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

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.

SUBMITTER: Beck DB

PROVIDER: S-EPMC7817106 | biostudies-literature |

REPOSITORIES: biostudies-literature

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

Project description:This SuperSeries is composed of the SubSeries listed below.

2020-11-02 | GSE160590 | GEO

Linkage-specific deubiquitylation by OTUD5 defines an embryonic pathway intolerant to genomic variation [RNA-Seq]

Project description:Reversible modification of proteins with linkage-specific ubiquitin chains is critical for intracellular signaling. Yet, information on physiological roles and underlying signaling mechanisms of particular ubiquitin linkages during human development are limited. Here, relying on genomic constraint scores, we identify 10 patients with a novel multiple congenital anomaly disorder 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 a select group of chromatin regulators. These include ARID1A/B, HDAC2, and HCF1, mutation of which underlie different developmental disorders that exhibit phenotypic overlap with OTUD5 patients. Consequently, loss of OTUD5 during early differentiation leads to less accessible chromatin at neuroectodermal enhancers and thus aberrant rewiring of gene expression networks. Our study describes a novel developmental disorder we name LINKED (LINKage-specific-deubiquitylation-deficiency-induced Embryonic Defects) syndrome, provides a previously unrecognized mechanistic link between phenotypically related diseases, and reveals linkage-specific ubiquitin cleavage from substrate groups (i.e. chromatin remodelers) as an essential mode of signaling required to coordinate embryonic differentiation pathways.

2020-11-02 | GSE160589 | GEO

Linkage-specific deubiquitylation by OTUD5 defines an embryonic pathway intolerant to genomic variation [ATAC-Seq]

2020-11-02 | GSE160588 | GEO

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

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

| PRJNA673701 | ENA

Linkage-specific deubiquitylation by OTUD5 defines an embryonic pathway intolerant to genomic variation [ATAC-Seq]

Project description:Linkage-specific deubiquitylation by OTUD5 defines an embryonic pathway intolerant to genomic variation [ATAC-Seq]

| PRJNA673703 | ENA

Linkage-specific deubiquitylation by OTUD5 defines an embryonic pathway intolerant to genomic variation [RNA-Seq]

Project description:Linkage-specific deubiquitylation by OTUD5 defines an embryonic pathway intolerant to genomic variation [RNA-Seq]

| PRJNA673704 | ENA

Deubiquitylation machinery is required for embryonic polarity in Caenorhabditis elegans.

Project description:The Caenorhabditis elegans one-cell embryo polarizes in response to a cue from the paternally donated centrosome and asymmetrically segregates cell fate determinants that direct the developmental program of the worm. We have found that genes encoding putative deubiquitylating enzymes (DUBs) are required for polarization of one-cell embryos. Maternal loss of the proteins MATH-33 and USP-47 leads to variable inability to correctly establish and maintain asymmetry as defined by posterior and anterior polarity proteins PAR-2 and PAR-3. The first observable defect is variable positioning of the centrosome with respect to the cell cortex and the male pronucleus. The severity of the polarity defects correlates with distance of the centrosome from the cortex. Furthermore, polarity defects can be bypassed by mutations that bring the centrosome in close proximity to the cortex. In addition we find that polarity and centrosome positioning defects can be suppressed by compromising protein turnover. We propose that the DUB activity of MATH-33 and USP-47 stabilizes one or more proteins required for association of the centrosome with the cortex. Because these DUBs are homologous to two members of a group of DUBs that act in fission yeast polarity, we tested additional members of that family and found that another C. elegans DUB gene, usp-46, also contributes to polarity. Our finding that deubiquitylating enzymes required for polarity in Schizosaccharomyces pombe are also required in C. elegans raises the possibility that these DUBs act through an evolutionarily conserved mechanism to control cell polarity.

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Extensive genomic copy number variation in embryonic stem cells.

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Genomic variation in rice: genesis of highly polymorphic linkage blocks during domestication.

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