Apr 1, 2020

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

BioRxiv : the Preprint Server for Biology
Nicola NadeauChris Jiggins

Abstract

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 HNF4a. Thus, the FoxA factors act continuously, guarding hepatic enhancer activity throughout life.

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Mentioned in this Paper

Patterns
Cortex Bone Disorders
Adrenal Cortex Diseases
Genes
Heliconius numata
Heliconius erato
Drosophila
Mimetics
Gene Expression
Heterogeneous Nuclear RNA

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