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

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.

PI3K pathway regulates ER-dependent transcription in breast cancer through the epigenetic regulator KMT2D

“…The possibility that PI3K-AKT signaling alters the transcriptional repertoires of cancer cells by modulating the function of additional histone methyltransferases remains to be investigated. In agreement with studies in which epigenetic regulators such as EZH2 (27–29), KDM5A (30), DOT1L (31), LSD1 (32), MLL3 (33), and others have been shown to be critical in oncogenesis, our findings highlight the importance of epigenetic regulators in cancer and their potential as therapeutic targets. The discovery of the specific role of KMT2D in the interplay between ER and PI3K signaling provides a rationale for epigenetically informed combination therapies with PI3K inhibitors in ER-positive breast cancer.…”

Novel Androgen Receptor Coregulator GRHL2 Exerts Both Oncogenic and Antimetastatic Functions in Prostate Cancer

“…Indeed, de novo motif generation identified a direct repeat of the FoxA1 motif as one of the most enriched sequences in the GRHL2-specific peak set (Figure 5C). Supporting this finding, the GRHL2 cistrome overlapped substantially (25-41%) with published LNCaP FoxA1 cistromes (Supplementary Figure 7), an interaction that was experimentally validated in a recent study (37). …”

Pioneer transcription factors shape the epigenetic landscape

“…Pax7 was suggested to recruit the MLL1/2 complex through interaction with its component protein WDR5 (61) and FoxA1 directs H3K4me1 deposition through recruitment of MLL3 at enhancers (62). Indeed, this complex has H3K4me1 methylation activity and thus may lead to enhancer activation.…”