title: Histone demethylase JMJD2B coordinates H3K4/H3K9 methylation and promotes hormonally responsive breast carcinogenesis.
abstract: It is well-documented that the methylation of histone H3 lysine 4 (H3K4) and of H3K9 are mutually exclusive, an epigenetic phenomenon conserved from yeast to humans. How this opposed methylation modification is accomplished and coordinated in mammalian cells is poorly understood. Here we report that the H3K9 trimethyl demethylase JMJD2B is an integral component of the H3K4-specific methyltransferase, the mixed-lineage leukemia (MLL) 2 complex. We show that the JMJD2B/MLL2 complex is copurified with estrogen receptor α (ERα) and is required for ERα-regulated transcription. We demonstrate that H3K9 demethylation and H3K4 methylation are coordinated in ERα-activated transcription such that H3K9 demethylation is a prerequisite for H3K4 methylation. Significantly, depletion of JMJD2B impairs the estrogen-induced G(1)/S transition of the cell cycle in vitro and inhibits breast tumorigenesis in vivo. Interestingly, JMJD2B itself is an ERα target gene, and forms a feed-forward regulatory loop in regulation of the hormone response. Our results provide a molecular basis for the coordinated H3K4 methylation/H3K9 demethylation in transcription activation, link the trimethyl demethylase JMJD2B to euchromatin functions, and provide a mechanism for JMJD2B in breast carcinogenesis.
authors.affiliation: Key Laboratory of Carcinogenesis and Translational Research Ministry of Education, Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Shi
authors.forename: Luyang
authors.initials: L
authors.lastname: Sun
authors.forename: Qian
authors.initials: Q
authors.lastname: Li
authors.forename: Jing
authors.initials: J
authors.lastname: Liang
authors.forename: Wenhua
authors.initials: W
authors.lastname: Yu
authors.forename: Xia
authors.initials: X
authors.lastname: Yi
authors.forename: Xiaohan
authors.initials: X
authors.lastname: Yang
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Li
authors.forename: Xiao
authors.initials: X
authors.lastname: Han
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.forename: Chenghao
authors.initials: C
authors.lastname: Xuan
authors.forename: Zhi
authors.initials: Z
authors.lastname: Yao
authors.forename: Yongfeng
authors.initials: Y
authors.lastname: Shang
mesh_terms: D001943:Breast Neoplasms / Q000378:metabolism* / Q000503:physiopathology; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics / Q000502:physiology*; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism*; D006657:Histones / Q000378:metabolism*; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000378:metabolism*; D016086:Lentivirus; D008745:Methylation; D046912:Multiprotein Complexes / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism; D034622:RNA Interference; D014461:Ultracentrifugation
chemical_list: D004268:DNA-Binding Proteins; D047628:Estrogen Receptor alpha; D006657:Histones; C120898:KMT2D protein, human; D046912:Multiprotein Complexes; D009363:Neoplasm Proteins; D056484:Jumonji Domain-Containing Histone Demethylases; C523637:KDM4B protein, human; D011495:Histone-Lysine N-Methyltransferase