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Vitamin C–dependent lysine demethylase 6 (KDM6)-mediated demethylation promotes a chromatin state that supports the endothelial-to-hematopoietic transition

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE132970 | GEO | 2019/07/22

REPOSITORIES: GEO

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Vitamin C-dependent lysine demethylase 6 (KDM6)-mediated demethylation promotes a chromatin state that supports the endothelial-to-hematopoietic transition.

Project description:Hematopoietic stem cells (HSCs)/progenitor cells (HPCs) are generated from hemogenic endothelial cells (HECs) during the endothelial-to-hematopoietic transition (EHT); however, the underlying mechanism remains poorly understood. Here, using an array of approaches, including CRSPR/Cas9 gene knockouts, RNA-Seq, ChIP-Seq, ATAC-Seq etc., we report that vitamin C (Vc) is essential in HPC generation during human pluripotent stem cell (hPSC) differentiation in defined culture conditions. Mechanistically, we found that the endothelial cells generated in the absence of Vc fail to undergo the EHT because of an apparent failure in opening up genomic loci essential for hematopoiesis. Under Vc deficiency, these loci exhibited abnormal accumulation of histone H3 trimethylation at Lys-27 (H3K27me3), a repressive histone modification that arose because of lower activities of demethylases that target H3K27me3. Consistently, deletion of the two H3K27me3 demethylases, Jumonji domain-containing 3 (JMJD3 or KDM6B) and histone demethylase UTX (UTX or KDM6A), impaired HPC generation even in the presence of Vc. Furthermore, we noted that Vc and jmjd3 are also important for HSC generation during zebrafish development. Together, our findings reveal an essential role for Vc in the EHT for hematopoiesis, and identify KDM6-mediated chromatin demethylation as an important regulatory mechanism in hematopoietic cell differentiation.

| S-EPMC6746450 | biostudies-literature

Vitamin C-dependent lysine demethylase 6 (KDM6)-mediated demethylation promotes a chromatin state that supports the endothelial-to-hematopoietic transition

2019-07-22 | GSE132833 | GEO

Vitamin C dependent KDM6 demethylation specifies a functional chromatin state for endothelial-to-hematopoietic transition [RNA-Seq]

Project description:Hematopoietic stem/progenitor cells (HSPCs) are generated from hemogenic endothelial cells (HECs) through endothelial-to-hematopoietic transition (EHT); however, the underlying mechanism remains poorly understood. Here, we report that HPC generation is significantly reduced in hPSC differentiatiation in a defined condition without vitamin C (Vc). Mechanistically, the endothelial cells generated in the absence of Vc fail to undergo EHT due to apparent failure in opening genomic loci essential for hematopoiesis. These loci exhibit abnormal accumulation of H3K27me3, a repressive histone modification due to lower activity of its demethylases. Consistently, deletion of H3K27me3 demethylases, JMJD3 and UTX, impaires HPC generation in the presence of Vc. Furthermore, Vc and jmjd3 are also important for HSC generation during zebrafish development. Together, we reveal an obligatory role of Vc underlying EHT process in hematopoisis and further support the important function of Vc during development.

2019-07-22 | GSE132969 | GEO

Vitamin C dependent KDM6 demethylation specifies a functional chromatin state for endothelial-to-hematopoietic transition [ChIP-Seq]

2019-07-22 | GSE132834 | GEO

Vitamin C–dependent lysine demethylase 6 (KDM6)-mediated demethylation promotes a chromatin state that supports the endothelial-to-hematopoietic transition

Project description:Vitamin C–dependent lysine demethylase 6 (KDM6)-mediated demethylation promotes a chromatin state that supports the endothelial-to-hematopoietic transition

| PRJNA549595 | ENA

Vitamin C-dependent lysine demethylase 6 (KDM6)-mediated demethylation promotes a chromatin state that supports the endothelial-to-hematopoietic transition

Project description:Vitamin C-dependent lysine demethylase 6 (KDM6)-mediated demethylation promotes a chromatin state that supports the endothelial-to-hematopoietic transition

| PRJNA549250 | ENA

KDM6 demethylase independent loss of histone H3 lysine 27 trimethylation during early embryonic development.

Project description:The early mammalian embryo utilizes histone H3 lysine 27 trimethylation (H3K27me3) to maintain essential developmental genes in a repressive chromatin state. As differentiation progresses, H3K27me3 is removed in a distinct fashion to activate lineage specific patterns of developmental gene expression. These rapid changes in early embryonic chromatin environment are thought to be dependent on H3K27 demethylases. We have taken a mouse genetics approach to remove activity of both H3K27 demethylases of the Kdm6 gene family, Utx (Kdm6a, X-linked gene) and Jmjd3 (Kdm6b, autosomal gene). Male embryos null for active H3K27 demethylation by the Kdm6 gene family survive to term. At mid-gestation, embryos demonstrate proper patterning and activation of Hox genes. These male embryos retain the Y-chromosome UTX homolog, UTY, which cannot demethylate H3K27me3 due to mutations in catalytic site of the Jumonji-C domain. Embryonic stem (ES) cells lacking all enzymatic KDM6 demethylation exhibit a typical decrease in global H3K27me3 levels with differentiation. Retinoic acid differentiations of these ES cells demonstrate loss of H3K27me3 and gain of H3K4me3 to Hox promoters and other transcription factors, and induce expression similar to control cells. A small subset of genes exhibit decreased expression associated with reduction of promoter H3K4me3 and some low-level accumulation of H3K27me3. Finally, Utx and Jmjd3 mutant mouse embryonic fibroblasts (MEFs) demonstrate dramatic loss of H3K27me3 from promoters of several Hox genes and transcription factors. Our results indicate that early embryonic H3K27me3 repression can be alleviated in the absence of active demethylation by the Kdm6 gene family.

| S-EPMC4125042 | biostudies-literature

Vitamin C dependent KDM6 demethylation specifies a functional chromatin state for endothelial-to-hematopoietic transition [ChIP-Seq]

Project description:Vitamin C dependent KDM6 demethylation specifies a functional chromatin state for endothelial-to-hematopoietic transition [ChIP-Seq]

| PRJNA549249 | ENA

Vitamin C dependent KDM6 demethylation specifies a functional chromatin state for endothelial-to-hematopoietic transition [RNA-Seq]

Project description:Vitamin C dependent KDM6 demethylation specifies a functional chromatin state for endothelial-to-hematopoietic transition [RNA-Seq]

| PRJNA549598 | ENA

RNA-dependent chromatin localization of KDM4D lysine demethylase promotes H3K9me3 demethylation.

Project description:The JmjC-containing lysine demethylase, KDM4D, demethylates di-and tri-methylation of histone H3 on lysine 9 (H3K9me3). How KDM4D is recruited to chromatin and recognizes its histone substrates remains unknown. Here, we show that KDM4D binds RNA independently of its demethylase activity. We mapped two non-canonical RNA binding domains: the first is within the N-terminal spanning amino acids 115 to 236, and the second is within the C-terminal spanning amino acids 348 to 523 of KDM4D. We also demonstrate that RNA interactions with KDM4D N-terminal region are critical for its association with chromatin and subsequently for demethylating H3K9me3 in cells. This study implicates, for the first time, RNA molecules in regulating the levels of H3K9 methylation by affecting KDM4D association with chromatin.

| S-EPMC4245933 | biostudies-literature

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