title: Establishment of active chromatin structure at enhancer elements by mixed-lineage leukemia 1 to initiate estrogen-dependent gene expression.
abstract: A number of genome-wide analyses have revealed that estrogen receptor α binding to and regulation of its target genes correlate with binding of FOXA1, a pioneer factor, to nearby DNA sites in MCF-7 breast cancer cells. The enhancer element-specific histone H3K4me1/2 mark is enriched at the specific FOXA1/ERα recruitment sites in chromatin, but the mechanism by which these enhancer marks are established in chromatin before hormone treatment is unclear. Here, we show that mixed-lineage leukemia 1 (MLL1) protein is a key determinant that maintains permissive chromatin structure of the TFF1 enhancer region. MLL1 occupies the TFF1 enhancer region and methylates H3K4 before hormone stimulation. In vitro, MLL1 binds directly to the CpG-rich region of the TFF1 enhancer, and its binding is dependent on hypomethylation of DNA. Furthermore, the depletion of MLL1 in MCF-7 cells results in a dramatic decrease of chromatin accessibility and recruitment of FOXA1 and ERα to the enhancer element. Our study defines the mechanism by which MLL1 nucleates histone H3K4 methylation marks in CpG-enriched regions to maintain permissive chromatin architecture and allow FOXA1 and estrogen receptor α binding to transcriptional regulatory sites in breast cancer cells.
authors.affiliation: Gachon Institute of Pharmaceutical Sciences, College of Pharmacy, Gachon University, Incheon 406-840, Republic of Korea, Departments of Urology and Biochemistry and Molecular Biology, USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089-9176, USA, Department of Biochemistry, School of Medicine, Konkuk University, Seoul 143-701, Republic of Korea and Department of Biochemistry and Molecular Biology, USC/Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089-9176, USA.
authors.forename: Kwang Won
authors.initials: KW
authors.lastname: Jeong
authors.forename: Claudia
authors.initials: C
authors.lastname: Andreu-Vieyra
authors.forename: Jueng Soo
authors.initials: JS
authors.lastname: You
authors.forename: Peter A
authors.initials: PA
authors.lastname: Jones
authors.forename: Michael R
authors.initials: MR
authors.lastname: Stallcup
mesh_terms: D002460:Cell Line; D002843:Chromatin / Q000737:chemistry* / Q000378:metabolism; D018899:CpG Islands; D004742:Enhancer Elements, Genetic; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005786:Gene Expression Regulation; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000378:metabolism; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D061986:MCF-7 Cells; D051788:Myeloid-Lymphoid Leukemia Protein / Q000378:metabolism*; D014158:Transcription, Genetic; D000071163:Trefoil Factor-1; D025521:Tumor Suppressor Proteins / Q000235:genetics
chemical_list: D002843:Chromatin; D047628:Estrogen Receptor alpha; D051541:Hepatocyte Nuclear Factor 3-alpha; C497422:KMT2A protein, human; C051838:TFF1 protein, human; D000071163:Trefoil Factor-1; D025521:Tumor Suppressor Proteins; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase