PGE2 alters chromatin through H2A.Zvariant enhancer nucleosome modification to promote hematopoietic stem cell fate (ATAC-Seq)

Hematopoietic stem and progenitor cells (HSPCs) need require tight transcriptional regulation. In-depth knowledge on how epigenetic mechanisms regulate chromatin landscape in order to control gene expression, particularly in response to external stimuli, will be key to understand the pathogenesis of hematologic disorders and improve blood stem cell-based therapies. Prostaglandin E2 (PGE2) and its metabolically resistant analog 16,16-dimethyl-PGE2 (dmPGE2) were previously identified as a potent external stimulus to enhance HSPC engraftment. PGE2 has been evaluated in various clinical trials to improve engraftment of stem cells. To understand the mechanism of gene expression changes, Wwe identified that dmPGE2 mediates chromatin flexibility at HSPC-specific enhancers through histone-variant H2A.Z acetylation to promote master transcription factor (TF) binding and reinforce expression of genes involved in stem cell fate and engraftment. ATAC-seq was performed, after a 2hr pulse with either dmPGE2 or DMSO on human CD34+ HSPCs

造血干细胞与祖细胞（Hematopoietic stem and progenitor cells, HSPCs）需要严谨的转录调控。系统阐明表观遗传机制如何调控染色质景观以控制基因表达，尤其是在响应外界刺激时的调控逻辑，对于解析血液系统疾病的发病机制、优化基于造血干细胞的治疗策略具有关键意义。此前研究已证实，前列腺素E2（Prostaglandin E2, PGE2）及其代谢抗性类似物16,16-二甲基前列腺素E2（16,16-dimethyl-PGE2, dmPGE2）是增强HSPCs造血植入能力的强效外界刺激因子。PGE2已在多项临床试验中被用于提升干细胞的造血植入效率。为阐明基因表达变化的潜在机制，本研究发现dmPGE2可通过介导HSPCs特异性增强子区域的组蛋白变体H2A.Z乙酰化修饰，进而促进主转录因子（Transcription Factor, TF）结合，强化与干细胞命运及造血植入相关基因的表达。本研究对人类CD34+造血干细胞与祖细胞分别施以dmPGE2或二甲基亚砜（DMSO）2小时脉冲刺激后，开展了转座酶可及性测序（ATAC-seq）实验。