title: Disease-dependent differently methylated regions (D-DMRs) of DNA are enriched on the X chromosome in uterine leiomyoma.
abstract: Uterine leiomyoma is the most common benign tumor in women. Although responsible gene mutations have not been found in leiomyomas, they represent a progressive disease with irreversible symptoms. To characterize epigenetic features of uterine leiomyomas, the DNA methylation status of a paired sample of leiomyoma and normal myometrium was subjected to a microarray-based DNA methylation analysis with restriction tag-mediated amplification (D-REAM). In the leiomyoma, we identified an aberrant DNA methylation status for 463 hypomethylated and 318 hypermethylated genes. Although these changes occurred on all chromosomes, aberrantly hypomethylated genes were preferentially located on the X chromosome. Using paired samples of normal myometrium and leiomyoma from 6 hysterectomy patients, methylation-sensitive quantitative real-time PCR revealed 14 shared X chromosome genes with an abnormal DNA hypomethylation status (FAM9A, CPXCR1, CXORF45, TAF1, NXF5, VBP1, GABRE, DDX53, FHL1, BRCC3, DMD, GJB1, AP1S2 and  PCDH11X) and one hypermethylated locus (HDAC8). Expression of XIST, which is involved in X chromosome inactivation, was equivalent in the normal myometrium and leiomyoma, indicating that the epigenetic abnormality on the X chromosome did not result from aberration of XIST gene expression. Based on these data, a unique epigenetic signature for uterine leiomyomas has emerged. The 14 hypomethylated and one hypermethylated loci provide valuable biomarkers for understanding the molecular pathogenesis of leiomyoma.
authors.affiliation: Department of Obstetrics and Gynecology, Yamaguchi University Graduate School of Medicine, Ube 755-8505, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Maekawa
authors.forename: Shintaro
authors.initials: S
authors.lastname: Yagi
authors.forename: Jun
authors.initials: J
authors.lastname: Ohgane
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Yamagata
authors.forename: Hiromi
authors.initials: H
authors.lastname: Asada
authors.forename: Isao
authors.initials: I
authors.lastname: Tamura
authors.forename: Norihiro
authors.initials: N
authors.lastname: Sugino
authors.forename: Kunio
authors.initials: K
authors.lastname: Shiota
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D002874:Chromosome Mapping / Q000379:methods; D041321:Chromosomes, Human, X / Q000235:genetics* / Q000378:metabolism; D019175:DNA Methylation; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007889:Leiomyoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D046228:Microarray Analysis; D008875:Middle Aged; D008954:Models, Biological; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics*; D015854:Up-Regulation; D014594:Uterine Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology