Regulation of human development by ubiquitin chain editing of chromatin remodelers

David B. Beck, Mohammed A. Basar, Anthony J. Asmar, Joyce Thompson, Hirotsugu Oda, Daniela T. Uehara, Ken Saida, Precilla D’Souza, Joann Bodurtha, Weiyi Mu, Kristin W. Barañano, Noriko Miyake, Raymond Wang, Marlies Kempers, Yutaka Nishimura, Satoshi Okada, Tomoki Kosho, Ryan Dale, Apratim Mitra, Ellen MacnamaraUndiagnosed Diseases Network, Naomichi Matsumoto, Johi Inazawa, Magdalena Walkiewicz, Cynthia J. Tifft, Ivona Aksentijevich, Daniel L. Kastner, Pedro P. Rocha, Achim Werner

Research output: Contribution to journalArticlepeer-review


Embryonic development occurs through commitment of pluripotent stem cells to differentiation programs that require highly coordinated changes in gene expression. Chromatin remodeling of gene regulatory elements is a critical component of how such changes are achieved. While many factors controlling chromatin dynamics are known, mechanisms of how different chromatin regulators are orchestrated during development are not well understood. Here, we describe LINKED (LINKage-specific-deubiquitylation-deficiency-induced Embryonic Defects) syndrome, a novel multiple congenital anomaly disorder caused by hypomorphic hemizygous missense variants in the deubiquitylase OTUD5/DUBA. Studying LINKED mutations in vitro, in mouse, and in models of neuroectodermal differentiation of human pluripotent stem cells, we uncover a novel regulatory circuit that coordinates chromatin remodeling pathways during early differentiation. We show that the K48-linkage-specific deubiquitylation activity of OTUD5 is essential for murine and human development and, if reduced, leads to aberrant cell-fate specification. OTUD5 controls differentiation through preventing the degradation of multiple chromatin regulators including ARID1A/B and HDAC2, mutation of which underlie developmental syndromes that exhibit phenotypic overlap with LINKED patients. Accordingly, loss of OTUD5 during early differentiation leads to less accessible chromatin at neural and neural crest enhancers and thus aberrant rewiring of gene expression networks. Our work identifies a novel mechanistic link between phenotypically related developmental disorders and an essential function for linkage-specific ubiquitin editing of substrate groups (i.e. chromatin remodeling complexes) during early cell-fate decisions – a regulatory concept, we predict to be a general feature of embryonic development.

Original languageEnglish (US)
JournalUnknown Journal
StatePublished - Jan 24 2020

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • Immunology and Microbiology(all)
  • Neuroscience(all)
  • Pharmacology, Toxicology and Pharmaceutics(all)

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