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Collapse of the hepatic gene regulatory network in the absence of FoxA factors.
Genes & Development ( IF 10.5 ) Pub Date : 2020-08-01 , DOI: 10.1101/gad.337691.120
Yitzhak Reizel 1 , Ashleigh Morgan 1 , Long Gao 1 , Yemin Lan 2 , Elisabetta Manduchi 3 , Eric L Waite 1 , Amber W Wang 1 , Andrew Wells 4 , Klaus H Kaestner 1, 2
Affiliation  

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.

中文翻译:

在没有 FoxA 因子的情况下肝基因调控网络的崩溃。

FoxA 转录因子通过其开创性活动对肝脏发育至关重要,它启动了一个高度复杂的调节网络,被认为通过相互冗余逐渐抵抗任何单个肝脏转录因子的损失。为了研究 FoxA 因子对维持这种调节网络的可有性,我们消融了成年小鼠肝脏中的所有 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而大量减少。这些基因的活性降低到胎儿肝前内胚层阶段的低水平,在几天内导致坏死和死亡。从机制上讲,我们发现 FoxA 蛋白是维持增强子活性、染色质可及性、核小体定位和 HNF4α 结合所必需的。因此,
更新日期:2020-08-03
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