Transcription Factors GATA4 and HNF4A Control Distinct Aspects of Intestinal Homeostasis in Conjunction With the Transcription Factor CDX2 [Developmental Biology]

December 8th, 2014 by San Roman, A. K., Aronson, B. E., Krasinski, S. D., Shivdasani, R. A., Verzi, M. P.

Distinct groups of transcription factors (TFs) assemble at tissue-specific cis-regulatory sites, implying that different TF combinations may control different genes and cellular functions. Within such combinations, TFs that specify or maintain a lineage, and are therefore considered master regulators, may play a key role. Gene enhancers often attract these tissue-restricted TFs as well as TFs that are expressed more broadly. However, the contributions of the individual TFs toward combinatorial regulatory activity have not been examined critically in many cases in vivo. We address this question using a genetic approach in mice to inactivate the intestine-specifying and intestine-restricted factor CDX2, alone or in combination with its more broadly expressed partner factors, GATA4 or HNF4A. Compared to single mutants, each combination produced significantly greater defects and rapid lethality, through distinct anomalies. Intestines lacking Gata4 and Cdx2 were deficient in crypt cell replication, whereas combined loss of Hnf4a and Cdx2 specifically impaired viability and maturation of villus enterocytes. Integrated analysis of TF binding and of transcripts affected in Cdx2;Hnf4a compound mutant intestines indicated that this TF pair controls genes required to construct the apical brush border and absorb nutrients, including dietary lipids. This study thus defines combinatorial TF activities, their specific requirements during tissue homeostasis, and modules of transcriptional targets in intestinal epithelial cells in vivo.
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