Disease-dependent Differently Methylated Regions (D-DMRs) of DNA are Enriched on the X Chromosome in Uterine Leiomyoma

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  • MAEKAWA Ryo
    Department of Obstetrics and Gynecology, Yamaguchi University Graduate School of Medicine, Ube 755-8505, Japan
  • YAGI Shintaro
    Laboratory of Cellular Biochemistry, Department of Animal Resource Sciences/Veterinary Medical Sciences, The University of Tokyo, Tokyo 113-8657, Japan
  • OHGANE Jun
    Laboratory of Cellular Biochemistry, Department of Animal Resource Sciences/Veterinary Medical Sciences, The University of Tokyo, Tokyo 113-8657, Japan
  • YAMAGATA Yoshiaki
    Department of Obstetrics and Gynecology, Yamaguchi University Graduate School of Medicine, Ube 755-8505, Japan
  • ASADA Hiromi
    Department of Obstetrics and Gynecology, Yamaguchi University Graduate School of Medicine, Ube 755-8505, Japan
  • TAMURA Isao
    Department of Obstetrics and Gynecology, Yamaguchi University Graduate School of Medicine, Ube 755-8505, Japan
  • SUGINO Norihiro
    Department of Obstetrics and Gynecology, Yamaguchi University Graduate School of Medicine, Ube 755-8505, Japan
  • SHIOTA Kunio
    Laboratory of Cellular Biochemistry, Department of Animal Resource Sciences/Veterinary Medical Sciences, The University of Tokyo, Tokyo 113-8657, Japan

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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.<br>

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