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The Histone H2B Monoubiquitination Regulatory Pathway is Required for Differentiation of Multipotent Stem Cells

ABSTRACT: Extensive changes in post-translational histone modifications accompany the rewiring of the transcriptional program during stem cell differentiation. However, the mechanisms controlling the changes in specific chromatin modifications and their function during differentiation remain only poorly understood. We show that histone H2B monoubiquitination (H2Bub1) significantly increases during differentiation of human mesenchymal stem cells (hMSCs), various lineage-committed precursor cells and in diverse organisms. Furthermore, the H2B ubiquitin ligase RNF40 is required for the induction of differentiation markers and transcriptional reprogramming of hMSC. This function is dependent upon CDK9 and the WAC adaptor protein, which are required for H2B monoubiquitination. Finally, we show that RNF40 is required for the resolution of the H3K4me3/H3K27me3 bivalent poised state on lineage-specific genes during the transition from an inactive to active chromatin conformation. Thus, these data indicate that H2Bub1 is required for maintaining multipotency of hMSC cells and plays a central role in controlling stem cell differentiation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE38173 | GEO | 2013/01/03

SECONDARY ACCESSION(S): PRJNA167361

REPOSITORIES: GEO

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The Histone H2B Monoubiquitination Regulatory Pathway is Required for Differentiation of Multipotent Stem Cells

Project description:Extensive changes in post-translational histone modifications accompany the rewiring of the transcriptional program during stem cell differentiation. However, the mechanisms controlling the changes in specific chromatin modifications and their function during differentiation remain only poorly understood. We show that histone H2B monoubiquitination (H2Bub1) significantly increases during differentiation of human mesenchymal stem cells (hMSCs), various lineage-committed precursor cells and in diverse organisms. Furthermore, the H2B ubiquitin ligase RNF40 is required for the induction of differentiation markers and transcriptional reprogramming of hMSC. This function is dependent upon CDK9 and the WAC adaptor protein, which are required for H2B monoubiquitination. Finally, we show that RNF40 is required for the resolution of the H3K4me3/H3K27me3 bivalent poised state on lineage-specific genes during the transition from an inactive to active chromatin conformation. Thus, these data indicate that H2Bub1 is required for maintaining multipotency of hMSC cells and plays a central role in controlling stem cell differentiation. This set contains 29 microarray samples and includes the following 5 conditions: undifferentiated hMSCs, 2 day osteoblast differentiation, 5 day osteoblast differentiation, 2 day adipocyte differentiation, and 5 day adipocyte differentiation. 3 siRNA control samples and 3 RNF40 knockdown samples for each condition (except two control siRNA samples for 2 days osteoblast differentiation).

2013-01-03 | E-GEOD-38173 | biostudies-arrayexpress

Regulation of gene expression by WAC/RNF20/RNF40 in HEK293A cells

2015-12-17 | GSE66475 | GEO

Regulation of gene expression by WAC/RNF20/RNF40 in HEK293A cells

Project description:WAC is a known positive regulator of (macro)autophagy. WAC also forms a complex with RNF20/RNF40 to promote H2B monoubiquitination and hence to affect transcriptional regulation. This study addresses whether the WAC/RNF20/RNF40 complex regulates autophagy through effects on gene expression. WAC, RNF20 and RNF40 were knocked-down using pools of siRNAs in HEK293A cells. Each knockdown was in triplicate and the control was RISCfree siRNA. mRNA expression profiles were investigated using an Illumina HT12v4 Bead Array.

2015-12-17 | E-GEOD-66475 | biostudies-arrayexpress

Role of Rnf40-dependent histone monoubiquitination in peripheral nervous system myelination [ChIP-Seq]

Project description:To address the role of monoubiquitination of histone H2B at lysine 120 (H2Bub1), we inactivated the responsible E3 ligase by deleting Rnf40 in developing Schwann cells. Rnf40 becomes important for proper Schwann cell development shortly before and during differentiation. Its absence in Schwann cells leads to a peripheral neuropathy. ChIP-Seq studies with H2Bub1-specific antibodies were performed on sciatic nerves from control mice and mice with a Schwann cell-specific deletion of Rnf40 to detect alterations in genomic H2Bub1 occupancy. These correlated with changes in the expression of genes associated with myelination and lipid metabolism.

2020-07-13 | GSE146645 | GEO

BMAL1-TTK-H2Bub1 loop deficiency contributes to impaired BM-MSC-mediated bone formation in senile osteoporosis

Project description:We performed multiomic high-throughput sequencing to recapitulated the BMAL1-H2Bub1 loop in mesenchymal stem cells osteogenesis. We used lentiviruses to diminish RNF40 and WAC, which are parts of the obligate complex and monoubiquitinated histone H2B, in MSCs, and analysed the H2Bub1 and PolII CUT&Tag-seq.

2022-08-06 | GSE210425 | GEO

Role of Rnf40-dependent histone monoubiquitination in peripheral nervous system myelination [RNA-Seq]

Project description:To address the role of monoubiquitination of histone H2B at lysine 120 (H2Bub1), we inactivated the responsible E3 ligase by deleting Rnf40 in developing Schwann cells. Rnf40 becomes important for proper Schwann cell development shortly before and during differentiation. Its absence in Schwann cells leads to a peripheral neuropathy. RNA-Seq studies were performed on sciatic nerves from control mice and mice with a Schwann cell-specific deletion of Rnf40 to analyze changes in gene expression. These revealed substantial changes in the expression of genes associated with myelination, lipid metabolism and cell adhesion.

2020-07-13 | GSE146629 | GEO

The H2Bub1-deposition complex is required for human and mouse cardiogenesis (RNA-Seq)

Project description:De novo variants affecting monoubiquitination of histone H2B (H2Bub1) are enriched in human congenital heart disease. H2Bub1 is required in stem cell differentiation, cilia function, post-natal cardiomyocyte maturation, and transcriptional elongation. However, how H2Bub1 affects cardiogenesis is unknown. We show that the H2Bub1-deposition complex (RNF20-RNF40-UBE2B) is required for mouse cardiogenesis and for differentiation of human iPSCs into cardiomyocytes. Mice with cardiac-specific Rnf20 deletion are embryonic lethal and have abnormal myocardium. We then analyzed H2Bub1 marks during differentiation of human iPSCs into cardiomyocytes. H2Bub1 is erased from most genes at transition from cardiac mesoderm to cardiac progenitor cells, but is preserved on a subset of long cardiac-specific genes. When H2Bub1 is reduced in iPSC-cardiomyocytes, long cardiac-specific genes have fewer full-length transcripts. This correlates with H2Bub1 accumulation near the center of these genes. H2Bub1 accumulation near the center of tissue-specific genes was also observed in embryonic fibroblasts and fetal osteoblasts. In summary, we show that normal H2Bub1 distribution is required for cardiogenesis and cardiomyocyte differentiation, and point to H2Bub1 regulating tissue-specific gene expression by increasing the amount of full-length transcripts.

2023-10-31 | GSE246411 | GEO

The H2Bub1-deposition complex is required for human and mouse cardiogenesis (ChIP-Seq)

2023-10-31 | GSE246410 | GEO

RNF40 exerts stage-dependent functions in differentiating osteoblasts and is essential for bone cell crosstalk [RNA-seq]

Project description:In this study, we focused on elucidating the role of Ring Finger Protein 40 (RNF40) in bone development by using a conditional knockout mouse approach during different stages of osteoblast (OB) differentiation and maturation. RNF40 forms an obligate E3 ubiquitin ligase complex together with RNF20 and mediates the monoubiquitination of lysine 120 of histone H2B (H2BK120ub1). We provide evidence that RNF40 regulates OB differentiation in a stage-dependent manner. Additionally, we show that RNF40 is required for bone cell crosstalk whereby loss of RNF40 leads to a reduction in osteoclast numbers and function through modulation of vitamin D receptor (VDR)-induced Rankl expression in OBs. Taken together, these data imply an important role of RNF40-mediated H2Bub1 in bone formation and remodeling and provide a basis for further investigation of its anti-resorptive potential for the treatment of conditions such as osteoporosis or cancer-associated osteolysis. In this study we show that RNF40 is required in earlier stages of osteoblast differentiation and is involved in bone cell crosstalk by regulating vitamin D induced Rankl expression

2021-02-24 | GSE135628 | GEO

RNF40 exerts stage-dependent functions in differentiating osteoblasts and is essential for bone cell crosstalk [ChIP-seq]

2021-02-24 | GSE135627 | GEO

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