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FoxA-dependent demethylation of DNA initiates epigenetic memory of cellular identity

ABSTRACT: Tissue-specific DNA methylation patterns are created by transcription factors that recruit methylation and demethylation enzymes to cis-regulatory elements. To date, it is not known whether transcription factors are needed to continuously maintain methylation profiles in development and mature tissues or whether they only establish these marks during organ development. We queried the role of the pioneer factor FoxA in generating hypomethylated DNA at liver enhancers. We discovered a set of FoxA binding sites that undergo regional, FoxA-dependent demethylation during organ development. Conditional ablation of FoxA genes in the adult liver demonstrated that continued FoxA presence was not required to maintain the hypomethylated state, even when massive cell proliferation was induced. This study provides strong evidence for the stable, epigenetic nature of tissue-specific DNA methylation patterns directed by lineage-determining transcription factors during organ development.

ORGANISM(S): Mus musculus

PROVIDER: GSE124384 | GEO | 2021/04/20

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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FoxA-dependent demethylation of DNA initiates epigenetic memory of cellular identity

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