Rutgers, the State University of New Jersey, Department of Genetics, Piscataway, NJ 08854, USA.
Cancer Institute of New Jersey, and Human Genetics Institute of New Jersey, Piscataway, NJ 08854, USA.
Development. 2019 Mar 1;146(5):dev172189. doi: 10.1242/dev.172189.
Lineage-restricted transcription factors, such as the intestine-specifying factor CDX2, often have dual requirements across developmental time. Embryonic loss of CDX2 triggers homeotic transformation of intestinal fate, whereas adult-onset loss compromises crucial physiological functions but preserves intestinal identity. It is unclear how such diverse requirements are executed across the developmental continuum. Using primary and engineered human tissues, mouse genetics, and a multi-omics approach, we demonstrate that divergent CDX2 loss-of-function phenotypes in embryonic versus adult intestines correspond to divergent CDX2 chromatin-binding profiles in embryonic versus adult stages. CDX2 binds and activates distinct target genes in developing versus adult mouse and human intestinal cells. We find that temporal shifts in chromatin accessibility correspond to these context-specific CDX2 activities. Thus, CDX2 is not sufficient to activate a mature intestinal program; rather, CDX2 responds to its environment, targeting stage-specific genes to contribute to either intestinal patterning or mature intestinal function. This study provides insights into the mechanisms through which lineage-specific regulatory factors achieve divergent functions over developmental time.
谱系限制转录因子，如肠道特异性因子 CDX2，通常在发育时间上具有双重要求。胚胎期 CDX2 的缺失会引发肠道命运的同源转化，而成年期的缺失则会损害关键的生理功能，但保留肠道身份。目前尚不清楚这种多样化的要求如何在整个发育过程中执行。通过使用原代和工程化的人类组织、小鼠遗传学和多组学方法，我们证明了胚胎期和成年期肠道中不同的 CDX2 功能丧失表型与胚胎期和成年期 CDX2 染色质结合谱的不同相对应。CDX2 在发育中和成年的小鼠和人类肠道细胞中结合并激活不同的靶基因。我们发现，染色质可及性的时间推移与这些特定于上下文的 CDX2 活性相对应。因此，CDX2 不足以激活成熟的肠道程序；相反，CDX2 会对其环境做出反应，靶向特定于阶段的基因，以促进肠道模式形成或成熟的肠道功能。这项研究为理解谱系特异性调节因子如何在发育时间上实现不同的功能提供了思路。
