Collapse of the hepatic gene regulatory network in the absence of FoxA factors

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 disp...

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Bibliographic Details
Published in:Genes & development 2020-08, Vol.34 (15-16), p.1039-1050
Main Authors: Reizel, Yitzhak, Morgan, Ashleigh, Gao, Long, Lan, Yemin, Manduchi, Elisabetta, Waite, Eric L, Wang, Amber W, Wells, Andrew, Kaestner, Klaus H
Format: Article
Language:English
Subjects:
Animals
Binding Sites
Chromatin - metabolism
Enhancer Elements, Genetic
Forkhead Transcription Factors - genetics
Forkhead Transcription Factors - metabolism
Forkhead Transcription Factors - physiology
Gene Expression Regulation
Gene Knockdown Techniques
Gene Regulatory Networks
Hepatocyte Nuclear Factor 3-alpha - genetics
Hepatocyte Nuclear Factor 3-beta - genetics
Hepatocyte Nuclear Factor 3-gamma - genetics
Hepatocyte Nuclear Factor 4 - metabolism
Liver - metabolism
Liver - pathology
Liver Failure - etiology
Liver Failure - pathology
Male
Mice
Nucleosomes
Research Paper
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Summary: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.
ISSN:0890-9369
1549-5477
DOI:10.1101/gad.337691.120