Department of Genetics, Human Genetics Institute of New Jersey, Rutgers University, Piscataway, NJ 08854, USA; Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903, USA.
Department of Genetics, Human Genetics Institute of New Jersey, Rutgers University, Piscataway, NJ 08854, USA.
Cell Rep. 2021 Jan 26;34(4):108679. doi: 10.1016/j.celrep.2020.108679.
Cells in renewing tissues exhibit dramatic transcriptional changes as they differentiate. The contribution of chromatin looping to tissue renewal is incompletely understood. Enhancer-promoter interactions could be relatively stable as cells transition from progenitor to differentiated states; alternatively, chromatin looping could be as dynamic as the gene expression from their loci. The intestinal epithelium is the most rapidly renewing mammalian tissue. Proliferative cells in crypts of Lieberkühn sustain a stream of differentiated cells that are continually shed into the lumen. We apply chromosome conformation capture combined with chromatin immunoprecipitation (HiChIP) and sequencing to measure enhancer-promoter interactions in progenitor and differentiated cells of the intestinal epithelium. Despite dynamic gene regulation across the differentiation axis, we find that enhancer-promoter interactions are relatively stable. Functionally, we find HNF4 transcription factors are required for chromatin looping at target genes. Depletion of HNF4 disrupts local chromatin looping, histone modifications, and target gene expression. This study provides insights into transcriptional regulatory mechanisms governing homeostasis in renewing tissues.
在分化过程中,更新组织中的细胞表现出显著的转录变化。染色质环化在组织更新中的作用尚未完全理解。增强子-启动子相互作用在细胞从祖细胞向分化状态转变的过程中可能相对稳定;或者,染色质环化可能像其基因座的基因表达一样具有动态性。肠道上皮是哺乳动物中更新最快的组织。Lieberkühn 隐窝中的增殖细胞维持着不断分化的细胞流,这些细胞不断脱落到腔中。我们应用染色质构象捕获结合染色质免疫沉淀(HiChIP)和测序来测量肠道上皮祖细胞和分化细胞中的增强子-启动子相互作用。尽管在分化轴上存在动态的基因调控,但我们发现增强子-启动子相互作用相对稳定。功能上,我们发现 HNF4 转录因子是靶基因染色质环化所必需的。HNF4 的耗竭会破坏局部染色质环化、组蛋白修饰和靶基因表达。这项研究为更新组织中维持内稳态的转录调控机制提供了深入了解。