The studies in this Project focus on understanding the RNA-binding proteins (RBPs) and noncoding (nc)RNAs that influence energy metabolism, since the processes that generate energy become impaired with aging. In particular, we have studied the regulation of insulin production, adipogenesis, and myogenesis by RBPs and ncRNAs. GLUCOSE HOMEOSTASIS. With rising appreciation that glucose metabolism is extensively regulated at the post-transcriptional level, we recently collaborated with the Lee laboratory (Catholic University, Seoul, Korea) in studies that found HuD to be an RNA-binding protein responsible for reducing triglyceride production in pancreatic cells through the influence of HuD as an enhancer of expression of insulin-induced gene 1 (Kim et al., Biochim Biophys Acta Gene Regulatory Mechanisms, 2016). In collaboration with the Auburger laboratory, we found that the cytoplasmic protein Ataxin-2 (ATXN2), whose deficiency leads to obesity, associates with translation initiation factors. As reported (Lastres-Becker et al., Biochimica Biophysica Acta, 2016), ATXN2 is a nutritional stress-inducible modulator of mRNA translation that affects the pre-initiation complex. Ongoing studies are linking HuD to genetic abnormalities in glucose homeostasis. A mouse model is being generated that expresses HuD in pancreatic beta cells. MITOCHONDRIA. Over the past reporting period, we have made important progress towards understanding the role and metabolism of long noncoding (lnc)RNA in mitochondrial function. Some mitochondrial lncRNAs are encoded by nuclear DNA, but the mechanisms that mediate their transport to mitochondria are poorly characterized. One such nuclear DNA-encoded lncRNA, RMRP, was found to be the target of RBPs HuR and GRSF1, which associated with RMRP and mobilized it to mitochondria. In cultured human cells, HuR bound RMRP in the nucleus and exported it to the cytosol; subsequently, GRSF1 facilitated the function of RMRP in the mitochondria. Accordingly, silencing GRSF1 impaired the import of RMRP into mitochondria and lowered oxygen consumption rates. Our findings delineate a mechanism whereby RBPs mediate the transport of nuclear DNA-encoded lncRNAs into the mitochondria (Noh et al., Genes and Development, 2016). In collaboration with the de Cabo laboratory (Di Francesco et al. Free Radical Biology and Medicine, 2016), we reported evidence that the NAD(P)H: quinone oxidoreductase (NQO1), besides its role in defense against reactive oxidative species, was also capable of binding RNA and forming ribonucleoprotein (RNP) complexes. One of its main targets, SERPINA1 mRNA, encodes the serine protease inhibitor -1-antitrypsin, A1AT, which is associated with disorders including obesity-related metabolic inflammation, chronic obstructive pulmonary disease (COPD), liver cirrhosis and hepatocellular carcinoma. NQO1 bound SERPINA1 mRNA but did not affect SERPINA1 mRNA levels; instead, it enhanced the translation of SERPINA1 mRNA. This novel mechanism of action of NQO1 as an RNA-binding protein may help explain its pleiotropic biological effects. In collaboration with the Bohr Laboratory, we investigated the roles of Cockayne Syndrome proteins CSA and CSB on DNA Repair (Scheibye-Knudsen et al., Proc Natl Acad Sci, 2017), and in collaboration with the Auburger lab we identified the role of Ataxin-2 on translational control during starvation (Lastres-Becker et al., Biochim Biophys Acta, 2016). Ongoing studies are examining the impact of GRSF1 on the production and processing of mitochondrial RNAs, particularly as they impact mitochondrial activity. MYOGENESIS. Other energy metabolism. During this review period, we also discovered that the myogenic regulatory factor (MRF) MYF5, which functions as a transcription factor in muscle progenitor cells (satellite cells) and myocytes, displayed a novel RNA-binding function. One prominent MYF5 target was Ccnd1 mRNA, which encodes the key cell cycle regulator CCND1 (Cyclin D1). Silencing MYF5 expression in proliferating myoblasts revealed that MYF5 promoted CCND1 translation and modestly increased transcription of Ccnd1 mRNA. Overexpression of MYF5 in C2C12 cells upregulated CCND1 expression while silencing MYF5 reduced myoblast proliferation as well as differentiation of myoblasts into myotubes. Thes findings led us to propose that MYF5 enhances early myogenesis in part by coordinately elevating Ccnd1 transcription and Ccnd1 mRNA translation (Panda et al., Nucleic Acids Research 2016). Ongoing studies are focused on exploring transcriptomic data from the GESTALT study to identify RNAs (coding and noncoding) changing significantly with advancing age in human skeletal muscle. These studies are being complemented by work with cultured myoblasts that differentiate in vitro into myotubes. Ongoing experiments are assessing the role of specific RNAs in skeletal myogenesis/regeneration.
| Kim, Kyoung Mi; Abdelmohsen, Kotb; Mustapic, Maja et al. (2017) RNA in extracellular vesicles. Wiley Interdiscip Rev RNA 8: |
| Kim, Kyoung Mi; Noh, Ji Heon; Abdelmohsen, Kotb et al. (2017) Mitochondrial noncoding RNA transport. BMB Rep 50:164-174 |
| Kim, Chongtae; Lee, Heejin; Kang, Hoin et al. (2016) RNA-binding protein HuD reduces triglyceride production in pancreatic ? cells by enhancing the expression of insulin-induced gene 1. Biochim Biophys Acta 1859:675-85 |
| Noh, Ji Heon; Kim, Kyoung Mi; Abdelmohsen, Kotb et al. (2016) HuR and GRSF1 modulate the nuclear export and mitochondrial localization of the lncRNA RMRP. Genes Dev 30:1224-39 |
| Kim, Jiyoung; Kim, Kyoung Mi; Noh, Ji Heon et al. (2016) Long noncoding RNAs in diseases of aging. Biochim Biophys Acta 1859:209-21 |
| Lastres-Becker, Isabel; Nonis, David; Eich, Florian et al. (2016) Mammalian ataxin-2 modulates translation control at the pre-initiation complex via PI3K/mTOR and is induced by starvation. Biochim Biophys Acta 1862:1558-69 |
| Scheibye-Knudsen, Morten; Tseng, Anne; Borch Jensen, Martin et al. (2016) Cockayne syndrome group A and B proteins converge on transcription-linked resolution of non-B DNA. Proc Natl Acad Sci U S A 113:12502-12507 |
| Di Francesco, Andrea; Di Germanio, Clara; Panda, Amaresh C et al. (2016) Novel RNA-binding activity of NQO1 promotes SERPINA1 mRNA translation. Free Radic Biol Med 99:225-233 |
| Panda, Amaresh C; Abdelmohsen, Kotb; Martindale, Jennifer L et al. (2016) Novel RNA-binding activity of MYF5 enhances Ccnd1/Cyclin D1 mRNA translation during myogenesis. Nucleic Acids Res 44:2393-408 |
| Lee, Kwang-Pyo; Shin, Yeo Jin; Panda, Amaresh C et al. (2015) miR-431 promotes differentiation and regeneration of old skeletal muscle by targeting Smad4. Genes Dev 29:1605-17 |
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