Faculty of Biology, Medicine and Health, University of Manchester, Michael Smith Building, Oxford Road, Manchester M13 9PT, UK.
Nucleic Acids Res. 2021 Feb 22;49(3):1345-1363. doi: 10.1093/nar/gkaa1281.
Enhancers play important roles in controlling gene expression in a choreographed spatial and temporal manner during development. However, it is unclear how these regulatory regions are established during differentiation. Here we investigated the genome-wide binding profile of the forkhead transcription factor FOXK2 in human embryonic stem cells (ESCs) and downstream cell types. This transcription factor is bound to thousands of regulatory regions in human ESCs, and binding at many sites is maintained as cells differentiate to mesendodermal and neural precursor cell (NPC) types, alongside the emergence of new binding regions. FOXK2 binding is generally associated with active histone marks in any given cell type. Furthermore newly acquired, or retained FOXK2 binding regions show elevated levels of activating histone marks following differentiation to NPCs. In keeping with this association with activating marks, we demonstrate a role for FOXK transcription factors in gene activation during NPC differentiation. FOXK2 occupancy in ESCs is therefore an early mark for delineating the regulatory regions, which become activated in later lineages.
增强子在发育过程中以协调的时空方式发挥重要作用，控制基因表达。然而，这些调控区域在分化过程中是如何建立的还不清楚。在这里，我们研究了叉头转录因子 FOXK2 在人类胚胎干细胞 (ESC) 和下游细胞类型中的全基因组结合谱。该转录因子在人类 ESC 中结合了数千个调控区域，并且随着细胞向中胚层和神经前体细胞 (NPC) 类型分化，许多结合位点的结合得以维持，同时也出现了新的结合区域。在任何给定的细胞类型中，FOXK2 结合通常与活性组蛋白标记相关。此外，在分化为 NPC 后，新获得或保留的 FOXK2 结合区域显示出激活组蛋白标记水平升高。与这种与激活标记的关联一致，我们证明了 FOXK 转录因子在 NPC 分化过程中的基因激活中的作用。因此，ESC 中的 FOXK2 占据是划定调控区域的早期标志，这些区域在后续谱系中被激活。
