2011 Grant Award - Jeongsik Yong, Ph.D.

Long Non-coding RNA in Mitochondrial Function and Insulin Resistance

Jeongsik Yong, Ph.D.
Department of Biochemistry, Molecular Biology & Biophysics, University of Minnesota

The peroxisome proliferator-activated receptor γ coactivator-1 (PGC-1) family of transcriptional coactivators has been implied as a master regulator of metabolic gene expression in response to environmental stimuli in diverse tissues. The PGC-1 family of coactivators has two highly conserved domains the activation domain (AD) and the RNA-binding domain (RBD). Most of the functional studies about the PGC-1 coactivators came from the characterization of the AD. In contrast, understanding the functional relevance of the RBD among the PGC-1 coactivators is largely missing. In addition to the highly conserved RBD, serine/arginine-rich (SR) motif closely located to the RBD of PGC-1α strongly suggests that PGC-1α is an RNA-binding protein and its function is related to RNA metabolism. The fact that PGC-1α associates with chromatin remodeling complexes and many epigenetic mechanisms use long non-coding RNAs (lncRNAs) to modulate the activity of chromatin remodeling complexes for specific gene regulations raises the possibility of lncRNA as a target RNA of PGC-1α. From all of these, we hypothesize that a previously uncharacterized lncRNA represses target genes of PGC-1α (i.e. genes for mitochondrial biogenesis and metabolism) by constitutively recruiting chromatin remodeling complexes and when PGC-1α associates with the lncRNA by specific RNA-binding activity, it brings in the coactivator complex to the repressed loci of chromosome and activates gene expression. Therefore, we suggest that the interaction between lncRNA-PGC-1α is a key regulatory step in this process. The studies described in this proposal will shed new light on an unanswered question of how specific target selection by PGC-1α is fulfilled among tissues in a given physiologic context. In conclusion, the work presented in this proposal will explore a novel regulatory role of lncRNA in the function of PGC-1α and how this is linked to mitochondrial function and its related disorders. This will also provide a novel therapeutic target of diseases related to metabolic disorders.