title: FOXA1 Directs H3K4 Monomethylation at Enhancers via Recruitment of the Methyltransferase MLL3.
abstract: FOXA1 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.
authors.affiliation: Cancer Research UK Cambridge Institute, University of Cambridge, Robinson Way, Cambridge CB2 ORE, UK.
authors.forename: Kamila M
authors.initials: KM
authors.lastname: Jozwik
authors.affiliation: Cancer Research UK Cambridge Institute, University of Cambridge, Robinson Way, Cambridge CB2 ORE, UK.
authors.forename: Igor
authors.initials: I
authors.lastname: Chernukhin
authors.affiliation: Cancer Research UK Cambridge Institute, University of Cambridge, Robinson Way, Cambridge CB2 ORE, UK; Genome Biology Unit, European Molecular Biology Laboratory, 69117 Heidelberg, Germany.
authors.forename: Aurelien A
authors.initials: AA
authors.lastname: Serandour
authors.affiliation: Cancer Research UK Cambridge Institute, University of Cambridge, Robinson Way, Cambridge CB2 ORE, UK. Electronic address: sankari.nagarajan@cruk.cam.ac.uk.
authors.forename: Sankari
authors.initials: S
authors.lastname: Nagarajan
authors.affiliation: Cancer Research UK Cambridge Institute, University of Cambridge, Robinson Way, Cambridge CB2 ORE, UK. Electronic address: jason.carroll@cruk.cam.ac.uk.
authors.forename: Jason S
authors.initials: JS
authors.lastname: Carroll
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D002843:Chromatin / Q000235:genetics*; D019175:DNA Methylation / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D004742:Enhancer Elements, Genetic; D047628:Estrogen Receptor alpha / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000235:genetics*; D006657:Histones / Q000235:genetics; D006801:Humans; D061986:MCF-7 Cells; D011401:Promoter Regions, Genetic
chemical_list: D002843:Chromatin; D004268:DNA-Binding Proteins; D047628:Estrogen Receptor alpha; C496499:FOXA1 protein, human; D051541:Hepatocyte Nuclear Factor 3-alpha; D006657:Histones; C452979:KMT2C protein, human
keywords: FOXA1; H3K4me1; MLL3; breast cancer; enhancers