title: Genome-wide DNA methylation analysis predicts an epigenetic switch for GATA factor expression in endometriosis.
abstract: Endometriosis is a gynecological disease defined by the extrauterine growth of endometrial-like cells that cause chronic pain and infertility. The disease is limited to primates that exhibit spontaneous decidualization, and diseased cells are characterized by significant defects in the steroid-dependent genetic pathways that typify this process. Altered DNA methylation may underlie these defects, but few regions with differential methylation have been implicated in the disease. We mapped genome-wide differences in DNA methylation between healthy human endometrial and endometriotic stromal cells and correlated this with gene expression using an interaction analysis strategy. We identified 42,248 differentially methylated CpGs in endometriosis compared to healthy cells. These extensive differences were not unidirectional, but were focused intragenically and at sites distal to classic CpG islands where methylation status was typically negatively correlated with gene expression. Significant differences in methylation were mapped to 403 genes, which included a disproportionally large number of transcription factors. Furthermore, many of these genes are implicated in the pathology of endometriosis and decidualization. Our results tremendously improve the scope and resolution of differential methylation affecting the HOX gene clusters, nuclear receptor genes, and intriguingly the GATA family of transcription factors. Functional analysis of the GATA family revealed that GATA2 regulates key genes necessary for the hormone-driven differentiation of healthy stromal cells, but is hypermethylated and repressed in endometriotic cells. GATA6, which is hypomethylated and abundant in endometriotic cells, potently blocked hormone sensitivity, repressed GATA2, and induced markers of endometriosis when expressed in healthy endometrial cells. The unique epigenetic fingerprint in endometriosis suggests DNA methylation is an integral component of the disease, and identifies a novel role for the GATA family as key regulators of uterine physiology-aberrant DNA methylation in endometriotic cells correlates with a shift in GATA isoform expression that facilitates progesterone resistance and disease progression.
authors.affiliation: Division of Reproductive Biology Research, Dept. Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States of America.
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Dyson
authors.affiliation: Laboratory of Computational Functional Genomics, Dept. Bioengineering, University of Illinois at Chicago, Chicago, Illinois, United States of America.
authors.forename: Damian
authors.initials: D
authors.lastname: Roqueiro
authors.affiliation: Division of Reproductive Biology Research, Dept. Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States of America.
authors.forename: Diana
authors.initials: D
authors.lastname: Monsivais
authors.affiliation: Division of Reproductive Biology Research, Dept. Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States of America.
authors.forename: C Mutlu
authors.initials: CM
authors.lastname: Ercan
authors.affiliation: Division of Reproductive Biology Research, Dept. Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States of America.
authors.forename: Mary Ellen
authors.initials: ME
authors.lastname: Pavone
authors.affiliation: Division of Reproductive Biology Research, Dept. Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States of America.
authors.forename: David C
authors.initials: DC
authors.lastname: Brooks
authors.affiliation: Division of Reproductive Biology Research, Dept. Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States of America.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Kakinuma
authors.affiliation: Division of Reproductive Biology Research, Dept. Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States of America.
authors.forename: Masanori
authors.initials: M
authors.lastname: Ono
authors.affiliation: Division of Reproductive Biology Research, Dept. Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States of America.
authors.forename: Nadereh
authors.initials: N
authors.lastname: Jafari
authors.affiliation: Laboratory of Computational Functional Genomics, Dept. Bioengineering, University of Illinois at Chicago, Chicago, Illinois, United States of America.
authors.forename: Yang
authors.initials: Y
authors.lastname: Dai
authors.affiliation: Division of Reproductive Biology Research, Dept. Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States of America.
authors.forename: Serdar E
authors.initials: SE
authors.lastname: Bulun
mesh_terms: D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics*; D018450:Disease Progression; D004715:Endometriosis / Q000235:genetics*; D004717:Endometrium / Q000002:abnormalities; D044127:Epigenesis, Genetic; D005260:Female; D050989:GATA2 Transcription Factor / Q000235:genetics*; D005786:Gene Expression Regulation; D015894:Genome, Human; D006801:Humans; D017154:Stromal Cells; D014591:Uterine Diseases / Q000235:genetics
chemical_list: D050989:GATA2 Transcription Factor