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<p>5-Formylcytosine (5fC) has attracted increasing attention because of discoveries of its unique epigenetic functions as a gene activation marker beyond its role as an intermediate in the demethylation of 5-methylcytosine (5mC). However, there are scant clues to understanding the mechanisms by which 5fC affects nucleosome structures for regulating gene expression, except that 5fC promotes nucleosome formation and cross-linking with histone units via a Schiff base. The present study demonstrates that 5fC acts as a chemical cue that modulates the nucleosome positions preferred by a given DNA sequence. A series of nucleosomes designed with linker regions and 5fC at defined sites allowed systematic evaluation of the effect of formylation on the nucleosome positions, revealing site-dependent impacts of 5fC distinct from those of 5mC. The 5fC-mediated changes of relative preference for the possible nucleosome positions were not only associated with the cross-linking with histone units, but also energetic tolerance that was imparted by 5fC in terms of the base-stacking interaction against the DNA configuration characteristic at specific sites of nucleosomal DNA. These findings provide chemical insights into the regulatory mechanisms underlying 5fC-mediated nucleosome repositioning and gene expression in important biological events, such as cellular reprogramming.</p>

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5-Formylcytosine functions as a chemical regulator of nucleosome positioning

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月29日

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  • Takafumi Furuhata,
  • Yijing Lin,
  • Genki Hino,
  • Akimitsu Okamoto

摘要

5-Formylcytosine (5fC) has attracted increasing attention because of discoveries of its unique epigenetic functions as a gene activation marker beyond its role as an intermediate in the demethylation of 5-methylcytosine (5mC). However, there are scant clues to understanding the mechanisms by which 5fC affects nucleosome structures for regulating gene expression, except that 5fC promotes nucleosome formation and cross-linking with histone units via a Schiff base. The present study demonstrates that 5fC acts as a chemical cue that modulates the nucleosome positions preferred by a given DNA sequence. A series of nucleosomes designed with linker regions and 5fC at defined sites allowed systematic evaluation of the effect of formylation on the nucleosome positions, revealing site-dependent impacts of 5fC distinct from those of 5mC. The 5fC-mediated changes of relative preference for the possible nucleosome positions were not only associated with the cross-linking with histone units, but also energetic tolerance that was imparted by 5fC in terms of the base-stacking interaction against the DNA configuration characteristic at specific sites of nucleosomal DNA. These findings provide chemical insights into the regulatory mechanisms underlying 5fC-mediated nucleosome repositioning and gene expression in important biological events, such as cellular reprogramming.