PT  - JOURNAL ARTICLE
AU  - Yitzhak Reizel
AU  - Ashleigh Morgan
AU  - Long Gao
AU  - Yemin Lan
AU  - Elisabetta Manduchi
AU  - Eric L. Waite
AU  - Amber W. Wang
AU  - Andrew Wells
AU  - Klaus H. Kaestner
TI  - Collapse of the hepatic gene regulatory network in the absence of FoxA factors
AID  - 10.1101/2020.03.31.016006
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.03.31.016006
4099  - http://biorxiv.org/content/early/2020/04/01/2020.03.31.016006.short
4100  - http://biorxiv.org/content/early/2020/04/01/2020.03.31.016006.full
AB  - 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 hepatocyte dedifferentiation manifested by a massive reduction in the expression of key liver genes. Interestingly, expression 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 by HNF4α. Thus, the FoxA factors act continuously, guarding hepatic enhancer activity throughout life.