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.
Development. 2019 Aug 6;146(19):dev179432. doi: 10.1242/dev.179432.
As embryos mature, cells undergo remarkable transitions that are accompanied by shifts in transcription factor regulatory networks. Mechanisms driving developmental transitions are incompletely understood. The embryonic intestine transitions from a rapidly proliferating tube with pseudostratified epithelium prior to murine embryonic day (E) 14.5 to an exquisitely folded columnar epithelium in fetal stages. We sought to identify factors driving mouse fetal intestinal maturation by mining chromatin accessibility data for transcription factor motifs. ATAC-seq accessible regions shift during tissue maturation, with CDX2 transcription factor motifs abundant at chromatin-accessible regions of the embryo. Hepatocyte nuclear factor 4 (HNF4) transcription factor motifs are the most abundant in the fetal stages (>E16.5). Genetic inactivation of and its paralog revealed that HNF4 factors are redundantly required for fetal maturation. CDX2 binds to and activates Hnf4 gene loci to elevate HNF4 expression at fetal stages. HNF4 and CDX2 transcription factors then occupy shared genomic regulatory sites to promote chromatin accessibility and gene expression in the maturing intestine. Thus, HNF4 paralogs are key components of an intestinal transcription factor network shift during the embryonic to fetal transition.
随着胚胎的成熟，细胞经历了显著的转变，伴随着转录因子调控网络的变化。驱动发育转变的机制尚未完全理解。胚胎肠道在小鼠胚胎第 14.5 天之前经历了从快速增殖的管状结构和假复层上皮向胎儿阶段的精致折叠柱状上皮的转变。我们通过挖掘染色质可及性数据中的转录因子基序，试图鉴定驱动小鼠胎儿肠道成熟的因素。ATAC-seq 可及区域在组织成熟过程中发生变化，CDX2 转录因子基序在胚胎的染色质可及区域丰富。肝细胞核因子 4 (HNF4) 转录因子基序在胎儿阶段（>E16.5）最为丰富。和其同源物的基因失活表明，HNF4 因子在胎儿成熟过程中是冗余的。CDX2 结合并激活 Hnf4 基因座，以在胎儿阶段提高 HNF4 的表达。然后，HNF4 和 CDX2 转录因子占据共享的基因组调控位点，以促进成熟肠道的染色质可及性和基因表达。因此，HNF4 同源物是胚胎到胎儿过渡期间肠道转录因子网络转变的关键组成部分。
