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Genome-wide analysis of histone modifications H3K4me3, H3K4me1, and H3K27ac in primary human corneal epithelial cells

ABSTRACT: The corneal epithelium is a stratified squamous epithelium that protects the eye from mechanical and toxic stress. In this system, cells are continually being sloughed off from the surface of the eye, and replenished by proliferation from corneal stem cells in the limbus, which migrate in and differentiate. During tissue development and homeostasis, distal regulatory regions called enhancers, which contain binding sites for numerous transcription factors, help to control and coordinate gene expression in a temporal and spatial specific manner. To identify enhancers in cornea epithelia, we performed ChIP-Seq with antibodies to the histone marks H3K4me3, H3K4me1, and H3K27ac in primary human corneal epithelial cells. Active enhancers were defined as having high levels of H3K4me1 and H3K27ac, and low levels of H3K4me3: 12,900 such regions were identified in the corneal epithelial cells. In combination with primary cell histone modification ChIP-Seq data from BROAD, 2946 active enhancer regions were identified that are unique to the corneal epithelial cells: 1551 of theses 2946 also overlie regions of high evolutionary constraint. Motif enrichment analysis of these regions has revealed binding sites for a number of transcription factors, highlighting their roles as key regulators of corneal epithelial development.

ORGANISM(S): Homo sapiens

PROVIDER: GSE43499 | GEO | 2017/06/01

SECONDARY ACCESSION(S): PRJNA186601

REPOSITORIES: GEO

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Project description:FOXA1 is a pioneer factor that is important in hormone dependent cancer cells to stabilise nuclear receptors, such as estrogen receptor (ER) to chromatin. FOXA1 binds to enhancers regions that are enriched in H3K4mono- and dimethylation (H3K4me1, H3K4me2) histone marks and evidence suggests that these marks are requisite events for FOXA1 to associate with enhancers to initate subsequent gene expression events. However, exogenous expression of FOXA1 has been shown to induce H3K4me1 and H3K4me2 signal at enhancer elements and the order of events and the functional importance of these events is not clear. We performed a FOXA1 Rapid Immunoprecipitation Mass Spectrometry of Endogenous Proteins (RIME) screen in ERα-positive MCF-7 breast cancer cells in order to identify FOXA1 interacting partners and we found histone-lysine N-methyltransferase (MLL3) as the top FOXA1 interacting protein. MLL3 is typically thought to induce H3K4me3 at promoter regions, but recent findings suggest it may contribute to H3K4me1 deposition, in line with our observation that MLL3 associates with an enhancer specific protein. We performed MLL3 ChIP-seq in breast cancer cells and unexpectedly found that MLL3 binds mostly at non-promoter regions enhancers, in contrast to the prevailing hypothesis. MLL3 was shown to occupy regions marked by FOXA1 occupancy and as expected, H3K4me1 and H3K4me2. MLL3 binding was dependent on FOXA1, indicating that FOXA1 recruits MLL3 to chromatin. Motif analysis and subsequent genomic mapping revealed a role for Grainy head like protein-2 (GRHL2) which was shown to co-occupy regions of the chromatin with MLL3. Regions occupied by all three factors, namely FOXA1, MLL3 and GRHL2, were most enriched in H3K4me1. MLL3 silencing decreased H3K4me1 at enhancer elements, but had no appreciable impact on H3K4me3 at enhancer elements. We identify a complex relationship between FOXA1, MLL3 and H3K4me1 at enhancers in breast cancer and propose a mechanism whereby the pioneer factor FOXA1 can interact with a chromatin modifier MLL3, recruiting it to chromatin to facilitate the deposition of H3K4me1 histone marks, subsequently demarcating active enhancer elements.

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Genome-wide analysis of histone modifications H3K4me3, H3K4me1, and H3K27ac in primary human corneal epithelial cells

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