Abstract:

The peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1alpha) is a transcriptional coactivator that controls expression of metabolic/energetic genes, programming cellular responses to nutrient and environmental adaptations such as fasting, cold, or exercise. Unlike other coactivators, PGC-1alpha contains protein domains involved in RNA regulation such as serine/arginine (SR) and RNA recognition motifs (RRMs). However, the RNA targets of PGC-1alpha and how they pertain to metabolism are unknown. To address this, we performed enhanced ultraviolet (UV) cross-linking and immunoprecipitation followed by sequencing (eCLIP-seq) in primary hepatocytes induced with glucagon. A large fraction of RNAs bound to PGC-1alpha were intronic sequences of genes involved in transcriptional, signaling, or metabolic function linked to glucagon and fasting responses, but were not the canonical direct transcriptional PGC-1alpha targets such as OXPHOS or gluconeogenic genes. Among the top-scoring RNA sequences bound to PGC-1alpha were Foxo1, Camk1delta, Per1, Klf15, Pln4, Cluh, Trpc5, Gfra1, and Slc25a25 PGC-1alpha depletion decreased a fraction of these glucagon-induced messenger RNA (mRNA) transcript levels. Importantly, knockdown of several of these genes affected glucagon-dependent glucose production, a PGC-1alpha-regulated metabolic pathway. These studies show that PGC-1alpha binds to intronic RNA sequences, some of them controlling transcript levels associated with glucagon action.

Notes:

Tavares, Clint D JAigner, StefanSharabi, KfirSathe, ShashankMutlu, BesteYeo, Gene WPuigserver, PereengProc Natl Acad Sci U S A. 2020 Aug 26. pii: 2000643117. doi: 10.1073/pnas.2000643117.