Transcriptome-wide analysis of PGC-1α-binding RNAs identifies genes linked to glucagon metabolic action

Clint D.J. Tavares, Stefan Aigner, Kfir Sharabi, Shashank Sathe, Beste Mutlu, Gene W. Yeo, Pere Puigserver

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

Abstract

The peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) 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-1α contains protein domains involved in RNA regulation such as serine/arginine (SR) and RNA recognition motifs (RRMs). However, the RNA targets of PGC-1α 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-1α 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-1α targets such as OXPHOS or gluconeogenic genes. Among the top-scoring RNA sequences bound to PGC-1α were Foxo1, Camk1δ, Per1, Klf15, Pln4, Cluh, Trpc5, Gfra1, and Slc25a25. PGC-1α 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-1α-regulated metabolic pathway. These studies show that PGC-1α binds to intronic RNA sequences, some of them controlling transcript levels associated with glucagon action.

Original languageAmerican English
Pages (from-to)22204-22213
Number of pages10
JournalProceedings of the National Academy of Sciences of the United States of America
Volume117
Issue number36
DOIs
StatePublished - 8 Sep 2020
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2020 National Academy of Sciences. All rights reserved.

Keywords

  • Glucagon
  • Liver
  • Mitochondria
  • PGC-1α
  • RNA binding

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