title: Gene-specific patterns of coregulator requirements by estrogen receptor-α in breast cancer cells.
abstract: Progesterone receptor (PgR) controls the menstrual cycle, pregnancy, embryonic development, and homeostasis, and it plays important roles in breast cancer development and progression. However, the requirement of coregulators for estrogen-induced expression of the PgR gene has not been fully explored. Here we used RNA interference to demonstrate dramatic differences in requirements of 10 different coregulators for estrogen-regulated expression of six different genes, including PgR and the well-studied TFF1 (or pS2) gene in MCF-7 breast cancer cells. Full estrogen-induced expression of TFF1 required all ten coregulators, but PgR induction required only four of the 10 coregulators. Chromatin immunoprecipitation studies demonstrated several mechanisms responsible for the differential coregulator requirements. Actin-binding coregulator Flightless-I, required for TFF1 expression and recruited to that gene by estrogen receptor-α (ERα), is not required for PgR expression and not recruited to that gene. Protein acetyltransferase tat-interactive protein 60 and ATP-dependent chromatin remodeler Brahma Related Gene 1 are recruited to both genes but are required only for TFF1 expression. Histone methyltransferase G9a is recruited to both genes and required for estrogen-induced expression of TFF1 but negatively regulates estrogen-induced expression of PgR. In contrast, histone methyltransferase myeloid/lymphoid or mixed-lineage leukemia 1 (MLL1), pioneer factor Forkhead box A1, and p160 coregulator steroid receptor coactivator-3 are required for expression of and are recruited to both genes. Depletion of MLL1 decreased ERα binding to the PgR and TFF1 genes. In contrast, depletion of G9a enhanced ERα binding to the PgR gene but had no effect on ERα binding to the TFF1 gene. These studies suggest that differential promoter architecture is responsible for promoter-specific mechanisms of gene regulation.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Southern California/Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90089, USA.
authors.forename: Kwang
authors.initials: K
authors.lastname: Won Jeong
authors.forename: Rajas
authors.initials: R
authors.lastname: Chodankar
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Purcell
authors.forename: Danielle
authors.initials: D
authors.lastname: Bittencourt
authors.forename: Michael R
authors.initials: MR
authors.lastname: Stallcup
mesh_terms: D001943:Breast Neoplasms; D045744:Cell Line, Tumor; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D004958:Estradiol / Q000502:physiology; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D004967:Estrogens / Q000502:physiology; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006649:Histocompatibility Antigens / Q000378:metabolism; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D008745:Methylation; D051788:Myeloid-Lymphoid Leukemia Protein / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011499:Protein Processing, Post-Translational; D012319:RNA Polymerase II / Q000378:metabolism; D011980:Receptors, Progesterone / Q000235:genetics / Q000378:metabolism; D020218:Response Elements; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D000071163:Trefoil Factor-1; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D002843:Chromatin; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D004967:Estrogens; D006649:Histocompatibility Antigens; D006657:Histones; C497422:KMT2A protein, human; D011980:Receptors, Progesterone; C051838:TFF1 protein, human; D014157:Transcription Factors; D000071163:Trefoil Factor-1; D025521:Tumor Suppressor Proteins; D051788:Myeloid-Lymphoid Leukemia Protein; D004958:Estradiol; C445405:EHMT2 protein, human; D011495:Histone-Lysine N-Methyltransferase; D012319:RNA Polymerase II