Abstract
BackgroundUterine 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.Principal FindingsWe 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.ConclusionsThese results suggest a possible functional role of promoter DNA methylation-mediated gene silencing in the pathogenesis of uterine leiomyoma in African American women.
Highlights
Uterine leiomyomas or fibroids are benign smooth muscle tumors of myometrial origin; despite their benign nature, they are able to undergo rapid and considerable growth [1]
These results suggest a possible functional role of promoter DNA methylation-mediated gene silencing in the pathogenesis of uterine leiomyoma in African American women
One study demonstrated that hypomethylation of ESR1 in uterine leiomyoma correlates with increased mRNA expression in uterine leiomyoma [11]. These findings suggest that, DNA methylation might play a key role in the pathogenesis of uterine leiomyoma by altering the normal myometrial mRNA expression profile
Summary
Uterine leiomyomas or fibroids are benign smooth muscle tumors of myometrial origin; despite their benign nature, they are able to undergo rapid and considerable growth [1]. Uterine leiomyomas are the most common gynecological tumors in women of reproductive age, and they become symptomatic in 25–30% of all women and in up to 70% of African American women of reproductive age [2]. African American women are 3 times more likely to develop symptomatic leiomyoma, which develops at earlier ages with more numerous and larger fibroids [3]. The surgical costs alone represent an economic burden of $2 billion per year [5], and when taking into account the social costs and associated long-term health problems, it is clear that better prevention and treatment options for women with uterine leiomyoma are urgently needed. Fibroids, represent the most common benign tumor of the female reproductive tract. Epigenetic dysregulation of individual genes has been demonstrated in leiomyoma cells; the in vivo genome-wide distribution of such epigenetic abnormalities remains unknown
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