Studies on the nuclear cap-binding complex

The nuclear cap-binding complex (CBC), which consists of CBP20 and CBP80, controls gene expression in both the nucleus and the cytoplasm. For example, building on our discovery in the early 2000’s that NMD typically occurs during the pioneer round(s) of translation of CBC-bound mRNAs, we found that CBP80 facilitates NMD by interacting with UPF1 and UPF2.

More recently, we found that CBP80 recruits the transcriptional coactivator PGC‑1α (and PGC‑1β) to the 5'- m⁷G cap of nascent pre-mRNAs to promote gene transcription in skeletal muscle cells.

Cho H, Rambout X, Gleghorn ML, Nguyen PQT, Phipps CR, Miyoshi K, Myers JR, Kataoka N, Fasan R, Maquat LE. Transcriptional coactivator PGC-1α contains a novel CBP80-binding motif that orchestrates efficient target gene expression. Genes Dev. 2018 Apr 1;32(7-8):555-567. doi: 10.1101/gad.309773.117. Epub 2018 Apr 13. PMID: 29654059; PMCID: PMC5959238.

Whereas PGC-1α had been almost exclusively defined as a master regulator of mitochondrial biology, our subsequent research demonstrated that the PGC 1α–CBP80 complex activates RNAPII-transcribed pro-inflammatory genes during the process of promoter-proximal pausing (i) by recruiting the positive elongation factor P-TEFb, and (ii) by preventing the premature termination of transcription by Integrator. These findings described how PGC-1α and the CBC function in an unanticipated pre-mRNA capping quality-control pathway, which we showed sustains timely regeneration of injured skeletal muscles in mouse.

Rambout X, Cho H, Blanc R, Lyu Q, Miano JM, Chakkalakal JV, Nelson GM, Yalamanchili HK, Adelman K, Maquat LE. PGC-1α senses the CBC of pre-mRNA to dictate the fate of promoter-proximally paused RNAPII. Mol Cell. 2023 Jan 19;83(2):186-202.e11. doi: 10.1016

Open Project: In addition to activating pro-inflammatory genes, we have found that PGC-1α and CBP80 cooperate to promote the expression of RNAPIII-transcribed genes encoding long-noncoding RNAs. We aim to understand how PGC-1α binding to CBP80 activates these RNAPIII-transcribed genes, whose transcripts lack a 5ʹ-m⁷G cap. We believe that gene activation explains how PGC-1α and CBP80 repress a large network of protein-coding genes that function beyond mitochondrial biology and inflammation. Solving this paradigm-changing hypothesis will increase our understanding of how PGC-1α contributes to development and to pathologies that include cancers and neurologic, musculoskeletal, and metabolic diseases.