title: Tissue-Specific Expression of Estrogen Receptor 1 Is Regulated by DNA Methylation in a T-DMR.
abstract: The mechanism controlling tissue-specific expression of estrogen receptor 1 (ESR1) is unclear. In other genes, DNA methylation of a region called the tissue-dependent and differentially methylated region (T-DMR) has been associated with tissue-specific gene expression. This study investigated whether human ESR1 has a T-DMR and whether DNA methylation of the T-DMR regulates its expression. ESR1 expression was tissue-specific, being high in the endometrium and mammary gland and low/nil in the placenta and skin. Therefore, DNA methylation profiles of the promoter of ESR1 were analyzed in these tissues and in breast cancer tissues. In all of the normal tissues, the proximal promoter regions were unmethylated. On the other hand, the distal regions (T-DMR) were unmethylated in the endometrium and mammary gland, but were moderately methylated and hypermethylated in the placenta and skin, respectively. T-DMR-methylated reporter assay was performed to examine whether DNA methylation at the T-DMR suppresses ESR1 transcription. T-DMR, but not the promoter region, had transcriptional activities and DNA methylation of the T-DMR suppressed ESR1 transcription. Early growth response protein 1 was shown to be a possible transcription factor to bind the T-DMR and up-regulate ESR1 expression. ESR1 has several upstream exons, and each upstream exon, Exon-A/Exon-B/Exon-C, had its own T-DMR. In some breast cancer cases and breast cancer cell lines, ESR1 expression was not regulated by DNA methylation at T-DMR as it is in normal tissues. In conclusion, ESR1 has a T-DMR. DNA methylation status at the T-DMR is involved in tissue-specific ESR1 expression in normal tissues but not always in breast cancer.
authors.affiliation: Departments of Obstetrics and Gynecology (R.M., S.S., M.O., L.L., I.T., K.J., T.K., H.A., Y.Y., H.T., N.S.) and Digestive Surgery and Surgical Oncology (S.Y.), Yamaguchi University Graduate School of Medicine, Ube 755-8505, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Maekawa
authors.affiliation: Departments of Obstetrics and Gynecology (R.M., S.S., M.O., L.L., I.T., K.J., T.K., H.A., Y.Y., H.T., N.S.) and Digestive Surgery and Surgical Oncology (S.Y.), Yamaguchi University Graduate School of Medicine, Ube 755-8505, Japan.
authors.forename: Shun
authors.initials: S
authors.lastname: Sato
authors.affiliation: Departments of Obstetrics and Gynecology (R.M., S.S., M.O., L.L., I.T., K.J., T.K., H.A., Y.Y., H.T., N.S.) and Digestive Surgery and Surgical Oncology (S.Y.), Yamaguchi University Graduate School of Medicine, Ube 755-8505, Japan.
authors.forename: Maki
authors.initials: M
authors.lastname: Okada
authors.affiliation: Departments of Obstetrics and Gynecology (R.M., S.S., M.O., L.L., I.T., K.J., T.K., H.A., Y.Y., H.T., N.S.) and Digestive Surgery and Surgical Oncology (S.Y.), Yamaguchi University Graduate School of Medicine, Ube 755-8505, Japan.
authors.forename: Lifa
authors.initials: L
authors.lastname: Lee
authors.affiliation: Departments of Obstetrics and Gynecology (R.M., S.S., M.O., L.L., I.T., K.J., T.K., H.A., Y.Y., H.T., N.S.) and Digestive Surgery and Surgical Oncology (S.Y.), Yamaguchi University Graduate School of Medicine, Ube 755-8505, Japan.
authors.forename: Isao
authors.initials: I
authors.lastname: Tamura
authors.affiliation: Departments of Obstetrics and Gynecology (R.M., S.S., M.O., L.L., I.T., K.J., T.K., H.A., Y.Y., H.T., N.S.) and Digestive Surgery and Surgical Oncology (S.Y.), Yamaguchi University Graduate School of Medicine, Ube 755-8505, Japan.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Jozaki
authors.affiliation: Departments of Obstetrics and Gynecology (R.M., S.S., M.O., L.L., I.T., K.J., T.K., H.A., Y.Y., H.T., N.S.) and Digestive Surgery and Surgical Oncology (S.Y.), Yamaguchi University Graduate School of Medicine, Ube 755-8505, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Kajimura
authors.affiliation: Departments of Obstetrics and Gynecology (R.M., S.S., M.O., L.L., I.T., K.J., T.K., H.A., Y.Y., H.T., N.S.) and Digestive Surgery and Surgical Oncology (S.Y.), Yamaguchi University Graduate School of Medicine, Ube 755-8505, Japan.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Asada
authors.affiliation: Departments of Obstetrics and Gynecology (R.M., S.S., M.O., L.L., I.T., K.J., T.K., H.A., Y.Y., H.T., N.S.) and Digestive Surgery and Surgical Oncology (S.Y.), Yamaguchi University Graduate School of Medicine, Ube 755-8505, Japan.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Yamagata
authors.affiliation: Departments of Obstetrics and Gynecology (R.M., S.S., M.O., L.L., I.T., K.J., T.K., H.A., Y.Y., H.T., N.S.) and Digestive Surgery and Surgical Oncology (S.Y.), Yamaguchi University Graduate School of Medicine, Ube 755-8505, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Tamura
authors.affiliation: Departments of Obstetrics and Gynecology (R.M., S.S., M.O., L.L., I.T., K.J., T.K., H.A., Y.Y., H.T., N.S.) and Digestive Surgery and Surgical Oncology (S.Y.), Yamaguchi University Graduate School of Medicine, Ube 755-8505, Japan.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Yamamoto
authors.affiliation: Departments of Obstetrics and Gynecology (R.M., S.S., M.O., L.L., I.T., K.J., T.K., H.A., Y.Y., H.T., N.S.) and Digestive Surgery and Surgical Oncology (S.Y.), Yamaguchi University Graduate School of Medicine, Ube 755-8505, Japan.
authors.forename: Norihiro
authors.initials: N
authors.lastname: Sugino
mesh_terms: D001483:Base Sequence; D001943:Breast Neoplasms / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics*; D047628:Estrogen Receptor alpha / Q000235:genetics* / Q000378:metabolism; D005091:Exons / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D006657:Histones / Q000378:metabolism; D006801:Humans; D061986:MCF-7 Cells; D009928:Organ Specificity / Q000235:genetics*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
chemical_list: C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D006657:Histones; D012333:RNA, Messenger; D014157:Transcription Factors