Linkage-specific deubiquitylation by OTUD5 defines an embryonic pathway intolerant to genomic variation
David B Beck1,2, Mohammed A Basar2, Anthony J Asmar2
1Metabolic, Cardiovascular and Inflammatory Disease Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
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.
Insights
Genetic variants in OTUD5 cause LINKED syndrome, a disorder affecting embryonic development. OTUD5 regulates neuroectodermal differentiation by cleaving specific ubiquitin chains, maintaining chromatin accessibility and gene expression.
Area of Science:
- Genetics
- Molecular Biology
- Developmental Biology
Background:
- Ubiquitin chain modifications are crucial for intracellular signaling pathways.
- Understanding the roles of specific ubiquitin linkages in human development is limited.
Purpose of the Study:
- To identify the genetic basis and molecular mechanisms of a novel congenital anomaly disorder.
- To investigate the function of OTUD5 in human embryonic development.
Main Methods:
- Genomic constraint scores were used to identify patients with variants in OTUD5.
- Functional studies were performed on patient-derived mutations to assess OTUD5 activity.
- Chromatin accessibility and gene expression were analyzed in cells with altered OTUD5 levels.
Main Results:
- Ten patients with multiple congenital anomalies were identified with hemizygous variants in OTUD5.
- OTUD5, a K48/K63 linkage-specific deubiquitylase, controls neuroectodermal differentiation.
- Loss of OTUD5 function leads to impaired chromatin accessibility and aberrant gene expression.
Conclusions:
- A novel disorder, LINKED syndrome, is described, caused by OTUD5 deficiency.
- Linkage-specific ubiquitin cleavage by OTUD5 is essential for chromatin remodeling during embryogenesis.
- OTUD5 counteracts the degradation of chromatin regulators, impacting neurodevelopment.
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