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<p>Facioscapulohumeral muscular dystrophy (FSHD) is a progressive and debilitating muscle disease for which no cure currently exists. In the majority of cases, FSHD is associated with the contraction of the D4Z4 macrosatellite repeat array at the 4q35 locus, leading to the inappropriate activation of <i>DUX4</i>, normally expressed during early embryogenesis. In FSHD, the genetic contraction is accompanied by hypomethylation of the D4Z4 array. Although a connection between DNA hypomethylation and <i>DUX4</i> expression has been suggested, the precise mechanisms that regulate <i>DUX4</i> transcription remain incompletely defined. The post-translational modification by SUMO was shown previously to repress the expression of <i>Dux</i>, the <i>DUX4</i> homolog, in mouse embryonic stem cells. Based on these findings, we explored here the contribution of SUMOylation in the regulation of <i>DUX4</i> in human muscle cells. We demonstrate that TAK‑981 (subasumstat), a selective SUMOylation inhibitor, promotes transcriptional reprogramming of the 4q35 locus and induces <i>DUX4</i> expression. Importantly, this activation occurs independently of changes in DNA methylation or SMCHD1 ATPase activity. Our findings identify SUMOylation inhibition as a novel regulatory process driving <i>DUX4</i> expression. This work uncovers the importance of SUMOylation in the epigenetic control of the 4q35 locus and <i>DUX4</i> transcription, providing a potential therapeutic strategy to modulate <i>DUX4</i> expression in FSHD.</p>

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Chemical inhibition of SUMOylation activates the FSHD locus

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月9日

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  • Alice Nordlinger,
  • Loéva Morin,
  • Alexandra Andrieux,
  • Jean Philippe Trani,
  • Pierre Perrin,
  • Nathalie Eudes,
  • Anne Bigot,
  • Anne Dejean,
  • Frédérique Magdinier

摘要

Facioscapulohumeral muscular dystrophy (FSHD) is a progressive and debilitating muscle disease for which no cure currently exists. In the majority of cases, FSHD is associated with the contraction of the D4Z4 macrosatellite repeat array at the 4q35 locus, leading to the inappropriate activation of DUX4, normally expressed during early embryogenesis. In FSHD, the genetic contraction is accompanied by hypomethylation of the D4Z4 array. Although a connection between DNA hypomethylation and DUX4 expression has been suggested, the precise mechanisms that regulate DUX4 transcription remain incompletely defined. The post-translational modification by SUMO was shown previously to repress the expression of Dux, the DUX4 homolog, in mouse embryonic stem cells. Based on these findings, we explored here the contribution of SUMOylation in the regulation of DUX4 in human muscle cells. We demonstrate that TAK‑981 (subasumstat), a selective SUMOylation inhibitor, promotes transcriptional reprogramming of the 4q35 locus and induces DUX4 expression. Importantly, this activation occurs independently of changes in DNA methylation or SMCHD1 ATPase activity. Our findings identify SUMOylation inhibition as a novel regulatory process driving DUX4 expression. This work uncovers the importance of SUMOylation in the epigenetic control of the 4q35 locus and DUX4 transcription, providing a potential therapeutic strategy to modulate DUX4 expression in FSHD.