Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, 30322, USA.
State Key Laboratory of Cellular Stress Biology, Fujian Provincial Key Laboratory of Reproductive Health Research, School of Medicine, Faculty of Medicine and Life Sciences, Xiamen University, 361102, Xiamen, China.
Nat Commun. 2023 Oct 9;14(1):6314. doi: 10.1038/s41467-023-41964-6.
Transcription reprogramming during cell differentiation involves targeting enhancers to genes responsible for establishment of cell fates. To understand the contribution of CTCF-mediated chromatin organization to cell lineage commitment, we analyzed 3D chromatin architecture during the differentiation of human embryonic stem cells into pancreatic islet organoids. We find that CTCF loops are formed and disassembled at different stages of the differentiation process by either recruitment of CTCF to new anchor sites or use of pre-existing sites not previously involved in loop formation. Recruitment of CTCF to new sites in the genome involves demethylation of H3K9me3 to H3K9me2, demethylation of DNA, recruitment of pioneer factors, and positioning of nucleosomes flanking the new CTCF sites. Existing CTCF sites not involved in loop formation become functional loop anchors via the establishment of new cohesin loading sites containing NIPBL and YY1 at sites between the new anchors. In both cases, formation of new CTCF loops leads to strengthening of enhancer promoter interactions and increased transcription of genes adjacent to loop anchors. These results suggest an important role for CTCF and cohesin in controlling gene expression during cell differentiation.
在细胞分化过程中的转录重编程涉及到将增强子靶向负责建立细胞命运的基因。为了了解 CTCF 介导的染色质组织对细胞谱系决定的贡献，我们分析了人类胚胎干细胞分化为胰岛类器官过程中的三维染色质结构。我们发现，CTCF 环在分化过程的不同阶段形成和解体，要么是通过募集 CTCF 到新的锚定点，要么是利用以前未参与环形成的预先存在的位点。CTCF 向基因组中新位点的募集涉及 H3K9me3 向 H3K9me2 的去甲基化、DNA 的去甲基化、先驱因子的募集以及围绕新 CTCF 位点的核小体的定位。以前不参与环形成的现有 CTCF 位点通过在新锚定点之间的位点建立含有 NIPBL 和 YY1 的新黏合蛋白加载位点而成为功能性环锚定点。在这两种情况下，新 CTCF 环的形成导致增强子启动子相互作用增强，并且与环锚定点相邻的基因的转录增加。这些结果表明 CTCF 和黏合蛋白在细胞分化过程中控制基因表达中起着重要作用。
