Epigenetic investigation of variably X chromosome inactivated genes in monozygotic female twins discordant for primary biliary cirrhosis

Michelle M. Mitchell, Ana Lleo, Luca Zammataro, Marlyn J. Mayo, Pietro Invernizzi, Nancy Bach, Shinji Shimoda, Stuart C. Gordon, Mauro Podda, M. Eric Gershwin, Carlo Selmi, Janine M. LaSalle

研究成果: ジャーナルへの寄稿記事

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Primary biliary cirrhosis (PBC) is an autoimmune chronic cholestatic liver disease with a strong genetic susceptibility due to the high concordance in monozygotic (MZ) twins and a striking female predominance. Women with PBC manifest an enhanced X monosomy rate in peripheral lymphocytes and we thus hypothesized an X chromosome epigenetic component to explain PBC female prevalence. While most genes on the female inactive X chromosome are silenced by promoter methylation following X chromosome inactivation (XCI), approximately 10% of X-linked genes exhibit variable escape from XCI in healthy females. This study was designed to test the hypothesis that susceptibility to PBC is modified by one or more X-linked gene with variable XCI status. Peripheral blood mRNA and DNA samples were obtained from a unique cohort of MZ twin sets discordant and concordant for PBC. Transcript levels of the 125 variable XCI status genes were determined by quantitative RT-PCR analysis and two genes (CLIC2 and PIN4) were identified as consistently downregulated in the affected twin of discordant pairs. Both CLIC2 and PIN4 demonstrated partial and variable methylation of CpG sites within 300 bp of the transcription start site that did not predict the XCI status. Promoter methylation of CLIC2 manifested no significant difference between samples and no significant correlation with transcript levels. PIN4 methylation showed a positive trend with transcription in all samples but no differential methylation was observed between discordant twins. A genetic polymorphism affecting the number of CpG sites in the PIN4 promoter did not impact methylation or transcript levels in a heterozygous twin pair and showed a similar frequency in independent series of unrelated PBC cases and controls. Our results suggest that epigenetic factors influencing PBC onset are more complex than methylation differences at X-linked promoters and variably inactivated X-linked genes may be characterized by partial promoter methylation and biallelic transcription.

元の言語英語
ページ(範囲)95-102
ページ数8
ジャーナルEpigenetics
6
発行部数1
DOI
出版物ステータス出版済み - 1 2011

    フィンガープリント

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cancer Research

これを引用

Mitchell, M. M., Lleo, A., Zammataro, L., Mayo, M. J., Invernizzi, P., Bach, N., ... LaSalle, J. M. (2011). Epigenetic investigation of variably X chromosome inactivated genes in monozygotic female twins discordant for primary biliary cirrhosis. Epigenetics, 6(1), 95-102. https://doi.org/10.4161/epi.6.1.13405