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Analysis of FoxA2 occupancy in mouse liver with endoderm ChIP-chip array

ABSTRACT: Understanding how silent genes can be competent for activation provides insight into development as well as cellular reprogramming and pathogenesis. We performed genomic location analysis of the pioneer transcription factor FoxA in the adult liver and found that about one-third of the FoxA bound sites are near silent genes, including genes without detectable RNA polymerase II. Virtually all of the FoxA-bound silent sites are within extended conserved sequences, suggesting possible function. Such sequences are enriched in motifs for transcriptional repressors, including for Rfx1. We found one such target site containing functional FoxA and Rfx1 sites is a cryptic enhancer 7 kb downstream of the Cdx2 gene, the latter being an effector of esophageal metaplasia. Indeed, Rfx1 sites restrict transcriptional activation by FoxA at the +7 kb Cdx2 element. Furthermore, Rfx1 expression in the esophageal epithelium becomes extinguished during its metaplastic progression to carcinoma. We propose that motif analysis of other transcription factors bound to silent genes can reveal unanticipated regulatory networks that provide insights into reprogramming and oncogenic progression.

ORGANISM(S): Mus musculus

PROVIDER: GSE23551 | GEO | 2011/07/19

SECONDARY ACCESSION(S): PRJNA131815

REPOSITORIES: GEO

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Project description:Converting epithelial into mesenchymal cells through epithelial-mesenchymal transition (EMT) requires massive changes in gene expression. How this is brought about is currently not clear. Here we examined the impact of the EMT master regulator SNAIL1 on the FOXA family of transcription factors which are distinguished by their particular competence to induce chromatin reorganization for the activation of transcriptional enhancer elements. We show that the expression of SNAIL1 and FOXA genes is anti-correlated in transcriptomes of colorectal tumors and cell lines. In two cellular EMT models, ectopically expressed Snail1 downregulates FOXA factors and directly represses FOXA1. To elucidate how FOXA factors contribute to the control of epithelial gene expression, we determined by ChIP-seq data analysis FOXA chromosomal distribution in relation to chromatin structural features characterizing distinct states of transcriptional activity. This revealed a preferential localization of FOXA1 and FOXA2 to transcriptional enhancers at signature genes that distinguish epithelial from mesenchymal colon tumors. To validate the significance of this association, we investigated the impact of FOXA factors on structure and function of transcriptional enhancers at the epithelial genes CDH1, CDX2 and EPHB3. Expression of dominant negative FOXA2 led to chromatin condensation at these enhancer elements. Site- directed mutagenesis of FOXA binding sites in reporter gene constructs and by genome- editing in situ impaired enhancer activity and completely abolished the active chromatin state of the EPHB3 enhancer. Conversely, expression of FOXA factors in cells with inactive CDX2 and EPHB3 enhancers led to chromatin opening and de novo deposition of the H3K4me1 and H3K27ac marks. These findings establish the pioneer function of FOXA factors at enhancer regions of epithelial genes and demonstrate their essential role in maintaining enhancer structure and function. Thus, by repressing FOXA family members, Snail1 targets transcription factors at strategically important positions in gene-regulatory hierarchies which may facilitate transcriptional reprogramming during EMT.

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Analysis of FoxA2 occupancy in mouse liver with endoderm ChIP-chip array

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