Scholarlink

<p>We analyze 10,986 participants (mean age 77; 63% women; 54% non-White) across seven U.S. cohorts to study the relationship between mitochondrial DNA (mtDNA) heteroplasmy and nuclear DNA methylation. We identify 597 CpGs associated with heteroplasmy burden, generally showing lower methylation. These CpGs are enriched in dynamically regulated island shores and depleted in CpG islands, indicating involvement in context-specific rather than constitutive gene regulation. In HEK293T cells, we introduce a truncating mtDNA mutation (MT-COX3, mt.9979) and observe a positive correlation between variant allele fraction and methylation at cg04569152, supporting a direct mtDNA–nDNA epigenetic link. Many heteroplasmy-associated CpGs overlap with known methylation-trait associations for metabolic and behavioral traits. Composite CpG scores predict all-cause mortality and incident CVD, with one-unit increases associated with 1.27-fold and 1.12-fold higher hazards, respectively. These findings suggest an mtDNA–nDNA epigenetic connection in aging and disease, though its direction and mechanisms remain to be studied.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Epigenome-wide association study of nuclear DNA methylation in relation to mitochondrial heteroplasmy

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年12月2日

查看全文
  • Meng Lai,
  • Kyeezu Kim,
  • Yinan Zheng,
  • Christina A. Castellani,
  • Scott M. Ratliff,
  • Mengyao Wang,
  • Xue Liu,
  • Jeffrey Haessler,
  • Tianxiao Huan,
  • Kwadwo Bonsu,
  • Charles Newcomb,
  • Kyler McKessy,
  • Lawrence F. Bielak,
  • Wei Zhao,
  • Roby Joehanes,
  • Jiantao Ma,
  • Xiuqing Guo,
  • JoAnn E. Manson,
  • Megan L. Grove,
  • Jan Bressler,
  • Kent D. Taylor,
  • Tuuli Lappalainen,
  • Silva Kasela,
  • Thomas W. Blackwell,
  • Nicole J. Lake,
  • Jessica D. Faul,
  • Kendra R. Ferrier,
  • Stephen C. Ekker,
  • Lifang Hou,
  • Charles Kooperberg,
  • Alexander P. Reiner,
  • Kai Zhang,
  • Patricia A. Peyser,
  • Myriam Fornage,
  • Eric Boerwinkle,
  • Laura M. Raffield,
  • April P. Carson,
  • Stephen S. Rich,
  • Yongmei Liu,
  • Daniel Levy,
  • Jerome I. Rotter,
  • Jennifer A. Smith,
  • Dan E. Arking,
  • Chunyu Liu,
  • Dan E. Arking,
  • Christina A. Castellani,
  • JoAnn E. Manson,
  • Wei Zhao,
  • Chunyu Liu

摘要

We analyze 10,986 participants (mean age 77; 63% women; 54% non-White) across seven U.S. cohorts to study the relationship between mitochondrial DNA (mtDNA) heteroplasmy and nuclear DNA methylation. We identify 597 CpGs associated with heteroplasmy burden, generally showing lower methylation. These CpGs are enriched in dynamically regulated island shores and depleted in CpG islands, indicating involvement in context-specific rather than constitutive gene regulation. In HEK293T cells, we introduce a truncating mtDNA mutation (MT-COX3, mt.9979) and observe a positive correlation between variant allele fraction and methylation at cg04569152, supporting a direct mtDNA–nDNA epigenetic link. Many heteroplasmy-associated CpGs overlap with known methylation-trait associations for metabolic and behavioral traits. Composite CpG scores predict all-cause mortality and incident CVD, with one-unit increases associated with 1.27-fold and 1.12-fold higher hazards, respectively. These findings suggest an mtDNA–nDNA epigenetic connection in aging and disease, though its direction and mechanisms remain to be studied.