FOXA1 Directs H3K4 Monomethylation at Enhancers via Recruitment of the Methyltransferase MLL3

Kamila M Jozwik,Igor Chernukhin,Aurelien A Serandour,Sankari Nagarajan,Jason S Carroll

doi:10.1016/j.celrep.2016.11.028

Kamila M Jozwik, Igor Chernukhin + Show 3 more

Open Access

https://doi.org/10.1016/j.celrep.2016.11.028

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Journal: Cell Reports	Publication Date: Dec 1, 2016
Citations: 125	License type: cc-by

Affiliation: Cancer Research UK, University of Cambridge

Abstract

SummaryFOXA1 is a pioneer factor that binds to enhancer regions that are enriched in H3K4 mono- and dimethylation (H3K4me1 and H3K4me2). We performed a FOXA1 rapid immunoprecipitation mass spectrometry of endogenous proteins (RIME) screen in ERα-positive MCF-7 breast cancer cells and 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. We performed MLL3 chromatin immunoprecipitation sequencing (ChIP-seq) in breast cancer cells, and MLL3 was shown to occupy regions marked by FOXA1 occupancy and H3K4me1 and H3K4me2. MLL3 binding was dependent on FOXA1, indicating that FOXA1 recruits MLL3 to chromatin. MLL3 silencing decreased H3K4me1 at enhancer elements but had no appreciable impact on H3K4me3 at enhancer elements. We propose a mechanism whereby the pioneer factor FOXA1 recruits the chromatin modifier MLL3 to facilitate the deposition of H3K4me1 histone marks, subsequently demarcating active enhancer elements.

Highlights

FOXA1 (Forkhead box protein A1) is a pioneer factor (Jozwik and Carroll, 2012) that binds to condensed chromatin and allows subsequent binding of other transcription factors
While it has been reported that FOXA1 binding requires H3K4me1/me2 marks (Lupien et al, 2008), more recent findings showed that exogenous expression of FOXA1 in the FOXA1-negative MDA-MB-231 cell line results in the acquisition of H3K4me1/me2 at FOXA1-bound sites (Serandour et al, 2011), suggesting that FOXA1 may contribute to deposition of the H3K4me1 and H3K4me2 marks rather than associate with enhancers that are demarcated by the presence of these marks
We hypothesized that this interaction may be functional, as the pioneer factor FOXA1 binds at enhancer regions enriched in H3K4me1/me2 histone marks and FOXA1 has been shown to contribute to the acquisition of the H3K4me1/me2 mark (Serandour et al, 2011)

Summary

Introduction

FOXA1 (Forkhead box protein A1) is a pioneer factor (Jozwik and Carroll, 2012) that binds to condensed chromatin and allows subsequent binding of other transcription factors. FOXA1 contributes to chromatin opening to facilitate binding of estrogen receptor a (ER) in breast cancer (Carroll et al, 2005) and androgen receptor (AR) in prostate and breast cancer cells (Robinson et al, 2011; Sahu et al, 2011; Yang and Yu, 2015). The order of these events is not resolved, yet FOXA1 binding and the H3K4me1/me signal result in a functional enhancer element that can recruit additional factors (such as ER) to drive expression of genes, including those involved in cell-cycle progression

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