Date Published:

Abstract:

The peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1 alpha) 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-1 alpha contains protein domains involved in RNA regulation such as serine/arginine (SR) and RNA recognition motifs (RRM5). However, the RNA targets of PGC-1 alpha 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-1 alpha 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-1 alpha targets such as OXPHOS or gluconeogenic genes. Among the top-scoring RNA sequences bound to PGC-1 alpha were Foxo1, Camk1 delta, Pert, Klf15, Pln4, Cluh, Trpc5, Gfra1, and Slc25a25. PGC-1 alpha 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-1 alpha-regulated metabolic pathway. These studies show that PGC-1 alpha binds to intronic RNA sequences, some of them controlling transcript levels associated with glucagon action.