Linkage-specific deubiquitylation by OTUD5 defines an embryonic pathway intolerant to genomic variation

Sci Adv. 2021 Jan 20;7(4):eabe2116. doi: 10.1126/sciadv.abe2116.

David B Beck ¹ ², Mohammed A Basar ², Anthony J Asmar ², Joyce J Thompson ³, Hirotsugu Oda ¹, Daniela T Uehara ⁴, Ken Saida ⁵, Sander Pajusalu ⁶ ⁷ ⁸, Inga Talvik ⁹, Precilla D'Souza ¹⁰, Joann Bodurtha ¹¹, Weiyi Mu ¹¹, Kristin W Barañano ¹², Noriko Miyake ⁵, Raymond Wang ¹³ ¹⁴, Marlies Kempers ¹⁵, Tomoko Tamada ¹⁶, Yutaka Nishimura ¹⁷, Satoshi Okada ¹⁸, Tomoki Kosho ¹⁹, Ryan Dale ²⁰, Apratim Mitra ²⁰, Ellen Macnamara ²¹, Undiagnosed Diseases Network, Naomichi Matsumoto ⁵, Johji Inazawa ⁴, Magdalena Walkiewicz ²², Katrin Õunap ⁶ ⁷, Cynthia J Tifft ¹⁰ ²¹, Ivona Aksentijevich ¹, Daniel L Kastner ¹, Pedro P Rocha ³ ²³, Achim Werner ²⁴

Affiliations

1 Metabolic, Cardiovascular and Inflammatory Disease Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
2 Stem Cell Biochemistry Unit, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA.
3 Unit on Genome Structure and Regulation, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
4 Department of Molecular Cytogenetics, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
5 Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.
6 Department of Clinical Genetics, United Laboratories, Tartu University Hospital, Tartu, Estonia.
7 Department of Clinical Genetics, Institute of Clinical Medicine, University of Tartu, Tartu, Estonia.
8 Department of Genetics, Yale University School of Medicine, New Haven, CT 06510, USA.
9 Department of Neurology and Rehabilitation, Tallinn Children's Hospital, Tallinn, Estonia.
10 Office of the Clinical Director, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
11 Department of Genetic Medicine, Johns Hopkins Hospital, Baltimore, MD 21287, USA.
12 Department of Neurology, Johns Hopkins Hospital, Baltimore, MD 21287, USA.
13 Division of Metabolic Disorders, CHOC Children's Specialists, Orange, CA 92868, USA.
14 Department of Pediatrics, University of California Irvine School of Medicine, Orange, CA 92967, USA.
15 Department of Human Genetics, Radboud University Medical Center, Nijmegen, Netherlands.
16 Department of Pediatrics, Hiroshima Prefectural Rehabilitation Center, Hiroshima, Japan.
17 Department of General Perinatology, Hiroshima City Hiroshima Citizens Hospital, Hiroshima, Japan.
18 Department of Pediatrics, Hiroshima University, Graduate School of Biomedical and Health Sciences, Hiroshima, Japan.
19 Department of Medical Genetics, Shinshu University School of Medicine, Nagano, Japan.
20 Bioinformatics and Scientific Programming Core, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
21 Undiagnosed Diseases Program, The Common Fund, Office of the Director, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
22 National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, MD 20892, USA.
23 National Cancer Institute, NIH, Bethesda, MD 20892, USA.
24 Stem Cell Biochemistry Unit, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA. achim.werner@nih.gov.

PMID: 33523931 DOI: 10.1126/sciadv.abe2116

Abstract

Reversible modification of proteins with linkage-specific ubiquitin chains is critical for intracellular signaling. Information on physiological roles and underlying mechanisms of particular ubiquitin linkages during human development are limited. Here, relying on genomic constraint scores, we identify 10 patients with multiple congenital anomalies caused by hemizygous variants in OTUD5, encoding a K48/K63 linkage-specific deubiquitylase. By studying these mutations, we find that OTUD5 controls neuroectodermal differentiation through cleaving K48-linked ubiquitin chains to counteract degradation of select chromatin regulators (e.g., ARID1A/B, histone deacetylase 2, and HCF1), mutations of which underlie diseases that exhibit phenotypic overlap with OTUD5 patients. Loss of OTUD5 during differentiation leads to less accessible chromatin at neuroectodermal enhancers and aberrant gene expression. Our study describes a previously unidentified disorder we name LINKED (LINKage-specific deubiquitylation deficiency-induced Embryonic Defects) syndrome and reveals linkage-specific ubiquitin cleavage from chromatin remodelers as an essential signaling mode that coordinates chromatin remodeling during embryogenesis.

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