组蛋白变体H2A.X的磷酸化状态控制人类干细胞和祖细胞的命运决定。

Phosphorylation state of the histone variant H2A.X controls human stem and progenitor cell fate decisions.

作者信息

Orlando Luca, Tanasijevic Borko, Nakanishi Mio, Reid Jennifer C, García-Rodríguez Juan L, Chauhan Kapil Dev, Porras Deanna P, Aslostovar Lili, Lu Justin D, Shapovalova Zoya, Mitchell Ryan R, Boyd Allison L, Bhatia Mickie

机构信息

McMaster University, Michael G. DeGroote School of Medicine, Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8N 3Z5, Canada.

出版信息

Cell Rep. 2021 Mar 9;34(10):108818. doi: 10.1016/j.celrep.2021.108818.

DOI:10.1016/j.celrep.2021.108818

PMID:33691101

Abstract

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 (γH2A.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 γH2A.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 γH2A.X at genomic loci associated with ectoderm versus mesoderm specification. Finally, drug modulation of H2A.X phosphorylation overcomes differentiation block of patient-derived 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.

摘要

组蛋白变体（HVs）是一类参与胚胎发育的表观遗传调控因子亚家族，但其在人类干细胞命运中的作用仍不清楚。在此，我们揭示了组蛋白变体H2A.X（γH2A.X）的磷酸化状态调控人类多能干细胞（hPSCs）和白血病祖细胞的自我更新与分化。如CRISPR-Cas基因敲除实验所示，H2A.X对维持hPSCs的正常行为至关重要。然而，γH2A.X水平降低会增强hPSCs向造血谱系的分化，同时抑制神经发育。相反，磷酸化H2A.X的激活及持续水平会增强hPSCs的神经分化命运，同时抑制造血作用。这种可控的谱系偏向与γH2A.X在与外胚层和中胚层分化相关的基因组位点上的占据情况相关。最后，对H2A.X磷酸化的药物调控克服了患者来源白血病祖细胞的分化阻滞。我们的研究表明，组蛋白变体可能用于调控多能细胞命运，并且这种生物学特性可能扩展到对体细胞癌干细胞的控制。