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Abstract In addition to regulating the actin cytoskeleton, Cofilin also senses and responds to environmental stress. Cofilin can promote cell survival or death depending on context. Yet, many aspects of Cofilin’s role in survival need clarification. Here, we show that exposing earlyDrosophilaembryos to mild heat stress (32°C) induces a Cofilin-mediated Actin Stress Response and upregulation of heat- and ER-stress response genes. However, these responses do not alleviate the negative impacts of heat exposure. Instead, heat stressed embryos show downregulation of hundreds of developmental genes, including determinants of the embryonic body plan, and are less likely to hatch as larvae and adults. Remarkably, reducing Cofilin dosage blunts induction of all stress response pathways, mitigates downregulation of developmental genes, and completely rescues survival. Thus, Cofilin intersects with multiple stress response pathways, and modulates the transcriptomic response to heat stress. Strikingly, Cofilin knockdown emerges as a potent pro-survival manipulation for embryos. 

Abstract Hypoxia-induced alternative splicing (AS) regulates tumor progression and metastasis. Little is known about how such AS is controlled and whether higher-order genome and nuclear domain (ND) organizations dictate these processes. We observe that hypoxia-responsive alternatively spliced genes position near nuclear speckle (NS), the ND that enhances splicing efficiency. NS-resident MALAT1 long noncoding RNA, induced in response to hypoxia, regulates hypoxia-responsive AS. MALAT1 achieves this by organizing the SR-family of splicing factor, SRSF1, near NS and regulating the binding of SRSF1 to pre-mRNAs. Mechanistically, MALAT1 enhances the recruitment of SRSF1 to elongating RNA polymerase II (pol II) by promoting the formation of phase-separated condensates of SRSF1, which are preferentially recognized by pol II. During hypoxia, MALAT1 regulates spatially organized AS by establishing a threshold SRSF1 concentration near NSs, potentially by forming condensates, critical for pol II-mediated recruitment of SRSF1 to pre-mRNAs.