Cookies on this website
We use cookies to ensure that we give you the best experience on our website. If you click 'Continue' we'll assume that you are happy to receive all cookies and you won't see this message again. Click 'Find out more' for information on how to change your cookie settings.

The forkhead box A (FOXA) family of pioneer transcription factors is critical for the development of many endoderm-derived tissues. Their importance in regulating biological processes in the lung and liver is extensively characterized, though much less is known about their role in intestine. Here we investigate the contribution of FOXA2 to coordinating intestinal epithelial cell function using postconfluent Caco2 cells, differentiated into an enterocyte-like model. FOXA2 binding sites genome-wide were determined by ChIP-seq and direct targets of the factor were validated by ChIP-qPCR and siRNA-mediated depletion of FOXA1/2 followed by RT-qPCR. Peaks of FOXA2 occupancy were frequent at loci contributing to gene ontology pathways of regulation of cell migration, cell motion, and plasma membrane function. Depletion of both FOXA1 and FOXA2 led to a significant reduction in the expression of multiple transmembrane proteins including ion channels and transporters, which form a network that is essential for maintaining normal ion and solute transport. One of the targets was the adenosine A2B receptor, and reduced receptor mRNA levels were associated with a functional decrease in intracellular cyclic AMP. We also observed that 30% of FOXA2 binding sites contained a GATA motif and that FOXA1/A2 depletion reduced GATA-4, but not GATA-6 protein levels. These data show that FOXA2 plays a pivotal role in regulating intestinal epithelial cell function. Moreover, that the FOXA and GATA families of transcription factors may work cooperatively to regulate gene expression genome-wide in the intestinal epithelium.

Original publication

DOI

10.1152/physiolgenomics.00024.2015

Type

Journal article

Journal

Physiol Genomics

Publication Date

07/2015

Volume

47

Pages

290 - 297

Keywords

FOXA2, GATA-4, enterocyte function, ion and solute transport, Base Sequence, Blotting, Western, Caco-2 Cells, Cell Membrane, Cell Movement, Chromatin Immunoprecipitation, Cyclic AMP, Epithelial Cells, Gene Expression Regulation, Gene Library, Gene Ontology, Gene Regulatory Networks, Hepatocyte Nuclear Factor 3-beta, Humans, Intestinal Mucosa, Luciferases, Molecular Sequence Data, RNA, Small Interfering, Real-Time Polymerase Chain Reaction, Receptor, Adenosine A2B, Sequence Analysis, DNA