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

Authors: RAMBOUT, XAVIER - University Of Rochester; CHO, HANA - University Of Rochester; BLANC, ROMEO - University Of Rochester; LYU, QING - Augusta University; MIANO, JOSEPH - Augusta University; CHAKKALAKAL, JOE - Duke University School Of Medicine; NELSON, GEOFFREY - Harvard Medical School; YALAMANCHILI, HARI - Children'S Nutrition Research Center (CNRC); ADELMAN, KAREN - Harvard Medical School; MAQUAT, LYNNE - University Of Rochester

Submitted to: Molecular Cell
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/19/2022
Publication Date: 1/19/2023
Citation: Rambout, X., Cho, H., Blanc, R., Lyu, Q., Miano, J.M., Chakkalakal, J.V., Nelson, G.M., Yalamanchili, H.K., Adelman, K., Maquat, L.E. 2023. PGC-1alpha senses the CBC of pre-mRNA to dictate the fate of promoter-proximally paused RNAPII. Molecular Cell. 83(2):186-202. https://doi.org/10.1016/j.molcel.2022.12.022.
DOI: https://doi.org/10.1016/j.molcel.2022.12.022

Interpretive Summary: How living cells handle stress can open us to a wide range of novel therapeutic avenues inhuman health. In this study, we investigate a protein in our bodies called PGC-1a. This protein is a superstar when it comes to turning on certain genes in response to stress. Primarily, it's known for controlling our metabolism, especially in muscles. Not only that, but it also helps reduce inflammation, aids in muscle formation, and boosts our muscle performance. In this study, we delve into one particularly interesting way it does this - by forming a complex called the PGC-1alpha PPP release complex (P4RC) to kickstart gene expression. Here's how it works. PGC-1a first binds to certain parts of our genes, where it helps kick off the process of turning these genes on. During this process, the newly forming gene gets a 'cap', which the PGC-1a latches onto. This then attracts more important pieces to the mix, like the P-TEFb, to form the P4RC. This whole formation then helps to release the gene to carry on its job. In conclusion, our findings provide some fascinating new insights into how PGC-1a can control the expression of genes in muscle cells, opening the door for further research into how this might be manipulated to treat muscle diseases or improve muscle performance and health.

Technical Abstract: PGC-1alpha is well established as a metazoan transcriptional coactivator of cellular adaptation in response to stress. However, the mechanisms by which PGC-1a activates gene transcription are incompletely understood. Here, we report that PGC-1alpha serves as a scaffold protein that physically and functionally connects the DNA-binding protein estrogen-related receptor a (ERRalpha), cap-binding protein 80 (CBP80), and Mediator to overcome promoter-proximal pausing of RNAPII and transcriptionally activate stress-response genes. We show that PGC-1alpha promotes pausing release in a two-arm mechanism (1) by recruiting the positive transcription elongation factor b (P-TEFb) and (2) by outcompeting the premature transcription termination complex Integrator. Using mice homozygous for five amino acid changes in the CBP80-binding motif (CBM) of PGC-1alpha that destroy CBM function, we show that efficient differentiation of primary myoblasts to myofibers and timely skeletal muscle regeneration after injury require PGC-1alpha binding to CBP80. Our findings reveal how PGC-1alpha activates stress-response gene transcription in a previously unanticipated pre-mRNA quality-control pathway.