title: Genome-wide DNA methylation indicates silencing of tumor suppressor genes in uterine leiomyoma.
abstract: BACKGROUND
  Uterine leiomyomas, or fibroids, represent the most common benign tumor of the female reproductive tract. Fibroids become symptomatic in 30% of all women and up to 70% of African American women of reproductive age. Epigenetic dysregulation of individual genes has been demonstrated in leiomyoma cells; however, the in vivo genome-wide distribution of such epigenetic abnormalities remains unknown.
  
  
  RESULTS
  We characterized and compared genome-wide DNA methylation and mRNA expression profiles in uterine leiomyoma and matched adjacent normal myometrial tissues from 18 African American women. We found 55 genes with differential promoter methylation and concominant differences in mRNA expression in uterine leiomyoma versus normal myometrium. Eighty percent of the identified genes showed an inverse relationship between DNA methylation status and mRNA expression in uterine leiomyoma tissues, and the majority of genes (62%) displayed hypermethylation associated with gene silencing. We selected three genes, the known tumor suppressors KLF11, DLEC1, and KRT19 and verified promoter hypermethylation, mRNA repression and protein expression using bisulfite sequencing, real-time PCR and western blot. Incubation of primary leiomyoma smooth muscle cells with a DNA methyltransferase inhibitor restored KLF11, DLEC1 and KRT19 mRNA levels.
  
  
  CONCLUSIONS
  These results suggest a possible functional role of promoter DNA methylation-mediated gene silencing in the pathogenesis of uterine leiomyoma in African American women.
authors.affiliation: Division of Reproductive Biology Research, Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States of America.
authors.forename: Antonia
authors.initials: A
authors.lastname: Navarro
authors.forename: Ping
authors.initials: P
authors.lastname: Yin
authors.forename: Diana
authors.initials: D
authors.lastname: Monsivais
authors.forename: Simon M
authors.initials: SM
authors.lastname: Lin
authors.forename: Pan
authors.initials: P
authors.lastname: Du
authors.forename: Jian-Jun
authors.initials: JJ
authors.lastname: Wei
authors.forename: Serdar E
authors.initials: SE
authors.lastname: Bulun
mesh_terms: D000328:Adult; D001741:Black or African American / Q000235:genetics; D000704:Analysis of Variance; D001483:Base Sequence; D015153:Blotting, Western; D019175:DNA Methylation / Q000235:genetics / Q000502:physiology*; D017931:DNA Primers / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D020868:Gene Silencing / Q000502:physiology*; D016147:Genes, Tumor Suppressor / Q000502:physiology*; D006801:Humans; D007889:Leiomyoma / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D008969:Molecular Sequence Data; D009215:Myometrium / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D014481:United States; D014594:Uterine Neoplasms / Q000235:genetics / Q000378:metabolism*
chemical_list: D017931:DNA Primers; D012333:RNA, Messenger