increased ACTL6A Occupancy Within mSWI/SNF Chromatin Remodelers Drives Human Squamous Cell Carcinoma Chiung-Ying Chang1,2,7, Zohar Shipony3,7, Ann Kuo1,2, Kyle M. Loh4,5, William J. Greenleaf3,6, Gerald R. Crabtree1,2,5* 1Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, California 94305, USA. 2Department of Pathology, Stanford University School of Medicine, Stanford, California 94305, USA. 3Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA. 4Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California 94305, USA. 5Department of Developmental Biology, Stanford University School of Medicine, Stanford, California 94305, USA. 6Department of Applied Physics, Stanford University, Stanford, California 94305, USA. 7These authors contributed equally. *Corresponding author: Gerald R. Crabtree, [email protected] Summary Mammalian SWI/SNF (BAF) chromatin remodelers play dosage-sensitive roles in many human malignancies and neurologic disorders. The gene encoding the BAF subunit, ACTL6A, is amplified at an early stage in the development of squamous cell carcinomas (SCCs), but its oncogenic role remains unclear. Here we demonstrate that ACTL6A overexpression leads to its stoichiometric assembly into BAF complexes and drives its interaction and engagement with specific regulatory regions in the genome. In normal epithelial cells, ACTL6A was sub-stoichiometric to other BAF subunits. However, increased ACTL6A levels by ectopic expression or in SCC cells led to near-saturation of ACTL6A within BAF complexes.
    [Show full text]