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<p>Multiple regulatory layers influence allele-specific expression (ASE), particularly through sequence-dependent and parent-of-origin-dependent mechanisms at the transcriptional level. However, little is known about ASE regulation at the post-transcriptional level. The most prevalent post-transcriptional mRNA modification, <i>N</i><sup>6</sup>-methyladenosine (m<sup>6</sup>A), plays important roles in regulating gene expression. Here, we conduct transcriptome-wide analysis of allele-specific m<sup>6</sup>A in mice. Using early postnatal tissues from reciprocal crosses of two divergent mouse strains, we measured allelic m<sup>6</sup>A differences at single-base resolution. Our study reveals widespread sequence-dependent allelic imbalance in m<sup>6</sup>A methylation, identifying thousands of allele-specific m<sup>6</sup>A (ASm<sup>6</sup>A) sites with statistically significant and reproducible allelic methylation differences. We find evidence of potential <i>cis</i>-regulatory variants within 50-nt flanking regions of ASm<sup>6</sup>As. Intriguingly, we detect parental effects on allelic methylation across m<sup>6</sup>As exhibiting parent-of-origin-dependent ASE. For both sequence- and parent-of-origin-dependent m<sup>6</sup>As, we observe opposing allelic preferences between methylation and expression, suggesting a potential role of ASm<sup>6</sup>A in regulating ASE through negative effects on gene expression. Overall, our findings reveal that both <i>cis</i>-acting and parent-of-origin effects influence ASm<sup>6</sup>A, offering new insights into post-transcriptional mechanisms of ASE regulation.</p>

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Sequence and parent-of-origin dependent m6A contribute to allele-specific gene expression

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年6月3日

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  • Ying Zhang,
  • Ze-Yu Zhang,
  • Hong-Xuan Chen,
  • Chao Liu,
  • Biao-Di Liu,
  • Ye-Lin Lan,
  • Ying-Yuan Xie,
  • Tao Chen,
  • Shaobo Chen,
  • Guihai Feng,
  • Zhang Zhang,
  • Wei Li,
  • Nan Cao,
  • Xiu-Jie Wang,
  • Guan-Zheng Luo

摘要

Multiple regulatory layers influence allele-specific expression (ASE), particularly through sequence-dependent and parent-of-origin-dependent mechanisms at the transcriptional level. However, little is known about ASE regulation at the post-transcriptional level. The most prevalent post-transcriptional mRNA modification, N6-methyladenosine (m6A), plays important roles in regulating gene expression. Here, we conduct transcriptome-wide analysis of allele-specific m6A in mice. Using early postnatal tissues from reciprocal crosses of two divergent mouse strains, we measured allelic m6A differences at single-base resolution. Our study reveals widespread sequence-dependent allelic imbalance in m6A methylation, identifying thousands of allele-specific m6A (ASm6A) sites with statistically significant and reproducible allelic methylation differences. We find evidence of potential cis-regulatory variants within 50-nt flanking regions of ASm6As. Intriguingly, we detect parental effects on allelic methylation across m6As exhibiting parent-of-origin-dependent ASE. For both sequence- and parent-of-origin-dependent m6As, we observe opposing allelic preferences between methylation and expression, suggesting a potential role of ASm6A in regulating ASE through negative effects on gene expression. Overall, our findings reveal that both cis-acting and parent-of-origin effects influence ASm6A, offering new insights into post-transcriptional mechanisms of ASE regulation.