Department of Genetics, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Epigenetics Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Genes Dev. 2020 Aug 1;34(15-16):1039-1050. doi: 10.1101/gad.337691.120. Epub 2020 Jun 19.
The FoxA transcription factors are critical for liver development through their pioneering activity, which initiates a highly complex regulatory network thought to become progressively resistant to the loss of any individual hepatic transcription factor via mutual redundancy. To investigate the dispensability of FoxA factors for maintaining this regulatory network, we ablated all FoxA genes in the adult mouse liver. Remarkably, loss of FoxA caused rapid and massive reduction in the expression of critical liver genes. Activity of these genes was reduced back to the low levels of the fetal prehepatic endoderm stage, leading to necrosis and lethality within days. Mechanistically, we found FoxA proteins to be required for maintaining enhancer activity, chromatin accessibility, nucleosome positioning, and binding of HNF4α. Thus, the FoxA factors act continuously, guarding hepatic enhancer activity throughout adult life.
FoxA 转录因子通过其开拓性活动对于肝脏发育至关重要，这种活动启动了一个高度复杂的调控网络，人们认为该网络通过相互冗余而逐渐抵抗任何单个肝转录因子的缺失。为了研究 FoxA 因子对于维持这个调控网络的可有可无性，我们在成年小鼠肝脏中敲除了所有的 FoxA 基因。值得注意的是，FoxA 的缺失导致关键肝脏基因的表达迅速且大量减少。这些基因的活性降低到胎儿前肝内胚层阶段的低水平，导致数天内坏死和死亡。从机制上讲，我们发现 FoxA 蛋白对于维持增强子活性、染色质可及性、核小体定位和 HNF4α 的结合是必需的。因此，FoxA 因子持续发挥作用，在成年期保护肝增强子活性。
