Genome-wide Transcription Factor binding maps reveal cell-specific changes in the regulatory architecture of human HSPC [HiChIP]

Hematopoietic stem and progenitor cells (HSPCs) rely on a complex interplay of transcription factors (TFs) to regulate their differentiation into mature blood cells. A heptad of TFs - FLI1, ERG, GATA2, RUNX1, TAL1, LYL1, LMO2 - has been shown to bind to regulatory elements in bulk CD34+ HSPCs. However, whether specific combinations of these TFs have distinct roles in regulating hematopoietic differentiation remained unknown. In this study, we mapped the genome-wide binding profiles of these TFs and other chromatin-associated markers in distinct HSPC subsets (HSC, CMP, GMP, MEP). We found that the heptad occupancy and enhancer-promoter interactions varied significantly across cell types and were associated with cell-type specific gene expression. Moreover, we observed distinct regulatory elements that were enriched with specific combinations of TFs, such as stem-cell specific elements with ERG, and myeloid and megakaryocyte-erythroid specific elements with combinations of FLI1, RUNX1, GATA2, TAL1, LYL1, and LMO2. These findings suggest that specific combinations of TFs play critical roles in the regulation of hematopoietic differentiation, and provide a valuable resource for the development of targeted therapies to manipulate specific HSPC subsets. HiChIP

造血干细胞与祖细胞（hematopoietic stem and progenitor cells，HSPCs）依赖转录因子（transcription factors，TFs）间的复杂相互作用，调控其向成熟血细胞的分化进程。已有研究证实，由FLI1、ERG、GATA2、RUNX1、TAL1、LYL1、LMO2组成的七转录因子组合，可结合于批量CD34+造血干细胞与祖细胞的调控元件区域。然而，这些转录因子的特定组合在调控造血分化过程中是否发挥独特作用，此前仍未明确。本研究中，我们绘制了上述转录因子及其他染色质相关标记物在不同造血干细胞与祖细胞亚群（HSC、CMP、GMP、MEP）中的全基因组结合谱。研究发现，该七转录因子组合的结合占据情况与增强子-启动子相互作用在不同细胞类型间存在显著差异，且与细胞类型特异性基因表达密切相关。此外，我们还观测到多类具有特定转录因子组合富集特征的调控元件：例如，造血干细胞特异性调控元件富集ERG，而髓系及巨核细胞-红细胞特异性调控元件则富集FLI1、RUNX1、GATA2、TAL1、LYL1与LMO2的组合。上述研究结果表明，特定转录因子组合在造血分化调控中发挥关键作用，同时也为开发靶向调控特定造血干细胞与祖细胞亚群的治疗手段提供了宝贵的研究资源。HiChIP