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

Autor:	Tavares CDJ; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215.; Department of Cell Biology, Harvard Medical School, Boston, MA 02215., Aigner S; Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA 92093.; Stem Cell Program, University of California San Diego, La Jolla, CA 92093., Sharabi K; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215.; Department of Cell Biology, Harvard Medical School, Boston, MA 02215., Sathe S; Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA 92093.; Stem Cell Program, University of California San Diego, La Jolla, CA 92093., Mutlu B; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215.; Department of Cell Biology, Harvard Medical School, Boston, MA 02215., Yeo GW; Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA 92093; geneyeo@ucsd.edu pere_puigserver@dfci.harvard.edu.; Stem Cell Program, University of California San Diego, La Jolla, CA 92093.; Institute for Genomic Medicine, University of California San Diego, La Jolla, CA 92093., Puigserver P; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215; geneyeo@ucsd.edu pere_puigserver@dfci.harvard.edu.; Department of Cell Biology, Harvard Medical School, Boston, MA 02215.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2020 Sep 08; Vol. 117 (36), pp. 22204-22213. Date of Electronic Publication: 2020 Aug 26.
DOI:	10.1073/pnas.2000643117
Abstrakt:	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 , Camk1 δ, 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. Competing Interests: G.W.Y. is cofounder, member of the Board of Directors, on the SAB, equity holder, and paid consultant for Locanabio and Eclipse BioInnovations. G.W.Y. is a visiting professor at the National University of Singapore. G.W.Y.’s interests have been reviewed and approved by the University of California San Diego in accordance with its conflict of interest policies. The authors declare no other competing interests.
Databáze:	MEDLINE
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