Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100144, China.
Key Laboratory of External Tissue and Organ Regeneration, Chinese Academy of Medical Sciences, Beijing 100144, China.
Nucleic Acids Res. 2023 Jul 21;51(13):6981-6998. doi: 10.1093/nar/gkad469.
The molecular mechanism underlying white adipogenesis in humans has not been fully elucidated beyond the transcriptional level. Here, we found that the RNA-binding protein NOVA1 is required for the adipogenic differentiation of human mesenchymal stem cells. By thoroughly exploring the interactions between NOVA1 and its binding RNA, we proved that NOVA1 deficiency resulted in the aberrant splicing of DNAJC10 with an in-frame premature stop codon, reduced DNAJC10 expression at the protein level and hyperactivation of the unfolded protein response (UPR). Moreover, NOVA1 knockdown abrogated the down-regulation of NCOR2 during adipogenesis and up-regulated the 47b+ splicing isoform, which led to decreased chromatin accessibility at the loci of lipid metabolism genes. Interestingly, these effects on human adipogenesis could not be recapitulated in mice. Further analysis of multispecies genomes and transcriptomes indicated that NOVA1-targeted RNA splicing is evolutionarily regulated. Our findings provide evidence for human-specific roles of NOVA1 in coordinating splicing and cell organelle functions during white adipogenesis.
人类白色脂肪生成的分子机制在转录水平之外尚未完全阐明。在这里，我们发现 RNA 结合蛋白 NOVA1 是人骨髓间充质干细胞脂肪生成分化所必需的。通过深入探究 NOVA1 与其结合 RNA 之间的相互作用，我们证明了 NOVA1 的缺失导致 DNAJC10 出现异常剪接，带有无义提前终止密码子，从而使 DNAJC10 蛋白水平的表达减少，未折叠蛋白反应（UPR）过度激活。此外，NOVA1 敲低会阻断脂肪生成过程中 NCOR2 的下调，并上调 47b+剪接异构体，从而降低脂质代谢基因座的染色质可及性。有趣的是，这些对人类脂肪生成的影响在小鼠中无法重现。对多物种基因组和转录组的进一步分析表明，NOVA1 靶向的 RNA 剪接受到进化调控。我们的研究结果为 NOVA1 在协调人类白色脂肪生成过程中的剪接和细胞细胞器功能方面的特异性作用提供了证据。
