PGC 1α senses the CBC of pre-mRNA to dictate the fate of promoter-proximally paused RNAPII

PGC-1α is well-established as a metazoan transcriptional coactivator of cellular adaptation in response to stress. However, the mechanisms by which PGC-1α activates gene transcription are incompletely understood. Here, we report that PGC 1α serves as a scaffold protein that physically and functionally connects the DNA-binding protein estrogen-related receptor α (ERRα), cap-binding protein 80 (CBP80), and Mediator to overcome promoter-proximal pausing of RNAPII and transcriptionally activate stress-response genes. We show that PGC-1α promotes pausing release in a two-arm mechanism: by recruiting the positive transcription elongation factor b (P-TEFb), and by outcompeting the premature transcription termination complex Integrator. Using mice homozygous for five amino-acid changes in the CBP80-binding motif (CBM) of PGC 1α that destroy CBM function, we show that efficient differentiation of primary myoblasts to myofibers and timely skeletal-muscle regeneration after injury require PGC 1α binding to CBP80. Our findings reveal how PGC-1α activates stress-response gene transcription in a previously unanticipated pre-mRNA quality-control pathway.过氧化物酶体增殖物激活受体γ辅激活因子1α（PGC-1α）作为多细胞生物应对应激时介导细胞适应性反应的转录辅激活因子，其功能已得到广泛证实。然而，PGC-1α激活基因转录的具体分子机制仍未完全明晰。本研究发现，PGC-1α可作为支架蛋白，在物理与功能层面连接DNA结合蛋白雌激素相关受体α（ERRα）、帽结合蛋白80（CBP80）与转录中介体（Mediator），从而克服RNA聚合酶II（RNAPII）在启动子近端的暂停现象，激活应激反应基因的转录。研究表明，PGC-1α通过双通路机制促进转录暂停释放：一是招募正性转录延伸因子b（P-TEFb），二是竞争性拮抗过早转录终止复合物整合子（Integrator）的功能。我们构建了PGC-1α帽结合蛋白80结合基序（CBM）发生5处氨基酸突变、致使该基序功能丧失的纯合子小鼠，实验证实，原代肌母细胞向肌纤维的有效分化，以及损伤后骨骼肌的及时再生，均依赖于PGC-1α与CBP80的结合。本研究揭示了PGC-1α通过此前未被发现的前mRNA质量控制通路激活应激反应基因转录的分子机制。