title: Reprogramming of the Epigenome by MLL1 Links Early-Life Environmental Exposures to Prostate Cancer Risk.
abstract: Tissue and organ development is a time of exquisite sensitivity to environmental exposures, which can reprogram developing tissues to increase susceptibility to adult diseases, including cancer. In the developing prostate, even brief exposure to endocrine-disrupting chemicals (EDCs) can increase risk for developing cancer in adulthood, with disruption of the epigenome thought to play a key role in this developmental reprogramming. We find that EDC-induced nongenomic phosphoinositide 3-kinase; (PI3K) signaling engages the histone methyltransferase mixed-lineage leukemia 1 (MLL1), responsible for the histone H3 lysine 4 trimethylation (H3K4me3) active epigenetic mark, to increase cleavage and formation of active MLL1 dimers. In the developing prostate, EDC-induced MLL1 activation increased H3K4me3 at genes associated with prostate cancer, with increased H3K4me3 and elevated basal and hormone-induced expression of reprogrammed genes persisting into adulthood. These data identify a mechanism for MLL1 activation that is vulnerable to disruption by environmental exposures, and link MLL1 activation by EDCs to developmental reprogramming of genes involved in prostate cancer.
authors.affiliation: Center for Translational Cancer Research (Q.W., L.S.T., R.L.Y.W., C.L.W.), Institute of Biosciences and Technology, Texas A&M University System Health Science Center, and Department of Molecular and Cellular Biology (C.E.F., C.C., B.W.O.), Baylor College of Medicine, Houston, Texas 77030; Department of Environmental Health (M.M., J.C., S.-m.H.), University of Cincinnati College of Medicine, Cincinnati, Ohio 45267; Department of Epigenetics and Molecular Carcinogenesis (J.S.), University of Texas MD Anderson Cancer Center, Smithville, Texas 78957; and Department of Biochemistry and Molecular Genetics (A.S.), Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611.
authors.forename: Quan
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Center for Translational Cancer Research (Q.W., L.S.T., R.L.Y.W., C.L.W.), Institute of Biosciences and Technology, Texas A&M University System Health Science Center, and Department of Molecular and Cellular Biology (C.E.F., C.C., B.W.O.), Baylor College of Medicine, Houston, Texas 77030; Department of Environmental Health (M.M., J.C., S.-m.H.), University of Cincinnati College of Medicine, Cincinnati, Ohio 45267; Department of Epigenetics and Molecular Carcinogenesis (J.S.), University of Texas MD Anderson Cancer Center, Smithville, Texas 78957; and Department of Biochemistry and Molecular Genetics (A.S.), Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611.
authors.forename: Lindsey S
authors.initials: LS
authors.lastname: Trevino
authors.affiliation: Center for Translational Cancer Research (Q.W., L.S.T., R.L.Y.W., C.L.W.), Institute of Biosciences and Technology, Texas A&M University System Health Science Center, and Department of Molecular and Cellular Biology (C.E.F., C.C., B.W.O.), Baylor College of Medicine, Houston, Texas 77030; Department of Environmental Health (M.M., J.C., S.-m.H.), University of Cincinnati College of Medicine, Cincinnati, Ohio 45267; Department of Epigenetics and Molecular Carcinogenesis (J.S.), University of Texas MD Anderson Cancer Center, Smithville, Texas 78957; and Department of Biochemistry and Molecular Genetics (A.S.), Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611.
authors.forename: Rebecca Lee Yean
authors.initials: RL
authors.lastname: Wong
authors.affiliation: Center for Translational Cancer Research (Q.W., L.S.T., R.L.Y.W., C.L.W.), Institute of Biosciences and Technology, Texas A&M University System Health Science Center, and Department of Molecular and Cellular Biology (C.E.F., C.C., B.W.O.), Baylor College of Medicine, Houston, Texas 77030; Department of Environmental Health (M.M., J.C., S.-m.H.), University of Cincinnati College of Medicine, Cincinnati, Ohio 45267; Department of Epigenetics and Molecular Carcinogenesis (J.S.), University of Texas MD Anderson Cancer Center, Smithville, Texas 78957; and Department of Biochemistry and Molecular Genetics (A.S.), Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611.
authors.forename: Mario
authors.initials: M
authors.lastname: Medvedovic
authors.affiliation: Center for Translational Cancer Research (Q.W., L.S.T., R.L.Y.W., C.L.W.), Institute of Biosciences and Technology, Texas A&M University System Health Science Center, and Department of Molecular and Cellular Biology (C.E.F., C.C., B.W.O.), Baylor College of Medicine, Houston, Texas 77030; Department of Environmental Health (M.M., J.C., S.-m.H.), University of Cincinnati College of Medicine, Cincinnati, Ohio 45267; Department of Epigenetics and Molecular Carcinogenesis (J.S.), University of Texas MD Anderson Cancer Center, Smithville, Texas 78957; and Department of Biochemistry and Molecular Genetics (A.S.), Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611.
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.affiliation: Center for Translational Cancer Research (Q.W., L.S.T., R.L.Y.W., C.L.W.), Institute of Biosciences and Technology, Texas A&M University System Health Science Center, and Department of Molecular and Cellular Biology (C.E.F., C.C., B.W.O.), Baylor College of Medicine, Houston, Texas 77030; Department of Environmental Health (M.M., J.C., S.-m.H.), University of Cincinnati College of Medicine, Cincinnati, Ohio 45267; Department of Epigenetics and Molecular Carcinogenesis (J.S.), University of Texas MD Anderson Cancer Center, Smithville, Texas 78957; and Department of Biochemistry and Molecular Genetics (A.S.), Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611.
authors.forename: Shuk-Mei
authors.initials: SM
authors.lastname: Ho
authors.affiliation: Center for Translational Cancer Research (Q.W., L.S.T., R.L.Y.W., C.L.W.), Institute of Biosciences and Technology, Texas A&M University System Health Science Center, and Department of Molecular and Cellular Biology (C.E.F., C.C., B.W.O.), Baylor College of Medicine, Houston, Texas 77030; Department of Environmental Health (M.M., J.C., S.-m.H.), University of Cincinnati College of Medicine, Cincinnati, Ohio 45267; Department of Epigenetics and Molecular Carcinogenesis (J.S.), University of Texas MD Anderson Cancer Center, Smithville, Texas 78957; and Department of Biochemistry and Molecular Genetics (A.S.), Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611.
authors.forename: Jianjun
authors.initials: J
authors.lastname: Shen
authors.affiliation: Center for Translational Cancer Research (Q.W., L.S.T., R.L.Y.W., C.L.W.), Institute of Biosciences and Technology, Texas A&M University System Health Science Center, and Department of Molecular and Cellular Biology (C.E.F., C.C., B.W.O.), Baylor College of Medicine, Houston, Texas 77030; Department of Environmental Health (M.M., J.C., S.-m.H.), University of Cincinnati College of Medicine, Cincinnati, Ohio 45267; Department of Epigenetics and Molecular Carcinogenesis (J.S.), University of Texas MD Anderson Cancer Center, Smithville, Texas 78957; and Department of Biochemistry and Molecular Genetics (A.S.), Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611.
authors.forename: Charles E
authors.initials: CE
authors.lastname: Foulds
authors.affiliation: Center for Translational Cancer Research (Q.W., L.S.T., R.L.Y.W., C.L.W.), Institute of Biosciences and Technology, Texas A&M University System Health Science Center, and Department of Molecular and Cellular Biology (C.E.F., C.C., B.W.O.), Baylor College of Medicine, Houston, Texas 77030; Department of Environmental Health (M.M., J.C., S.-m.H.), University of Cincinnati College of Medicine, Cincinnati, Ohio 45267; Department of Epigenetics and Molecular Carcinogenesis (J.S.), University of Texas MD Anderson Cancer Center, Smithville, Texas 78957; and Department of Biochemistry and Molecular Genetics (A.S.), Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611.
authors.forename: Cristian
authors.initials: C
authors.lastname: Coarfa
authors.affiliation: Center for Translational Cancer Research (Q.W., L.S.T., R.L.Y.W., C.L.W.), Institute of Biosciences and Technology, Texas A&M University System Health Science Center, and Department of Molecular and Cellular Biology (C.E.F., C.C., B.W.O.), Baylor College of Medicine, Houston, Texas 77030; Department of Environmental Health (M.M., J.C., S.-m.H.), University of Cincinnati College of Medicine, Cincinnati, Ohio 45267; Department of Epigenetics and Molecular Carcinogenesis (J.S.), University of Texas MD Anderson Cancer Center, Smithville, Texas 78957; and Department of Biochemistry and Molecular Genetics (A.S.), Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611.
authors.forename: Bert W
authors.initials: BW
authors.lastname: O'Malley
authors.affiliation: Center for Translational Cancer Research (Q.W., L.S.T., R.L.Y.W., C.L.W.), Institute of Biosciences and Technology, Texas A&M University System Health Science Center, and Department of Molecular and Cellular Biology (C.E.F., C.C., B.W.O.), Baylor College of Medicine, Houston, Texas 77030; Department of Environmental Health (M.M., J.C., S.-m.H.), University of Cincinnati College of Medicine, Cincinnati, Ohio 45267; Department of Epigenetics and Molecular Carcinogenesis (J.S.), University of Texas MD Anderson Cancer Center, Smithville, Texas 78957; and Department of Biochemistry and Molecular Genetics (A.S.), Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611.
authors.forename: Ali
authors.initials: A
authors.lastname: Shilatifard
authors.affiliation: Center for Translational Cancer Research (Q.W., L.S.T., R.L.Y.W., C.L.W.), Institute of Biosciences and Technology, Texas A&M University System Health Science Center, and Department of Molecular and Cellular Biology (C.E.F., C.C., B.W.O.), Baylor College of Medicine, Houston, Texas 77030; Department of Environmental Health (M.M., J.C., S.-m.H.), University of Cincinnati College of Medicine, Cincinnati, Ohio 45267; Department of Epigenetics and Molecular Carcinogenesis (J.S.), University of Texas MD Anderson Cancer Center, Smithville, Texas 78957; and Department of Biochemistry and Molecular Genetics (A.S.), Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611.
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: Walker
mesh_terms: D000818:Animals; D015153:Blotting, Western; D047369:Chromatin Immunoprecipitation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D052244:Endocrine Disruptors / Q000633:toxicity; D004781:Environmental Exposure / Q000009:adverse effects; D044127:Epigenesis, Genetic / Q000187:drug effects / Q000235:genetics*; D057809:HEK293 Cells; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics* / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D061986:MCF-7 Cells; D008297:Male; D008780:Methyltransferases / Q000235:genetics / Q000378:metabolism*; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics* / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; D052244:Endocrine Disruptors; D006657:Histones; C497422:KMT2A protein, human; C120898:KMT2D protein, human; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; D051788:Myeloid-Lymphoid Leukemia Protein; C473477:DOT1L protein, human; D008780:Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; D019869:Phosphatidylinositol 3-Kinases