PUBLICATION
Vitamin C-dependent lysine demethylase 6 (KDM6)-mediated demethylation promotes a chromatin state that supports the endothelial-to-hematopoietic transition
- Authors
- Zhang, T., Huang, K., Zhu, Y., Wang, T., Shan, Y., Long, B., Li, Y., Chen, Q., Wang, P., Zhao, S., Li, D., Wu, C., Kang, B., Gu, J., Mai, Y., Wang, Q., Li, J., Zhang, Y., Liang, Z., Guo, L., Wu, F., Su, S., Wang, J., Gao, M., Zhong, X., Liao, B., Chen, J., Zhang, X., Shu, X., Pei, D., Nie, J., Pan, G.
- ID
- ZDB-PUB-190726-2
- Date
- 2019
- Source
- The Journal of biological chemistry 294(37): 13657-13670 (Journal)
- Registered Authors
- Keywords
- H3K27me3, cell differentiation, chromatin regulation, epigenetics, hematopoiesis, hematopoietic stem cells, human pluripotent stem cells, lysine demethylase 6 (KDM6), vitamin C, zebrafish
- MeSH Terms
-
- Animals
- Animals, Genetically Modified
- Ascorbic Acid/metabolism*
- Cell Differentiation/genetics
- Cell Differentiation/physiology
- Chromatin/metabolism
- Chromatin/physiology
- Demethylation
- Endothelial Cells/metabolism
- Hematopoietic Stem Cells/metabolism*
- Histone Demethylases/genetics
- Histone Demethylases/metabolism*
- Histones/metabolism
- Humans
- Jumonji Domain-Containing Histone Demethylases/metabolism
- Lysine/metabolism
- Methylation
- Pluripotent Stem Cells/metabolism
- Zebrafish/genetics
- PubMed
- 31341023 Full text @ J. Biol. Chem.
Citation
Zhang, T., Huang, K., Zhu, Y., Wang, T., Shan, Y., Long, B., Li, Y., Chen, Q., Wang, P., Zhao, S., Li, D., Wu, C., Kang, B., Gu, J., Mai, Y., Wang, Q., Li, J., Zhang, Y., Liang, Z., Guo, L., Wu, F., Su, S., Wang, J., Gao, M., Zhong, X., Liao, B., Chen, J., Zhang, X., Shu, X., Pei, D., Nie, J., Pan, G. (2019) Vitamin C-dependent lysine demethylase 6 (KDM6)-mediated demethylation promotes a chromatin state that supports the endothelial-to-hematopoietic transition. The Journal of biological chemistry. 294(37):13657-13670.
Abstract
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, et al, 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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping