Hong Ma1,2, Shuo Yu1,2, Xiaojing Liu3, Yingao Zhang1,2, Thomas Fakadej1,2, Ziqing Liu1,2, Chaoying Yin1,2, Weining Shen4, Jason W Locasale3, Joan M Taylor1,2, Li Qian1,2, Jiandong Liu1,2. 1. Department of Pathology and Laboratory Medicine (H.M., S.Y., Y.Z., T.F., Z.L., C.Y., J.M.T., L.Q., J.L.), University of North Carolina at Chapel Hill. 2. McAllister Heart Institute (H.M., S.Y., Y.Z., T.F., Z.L., C.Y., J.M.T., L.Q., J.L.), University of North Carolina at Chapel Hill. 3. Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Duke University, Durham, NC (X.L., J.W.L.). 4. Department of Statistics, University of California at Irvine (W.S.).
Abstract
BACKGROUND: Hypertrophic response to pathological stimuli is a complex biological process that involves transcriptional and epigenetic regulation of the cardiac transcriptome. Although previous studies have implicated transcriptional factors and signaling molecules in pathological hypertrophy, the role of RNA-binding protein in this process has received little attention. METHODS: Here we used transverse aortic constriction and in vitro cardiac hypertrophy models to characterize the role of an evolutionary conserved RNA-binding protein Lin28a in pathological cardiac hypertrophy. Next-generation sequencing, RNA immunoprecipitation, and gene expression analyses were applied to identify the downstream targets of Lin28a. Epistatic analysis, metabolic assays, and flux analysis were further used to characterize the effects of Lin28a and its downstream mediator in cardiomyocyte hypertrophic growth and metabolic remodeling. RESULTS: Cardiac-specific deletion of Lin28a attenuated pressure overload-induced hypertrophic growth, cardiac dysfunction, and alterations in cardiac transcriptome. Mechanistically, Lin28a directly bound to mitochondrial phosphoenolpyruvate carboxykinase 2 ( Pck2) mRNA and increased its transcript level. Increasing Pck2 was sufficient to promote hypertrophic growth similar to that caused by increasing Lin28a, whereas knocking down Pck2 attenuated norepinephrine-induced cardiac hypertrophy. Epistatic analysis demonstrated that Pck2 mediated, at least in part, the role of Lin28a in cardiac hypertrophic growth. Furthermore, metabolomic analyses highlighted the role for Lin28a and Pck2 in promoting cardiac biosynthesis required for cell growth. CONCLUSIONS: Our study demonstrates that Lin28a promotes pathological cardiac hypertrophy and glycolytic reprograming, at least in part, by binding to and stabilizing Pck2 mRNA.
BACKGROUND:Hypertrophic response to pathological stimuli is a complex biological process that involves transcriptional and epigenetic regulation of the cardiac transcriptome. Although previous studies have implicated transcriptional factors and signaling molecules in pathological hypertrophy, the role of RNA-binding protein in this process has received little attention. METHODS: Here we used transverse aortic constriction and in vitro cardiac hypertrophy models to characterize the role of an evolutionary conserved RNA-binding proteinLin28a in pathological cardiac hypertrophy. Next-generation sequencing, RNA immunoprecipitation, and gene expression analyses were applied to identify the downstream targets of Lin28a. Epistatic analysis, metabolic assays, and flux analysis were further used to characterize the effects of Lin28a and its downstream mediator in cardiomyocyte hypertrophic growth and metabolic remodeling. RESULTS: Cardiac-specific deletion of Lin28a attenuated pressure overload-induced hypertrophic growth, cardiac dysfunction, and alterations in cardiac transcriptome. Mechanistically, Lin28a directly bound to mitochondrial phosphoenolpyruvate carboxykinase 2 ( Pck2) mRNA and increased its transcript level. Increasing Pck2 was sufficient to promote hypertrophic growth similar to that caused by increasing Lin28a, whereas knocking down Pck2 attenuated norepinephrine-induced cardiac hypertrophy. Epistatic analysis demonstrated that Pck2 mediated, at least in part, the role of Lin28a in cardiac hypertrophic growth. Furthermore, metabolomic analyses highlighted the role for Lin28a and Pck2 in promoting cardiac biosynthesis required for cell growth. CONCLUSIONS: Our study demonstrates that Lin28a promotes pathological cardiac hypertrophy and glycolytic reprograming, at least in part, by binding to and stabilizing Pck2 mRNA.
Authors: Paul K Whelton; Robert M Carey; Wilbert S Aronow; Donald E Casey; Karen J Collins; Cheryl Dennison Himmelfarb; Sondra M DePalma; Samuel Gidding; Kenneth A Jamerson; Daniel W Jones; Eric J MacLaughlin; Paul Muntner; Bruce Ovbiagele; Sidney C Smith; Crystal C Spencer; Randall S Stafford; Sandra J Taler; Randal J Thomas; Kim A Williams; Jeff D Williamson; Jackson T Wright Journal: Circulation Date: 2018-10-23 Impact factor: 29.690
Authors: Elena Piskounova; Christos Polytarchou; James E Thornton; Robert J LaPierre; Charalabos Pothoulakis; John P Hagan; Dimitrios Iliopoulos; Richard I Gregory Journal: Cell Date: 2011-11-23 Impact factor: 41.582
Authors: Surabhi Dangi-Garimella; Jieun Yun; Eva M Eves; Martin Newman; Stefan J Erkeland; Scott M Hammond; Andy J Minn; Marsha Rich Rosner Journal: EMBO J Date: 2009-01-15 Impact factor: 11.598
Authors: D M Brown; H Williams; K J P Ryan; T L Wilson; Z C T R Daniel; M H D Mareko; R D Emes; D W Harris; S Jones; J A D Wattis; I L Dryden; T C Hodgman; J M Brameld; T Parr Journal: Sci Rep Date: 2016-06-28 Impact factor: 4.379
Authors: Qinfeng Li; Chao Li; Abdallah Elnwasany; Gaurav Sharma; Yu A An; Guangyu Zhang; Waleed M Elhelaly; Jun Lin; Yingchao Gong; Guihao Chen; Meihui Wang; Shangang Zhao; Chongshan Dai; Charles D Smart; Juan Liu; Xiang Luo; Yingfeng Deng; Lin Tan; Shuang-Jie Lv; Shawn M Davidson; Jason W Locasale; Philip L Lorenzi; Craig R Malloy; Thomas G Gillette; Matthew G Vander Heiden; Philipp E Scherer; Luke I Szweda; Guosheng Fu; Zhao V Wang Journal: Circulation Date: 2021-06-09 Impact factor: 39.918