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

Yitzhak ReizelAshleigh MorganLong GaoYemin LanElisabetta ManduchiEric L WaiteAmber W WangAndrew WellsKlaus H Kaestner
Published in: Genes & development (2020)
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.
Keyphrases
  • transcription factor
  • genome wide identification
  • dna binding
  • genome wide
  • poor prognosis
  • gene expression
  • bioinformatics analysis
  • dna damage
  • young adults
  • nuclear factor
  • childhood cancer