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<p>Mammals tightly regulate their core body temperature, yet how cells sense and respond to small temperature changes remains incompletely understood. Here, we discover RNA G-quadruplexes (rG4s) as key thermosensors enriched near splice sites of cold-repressed exons. These thermosensing RNA structures, when stabilized, mask splice sites, reducing exon inclusion. Specifically, rG4s near splice sites of a cold-repressed poison exon in the neuroprotective RBM3 are stabilized at low temperatures, leading to exon exclusion. This enables evasion of nonsense-mediated decay, increasing RBM3 expression at cold. Importantly, stabilizing rG4 through increasing intracellular potassium with an FDA-approved potassium channel blocker, mimics the hypothermic effect on alternative splicing, thereby increasing RBM3 expression, leading to RBM3-dependent neuroprotection in a mouse model of subarachnoid hemorrhage. Our findings unveil a mechanism how mammalian RNAs directly sense temperature and potassium perturbations, integrating them into gene expression programs. This opens new avenues for treating diseases arising from splicing defects and disorders benefiting from therapeutic hypothermia, especially hemorrhagic stroke.</p>

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Stabilizing a mammalian RNA thermometer confers neuroprotection in subarachnoid hemorrhage

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年9月18日

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  • Min Zhang,
  • Bin Zhang,
  • Chengli Liu,
  • Marco Preußner,
  • Megha Ayachit,
  • Weiming Li,
  • Yafei Huang,
  • Deyi Liu,
  • Quanwei He,
  • Ann-Kathrin Emmerichs,
  • Stefan Meinke,
  • Shu Chen,
  • Lin Wang,
  • Liduan Zheng,
  • Qiubai Li,
  • Qin Huang,
  • Tom Haltenhof,
  • Ruoxi Gao,
  • Xianan Qin,
  • Aifang Cheng,
  • Tianzi Wei,
  • Li Yu,
  • Mario Schubert,
  • Xin Gao,
  • Mingchang Li,
  • Florian Heyd

摘要

Mammals tightly regulate their core body temperature, yet how cells sense and respond to small temperature changes remains incompletely understood. Here, we discover RNA G-quadruplexes (rG4s) as key thermosensors enriched near splice sites of cold-repressed exons. These thermosensing RNA structures, when stabilized, mask splice sites, reducing exon inclusion. Specifically, rG4s near splice sites of a cold-repressed poison exon in the neuroprotective RBM3 are stabilized at low temperatures, leading to exon exclusion. This enables evasion of nonsense-mediated decay, increasing RBM3 expression at cold. Importantly, stabilizing rG4 through increasing intracellular potassium with an FDA-approved potassium channel blocker, mimics the hypothermic effect on alternative splicing, thereby increasing RBM3 expression, leading to RBM3-dependent neuroprotection in a mouse model of subarachnoid hemorrhage. Our findings unveil a mechanism how mammalian RNAs directly sense temperature and potassium perturbations, integrating them into gene expression programs. This opens new avenues for treating diseases arising from splicing defects and disorders benefiting from therapeutic hypothermia, especially hemorrhagic stroke.