Journal
CELL REPORTS
Volume 34, Issue 10, Pages -Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2021.108818
Keywords
-
Categories
Funding
- Canada Chair Program
- DeGroote Chair in Stem Cell Biology
- CCS Impact Grant - Canadian Institute of Health Research (CIHR) foundation [706694, FRN 159925]
Ask authors/readers for more resources
Phosphorylation state of HV H2A.X regulates self-renewal and differentiation of human pluripotent stem cells and leukemic progenitors, with potential implications for somatic cancer stem cell control by targeting specific genomic loci.
Histone variants (HVs) are a subfamily of epigenetic regulators implicated in embryonic development, but their role in human stem cell fate remains unclear. Here, we reveal that the phosphorylation state of the HV H2A.X (gamma H2A.X) regulates self-renewal and differentiation of human pluripotent stem cells (hPSCs) and leukemic progenitors. As demonstrated by CRISPR-Cas deletion, H2A.X is essential in maintaining normal hPSC behavior. However, reduced levels of gamma H2A.X enhances hPSC differentiation toward the hematopoietic lineage with concomitant inhibition of neural development. In contrast, activation and sustained levels of phosphorylated H2A.X enhance hPSC neural fate while suppressing hematopoiesis. This controlled lineage bias correlates to occupancy of gamma H2A.X at genomic loci associated with ectoderm versus mesoderm specification. Finally, drug modulation of H2A.X phosphorylation overcomes differentiation block of patientderived leukemic progenitors. Our study demonstrates HVs may serve to regulate pluripotent cell fate and that this biology could be extended to somatic cancer stem cell control.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available