title: Global histone modification profiling reveals the epigenomic dynamics during malignant transformation in a four-stage breast cancer model.
abstract: BACKGROUND
  Epigenetic regulation has emerged to be the critical steps for tumorigenesis and metastasis. Multiple histone methyltransferase and demethylase have been implicated as tumor suppressors or oncogenes recently. But the key epigenomic events in cancer cell transformation still remain poorly understood.
  
  
  METHODS
  A breast cancer transformation model was established via stably expressing three oncogenes in primary breast epithelial cells. Chromatin immunoprecipitation followed by the next-generation sequencing of histone methylations was performed to determine epigenetic events during transformation. Western blot, quantitative RT-PCR, and immunostaining were used to determine gene expression in cells and tissues.
  
  
  RESULTS
  Histones H3K9me2 and me3, two repressive marks of transcription, decrease in in vitro breast cancer cell model and in vivo clinical tissues. A survey of enzymes related with H3K9 methylation indicated that KDM3A/JMJD1A, a demethylase for H3K9me1 and me2, gradually increases during cancer transformation and is elevated in patient tissues. KDM3A/JMJD1A deficiency impairs the growth of tumors in nude mice and transformed cell lines. Genome-wide ChIP-seq analysis reveals that the boundaries of decreased H3K9me2 large organized chromatin K9 modifications (LOCKs) are enriched with cancer-related genes, such as MYC and PAX3. Further studies show that KDM3A/JMJD1A directly binds to these oncogenes and regulates their transcription by removing H3K9me2 mark.
  
  
  CONCLUSIONS
  Our study demonstrates reduction of histones H3K9 me2 and me3, and elevation of KDM3A/JMJD1A as important events for breast cancer, and illustrates the dynamic epigenomic mechanisms during breast cancer transformation.
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Life Sciences, Wuhan University, Wuhan, 430072 Hubei China.
authors.forename: Quan-Yi
authors.initials: QY
authors.lastname: Zhao
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Life Sciences, Wuhan University, Wuhan, 430072 Hubei China.
authors.forename: Pin-Ji
authors.initials: PJ
authors.lastname: Lei
authors.affiliation: CAS-MPG Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, 200031 China.
authors.forename: Xiaoran
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Life Sciences, Wuhan University, Wuhan, 430072 Hubei China.
authors.forename: Jun-Yi
authors.initials: JY
authors.lastname: Zheng
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Life Sciences, Wuhan University, Wuhan, 430072 Hubei China.
authors.forename: Hui-Yi
authors.initials: HY
authors.lastname: Wang
authors.affiliation: Division of Gastroenterology, Department of Geriatrics, Zhongnan Hospital, Wuhan University, Wuhan, Hubei 430072 China.
authors.forename: Jiao
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Division of Gastroenterology, Department of Geriatrics, Zhongnan Hospital, Wuhan University, Wuhan, Hubei 430072 China.
authors.forename: Yi-Ming
authors.initials: YM
authors.lastname: Li
authors.affiliation: Division of Gastroenterology, Department of Geriatrics, Zhongnan Hospital, Wuhan University, Wuhan, Hubei 430072 China.
authors.forename: Mei
authors.initials: M
authors.lastname: Ye
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Life Sciences, Wuhan University, Wuhan, 430072 Hubei China.
authors.forename: Lianyun
authors.initials: L
authors.lastname: Li
authors.affiliation: CAS-MPG Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, 200031 China.
authors.forename: Gang
authors.initials: G
authors.lastname: Wei
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Life Sciences, Wuhan University, Wuhan, 430072 Hubei China.
authors.forename: Min
authors.initials: M
authors.lastname: Wu
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D044127:Epigenesis, Genetic; D057890:Epigenomics / Q000379:methods*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006657:Histones / Q000378:metabolism*; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000378:metabolism*; D061986:MCF-7 Cells; D008745:Methylation; D051379:Mice; D008819:Mice, Nude
chemical_list: D006657:Histones; D056484:Jumonji Domain-Containing Histone Demethylases; C530247:KDM3A protein, human
keywords: Breast cancer transformation; Epigenomics; H3K9 methylation; KDM3A; Transcription regulation