Linkage-specific deubiquitylation by OTUD5 defines an embryonic pathway intolerant to genomic variation [ATAC-Seq]
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PROVIDER: PRJNA673703 | ENA |
REPOSITORIES: ENA
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Project description:Linkage-specific deubiquitylation by OTUD5 defines an embryonic pathway intolerant to genomic variation
| PRJNA673701 | ENA
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
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 | GSE160588 | GEO
Project description:Linkage-specific deubiquitylation by OTUD5 defines an embryonic pathway intolerant to genomic variation [RNA-Seq]
| PRJNA673704 | ENA
Project description: Not available
| S-EPMC7817106 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2020-11-02 | GSE160590 | GEO
Project description:In Saccharomyces cerevisiae histone H2B is ubiquitylated at lysine 123. The SAGA complex component, Ubp8, is one of two proteases that remove this ubiquitin moiety. We analyzed gene expression in a strain containing a variant of histone H2B with lysine 123 converted to arginine to address the mechanisms by which ubiquitylation and deubiquitylation of histone H2B affects gene expression. We show that changes in gene expression observed upon deletion of ubp8 are suppressed by htb1K123R. This provides genetic evidence that Ubp8 alters gene expression through deubiquitylation of histone H2B. Second, microarray analyses of the htb1K123R strain show that loss of histone ubiquitylation results in a two-fold or greater change in expression of ~1.5% of the protein coding genes with greater than two-thirds increasing. For genes in which ubiquitylation represses expression, ubiquitylation principally acts through its effects on histone methylation. In contrast, decreased expression of the CWP1 gene was not paralleled by deletions of the methyltransferase components Swd3, Set2 or Dot1 and is thus likely independent of methylation. Finally, by comparing gene expression changes in the htb1K123R strain with those in a strain deleted for rad6, we conclude that lysine 123 affects transcription primarily because of its being a site of ubiquitylation. Keywords: yeast, histone ubiquitylation, Ubp8, gene expression, genetic modification, histone H2B Two dye-swapped, biological replicate experiments were performed for yeast strains CY1272(Htb1_K123R;htb2_delta0), BY10809(ubp8_delta0) and CY1383(Htb1_K123R;htb2_delta0;ubp8_delta0) with reference to BY4742(wt). Three biological replicates, including one dye-swap experiment, were performed comparing CY1272(Htb1_K123R;htb2_delta0) to BY13026(htb2_delta0).
2010-09-15 | E-GEOD-6316 | biostudies-arrayexpress
Project description:The main genetic factors for familial melanoma remain unknown in more than 75% of families. CDKN2A is mutated in around 20% of melanoma-prone families. Other high-risk melanoma susceptibility genes explain less than 3% of families studied to date. We performed the first genome-wide linkage analysis in CDKN2A-negative Spanish melanoma-prone families to identify novel melanoma susceptibility loci. We included 68 individuals from 2, 3 and 6 families with 2, 3 and at least 4 melanoma cases. We detected a locus with significant linkage evidence at 11q14.1-q14.3, with a maximum het-TLOD of 3.449 (rs12285365:A>G), using evidence from multiple pedigrees. The genes contained by the subregion with the strongest linkage evidence were: DLG2, PRSS23, FZD4 and TMEM135. We also detected several regions with suggestive linkage evidence (TLOD>1.9) (1q, 6p, 7p, 11q, 12p, 13q) including the region previously detected in melanoma-prone families from Sweden at 3q29. The family specific analysis revealed three loci with suggestive linkage evidence for family #1: 1q31.1-q32.1 (max. TLOD 2.447), 6p24.3-p22.3 (max. TLOD 2.409) and 11q13.3-q21 (max. TLOD 2.654). Future next generation sequencing studies of these regions may allow the identification of new melanoma susceptibility genetic factors.
2019-01-01 | GSE109207 | GEO
Project description:The main genetic factors for familial melanoma remain unknown in more than 75% of families. CDKN2A is mutated in around 20% of melanoma-prone families. Other high-risk melanoma susceptibility genes explain less than 3% of families studied to date. We performed the first genome-wide linkage analysis in CDKN2A-negative Spanish melanoma-prone families to identify novel melanoma susceptibility loci. We included 68 individuals from 2, 3 and 6 families with 2, 3 and at least 4 melanoma cases. We detected a locus with significant linkage evidence at 11q14.1-q14.3, with a maximum het-TLOD of 3.449 (rs12285365:A>G), using evidence from multiple pedigrees. The genes contained by the subregion with the strongest linkage evidence were: DLG2, PRSS23, FZD4 and TMEM135. We also detected several regions with suggestive linkage evidence (TLOD>1.9) (1q, 6p, 7p, 11q, 12p, 13q) including the region previously detected in melanoma-prone families from Sweden at 3q29. The family specific analysis revealed three loci with suggestive linkage evidence for family #1: 1q31.1-q32.1 (max. TLOD 2.447), 6p24.3-p22.3 (max. TLOD 2.409) and 11q13.3-q21 (max. TLOD 2.654). Future next generation sequencing studies of these regions may allow the identification of new melanoma susceptibility genetic factors.
2019-01-01 | GSE109206 | GEO
Project description:In Saccharomyces cerevisiae histone H2B is ubiquitylated at lysine 123. The SAGA complex component, Ubp8, is one of two proteases that remove this ubiquitin moiety. We analyzed gene expression in a strain containing a variant of histone H2B with lysine 123 converted to arginine to address the mechanisms by which ubiquitylation and deubiquitylation of histone H2B affects gene expression. We show that changes in gene expression observed upon deletion of ubp8 are suppressed by htb1K123R. This provides genetic evidence that Ubp8 alters gene expression through deubiquitylation of histone H2B. Second, microarray analyses of the htb1K123R strain show that loss of histone ubiquitylation results in a two-fold or greater change in expression of ~1.5% of the protein coding genes with greater than two-thirds increasing. For genes in which ubiquitylation represses expression, ubiquitylation principally acts through its effects on histone methylation. In contrast, decreased expression of the CWP1 gene was not paralleled by deletions of the methyltransferase components Swd3, Set2 or Dot1 and is thus likely independent of methylation. Finally, by comparing gene expression changes in the htb1K123R strain with those in a strain deleted for rad6, we conclude that lysine 123 affects transcription primarily because of its being a site of ubiquitylation. Keywords: yeast, histone ubiquitylation, Ubp8, gene expression, genetic modification, histone H2B
2007-01-19 | GSE6316 | GEO