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）已被广泛证实为后生生物应对应激时介导细胞适应性反应的转录辅激活因子。然而，PGC-1α激活基因转录的具体分子机制尚未完全阐明。本研究发现，PGC-1α可作为脚手架蛋白，在物理与功能层面连接DNA结合蛋白雌激素相关受体α（estrogen-related receptor α, ERRα）、帽结合蛋白80（cap-binding protein 80, CBP80）与中介体复合物（Mediator），从而克服RNA聚合酶II（RNAPII）在启动子近端的暂停现象，并转录激活应激反应基因。研究表明，PGC-1α通过双通路机制促进暂停释放：一是招募正转录延伸因子b（positive transcription elongation factor b, P-TEFb），二是竞争性拮抗过早转录终止复合物整合体（Integrator）。我们构建了PGC-1α帽结合蛋白80结合基序（CBP80-binding motif, CBM）发生5个氨基酸突变且该基序功能丧失的纯合子小鼠，实验证实原代成肌细胞高效分化为肌纤维以及损伤后骨骼肌及时再生，均依赖于PGC-1α与CBP80的结合。本研究结果揭示了PGC-1α如何通过此前未被发现的前体mRNA质量控制通路激活应激反应基因的转录。