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Project description:Genomic analyses of patients with congenital heart disease (CHD) have identified significant contribution from mutations affecting cilia genes and chromatin remodeling genes; however, the mechanism(s) connecting chromatin remodeling to CHD is unknown. Histone H2B monoubiquitination (H2Bub1) is catalyzed by the RNF20 complex consisting of RNF20, RNF40, and UBE2B. Here, we show significant enrichment of loss-of-function mutations affecting H2Bub1 in CHD patients (enrichment 6.01, P = 1.67 × 10-03), some of whom had abnormal laterality associated with ciliary dysfunction. In Xenopus, knockdown of rnf20 and rnf40 results in abnormal heart looping, defective development of left-right (LR) asymmetry, and impaired cilia motility. Rnf20, Rnf40, and Ube2b affect LR patterning and cilia synergistically. Examination of global H2Bub1 level in Xenopus embryos shows that H2Bub1 is developmentally regulated and requires Rnf20. To examine gene-specific H2Bub1, we performed ChIP-seq of mouse ciliated and nonciliated tissues and showed tissue-specific H2Bub1 marks significantly enriched at cilia genes including the transcription factor Rfx3 Rnf20 knockdown results in decreased levels of rfx3 mRNA in Xenopus, and exogenous rfx3 can rescue the Rnf20 depletion phenotype. These data suggest that Rnf20 functions at the Rfx3 locus regulating cilia motility and cardiac situs and identify H2Bub1 as an upstream transcriptional regulator controlling tissue-specific expression of cilia genes. Our findings mechanistically link the two functional gene ontologies that have been implicated in human CHD: chromatin remodeling and cilia function.
| S-EPMC6628794 | biostudies-literature
Project description:Genomic analyses of patients with congenital heart disease (CHD) have identified significant contribution from mutations affecting cilia genes and chromatin remodeling genes; however, the mechanism(s) connecting chromatin remodeling to CHD are unknown. Histone H2B mono-ubiquitination (H2Bub1) is catalyzed by the RNF20 complex consisting of RNF20, RNF40 and UBE2B. Here, we show significant enrichment of loss-of-function mutations affecting H2Bub1 in CHD patients (enrichment=6.01, p=1.67x10-03), some of whom had abnormal laterality associated with cilia dysfunction. In Xenopus, knockdown of rnf20 and rnf40 results in abnormal heart looping, defective development of left-right asymmetry and impaired cilia motility. Rnf20, Rnf40 and Ube2b affect LR patterning and cilia synergistically. Examination of global H2Bub1 level in Xenopus embryos shows that H2Bub1 is developmentally regulated and requires Rnf20. To examine gene-specific H2Bub1, we performed ChIP-seq of mouse ciliated and non-ciliated tissues and showed tissue-specific H2Bub1 marks significantly enriched at cilia genes including the transcription factor Rfx3. Rnf20 knockdown results in decreased levels of rfx3 mRNA in Xenopus, and exogenous rfx3 can rescue the Rnf20 depletion phenotype. These data suggest that Rnf20 functions at the Rfx3 locus regulating cilia motility and cardiac situs and identify H2Bub1 as an upstream transcriptional regulator controlling tissue-specific expression of cilia genes. Our findings mechanistically link the two functional gene ontologies that have been implicated in human CHD: chromatin remodeling and cilia function.
2019-06-04 | GSE132116 | GEO
Project description:Genomic analyses of patients with congenital heart disease (CHD) have identified significant contribution from mutations affecting cilia genes and chromatin remodeling genes; however, the mechanism(s) connecting chromatin remodeling to CHD are unknown. Histone H2B mono-ubiquitination (H2Bub1) is catalyzed by the RNF20 complex consisting of RNF20, RNF40 and UBE2B. Here, we show significant enrichment of loss-of-function mutations affecting H2Bub1 in CHD patients (enrichment=6.01, p=1.67x10-03), some of whom had abnormal laterality associated with cilia dysfunction. In Xenopus, knockdown of rnf20 and rnf40 results in abnormal heart looping, defective development of left-right asymmetry and impaired cilia motility. Rnf20, Rnf40 and Ube2b affect LR patterning and cilia synergistically. Examination of global H2Bub1 level in Xenopus embryos shows that H2Bub1 is developmentally regulated and requires Rnf20. To examine gene-specific H2Bub1, we performed ChIP-seq of mouse ciliated and non-ciliated tissues and showed tissue-specific H2Bub1 marks significantly enriched at cilia genes including the transcription factor Rfx3. Rnf20 knockdown results in decreased levels of rfx3 mRNA in Xenopus, and exogenous rfx3 can rescue the Rnf20 depletion phenotype. These data suggest that Rnf20 functions at the Rfx3 locus regulating cilia motility and cardiac situs and identify H2Bub1 as an upstream transcriptional regulator controlling tissue-specific expression of cilia genes. Our findings mechanistically link the two functional gene ontologies that have been implicated in human CHD: chromatin remodeling and cilia function.
2019-06-04 | GSE132115 | GEO
Project description:Histone H2B monoubiquitination regulates heart development via epigenetic control of cilia motility
| PRJNA545972 | ENA
Project description:Histone H2B monoubiquitination regulates heart development via epigenetic control of cilia motility [ChIP-Seq]
| PRJNA545971 | ENA
Project description:Histone H2B monoubiquitination regulates heart development via epigenetic control of cilia motility [RNA-Seq]
| PRJNA545973 | ENA
Project description:Autophagy is an evolutionarily conserved cellular process that primarily participates in lysosome-mediated protein degradation. Although autophagy is a cytoplasmic event, how epigenetic pathways are involved in the regulation of autophagy remains incompletely understood. Here, we found that H2B monoubiquitination (H2Bub1) is down-regulated in cells under starvation conditions and that the decrease in H2Bub1 results in the activation of autophagy. We also identified that the deubiquitinase USP44 is responsible for the starvation-induced decrease in H2Bub1. Furthermore, the changes in H2Bub1 affect the transcription of genes involved in the regulation of autophagy. Therefore, this study reveals a novel epigenetic pathway for the regulation of autophagy through H2Bub1.
| S-EPMC5388390 | biostudies-literature
Project description:Chromatin reorganization is governed by multiple post-translational modifications of chromosomal proteins and DNA. These histone modifications are reversible, dynamic events that can regulate DNA-driven cellular processes. However, the molecular mechanisms that coordinate histone modification patterns remain largely unknown. In metazoans, reversible protein modification by O-linked N-acetylglucosamine (GlcNAc) is catalysed by two enzymes, O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). However, the significance of GlcNAcylation in chromatin reorganization remains elusive. Here we report that histone H2B is GlcNAcylated at residue S112 by OGT in vitro and in living cells. Histone GlcNAcylation fluctuated in response to extracellular glucose through the hexosamine biosynthesis pathway (HBP). H2B S112 GlcNAcylation promotes K120 monoubiquitination, in which the GlcNAc moiety can serve as an anchor for a histone H2B ubiquitin ligase. H2B S112 GlcNAc was localized to euchromatic areas on fly polytene chromosomes. In a genome-wide analysis, H2B S112 GlcNAcylation sites were observed widely distributed over chromosomes including transcribed gene loci, with some sites co-localizing with H2B K120 monoubiquitination. These findings suggest that H2B S112 GlcNAcylation is a histone modification that facilitates H2BK120 monoubiquitination, presumably for transcriptional activation.
| S-EPMC7289526 | biostudies-literature
Project description:To investigate H2B monoubiquitination (uH2B) and H3K4 di- and tri-methylation (H3K4-2me, H3K4-3me) levels and their clinical significance in gastric cancer (GC).Immunohistochemistry (IGC) was used to detect the differential levels of uH2B, H3K4-2me and H3K4-3me modifications in GC specimens from chemo/radiotherapy-naïve patients who underwent potentially curative surgical resection (n = 159) and in a random sampling of non-tumor gastric epithelium specimens (normal controls, n = 20). The immunohistochemistry (IHC)-detected modifications were classified as negative, low-level, or high-level using a dual-rated (staining intensity and percentage of positively-stained cells) semi-quantitative method. The relationships between uH2B modification levels and clinicopathological parameters of GC were assessed by a Wilcoxon rank sum test (pairwise comparisons) and the Kruskal-Wallis H test (multiple comparisons). The correlation between uH2B modification and survival was estimated by Kaplan-Meier analysis, and the role of uH2B as an independent prognostic factor for survival was assessed by multivariate Cox regression analysis.The presence and level of H3K4-2me and H3K4-3me IHC staining was similar between the normal controls and GC specimens. In contrast, the level of uH2B was significantly lower in the malignant gastric tissues (vs normal control tissues) and decreased along with increases in dedifferentiation (well differentiated > moderately differentiated > poorly differentiated). The level of uH2B correlated with tumor differentiation (P < 0.001), Lauren's diffuse- and intestinal-type classification (P < 0.001), lymph node metastasis (P = 0.049) and tumor-node-metastasis stage (P = 0.005). Patients with uH2B+ staining had higher 5-year survival rates than patients with uH2B-staining (52.692 ± 2.452 vs 23.739 ± 5.207, P < 0.001). The uH2B level was an independent prognostic factor for cancer-specific survival (95%CI: 0.237-0.677, P = 0.001).uH2B displays differential IHC staining patterns corresponding to progressive stages of GC. uH2B may contribute to tumorigenesis and could be a potential therapeutic target.
| S-EPMC3848160 | biostudies-literature
Project description:Monoubiquitination of histone H2B on lysine 120 (H2Bub1) is an epigenetic mark generally associated with transcriptional activation, yet the global functions of H2Bub1 remain poorly understood. Ferroptosis is a form of non-apoptotic cell death characterized by the iron-dependent overproduction of lipid hydroperoxides, which can be inhibited by the antioxidant activity of the solute carrier family member 11 (SLC7A11/xCT), a component of the cystine/glutamate antiporter. Whether nuclear events participate in the regulation of ferroptosis is largely unknown. Here, we show that the levels of H2Bub1 are decreased during erastin-induced ferroptosis and that loss of H2Bub1 increases the cellular sensitivity to ferroptosis. H2Bub1 epigenetically activates the expression of SLC7A11. Additionally, we show that the tumor suppressor p53 negatively regulates H2Bub1 levels independently of p53's transcription factor activity by promoting the nuclear translocation of the deubiquitinase USP7. Moreover, our studies reveal that p53 decreases H2Bub1 occupancy on the SLC7A11 gene regulatory region and represses the expression of SLC7A11 during erastin treatment. These data not only suggest a noncanonical role of p53 in chromatin regulation but also link p53 to ferroptosis via an H2Bub1-mediated epigenetic pathway. Overall, our work uncovers a previously unappreciated epigenetic mechanism for the regulation of ferroptosis.
| S-EPMC6607012 | biostudies-literature