Jan 24, 2020

Regulation of human development by ubiquitin chain editing of chromatin remodelers

bioRxiv
David BeckAchim Werner

Abstract

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 ...Continue Reading

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Mentioned in this Paper

Mus
Chromatin Remodeling
Chromatin
Ubiquitinated Proteins
Regulation of Biological Process
Neural Crest
Deubiquitinating enzyme A, human
Cell Differentiation Process
Pluripotent Stem Cells
Genetic Linkage

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