The H19/let-7 double-negative feedback loop contributes to glucose metabolism in muscle cells.
The H19 lncRNA has been implicated in development and growth control and is associated with human genetic disorders and cancer. Acting as a molecular sponge, H19 inhibits microRNA (miRNA) let-7. Here we report that H19 is significantly decreased in muscle of human subjects with type-2 diabetes and insulin resistant rodents. This decrease leads to increased bioavailability of let-7, causing diminished expression of let-7 targets, which is recapitulated in vitro where H19 depletion results in impaired insulin signaling and decreased glucose uptake. Furthermore, acute hyperinsulinemia downregulates H19, a phenomenon that occurs through PI3K/AKT-dependent phosphorylation of the miRNA processing factor KSRP, which promotes biogenesis of let-7 and its mediated H19 destabilization. Our results reveal a previously undescribed double-negative feedback loop between sponge lncRNA and target miRNA that contributes to glucose regulation in muscle cells.
Department of Obstetrics, Gynecology and Reproductive Sciences, Yale Stem Cell Center, Yale University School of Medicine, New Haven, CT 06510, USA Department of Gynecology and Obstetrics, Chinese PLA General Hospital, Beijing 100853, P. R. China.
Yuan
Y
Gao
Department of Obstetrics, Gynecology and Reproductive Sciences, Yale Stem Cell Center, Yale University School of Medicine, New Haven, CT 06510, USA Department of Obstetrics and Gynecology, Jilin University, Changchun, Jilin 130021, P. R. China.
Fuju
F
Wu
Department of Obstetrics, Gynecology and Reproductive Sciences, Yale Stem Cell Center, Yale University School of Medicine, New Haven, CT 06510, USA Department of Surgical Oncology, Affiliated Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310016, P. R. China.
Jichun
J
Zhou
Department of Obstetrics, Gynecology and Reproductive Sciences, Yale Stem Cell Center, Yale University School of Medicine, New Haven, CT 06510, USA Department of Obstetrics and Gynecology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P. R. China.
Lei
L
Yan
Howard Hughes Medical Institute and Departments of Internal Medicine, Cellular & Molecular Physiology, Yale University School of Medicine, New Haven, CT 06510, USA.
Michael J
MJ
Jurczak
Howard Hughes Medical Institute and Departments of Internal Medicine, Cellular & Molecular Physiology, Yale University School of Medicine, New Haven, CT 06510, USA.
Hui-Young
HY
Lee
Department of Obstetrics, Gynecology and Reproductive Sciences, Yale Stem Cell Center, Yale University School of Medicine, New Haven, CT 06510, USA Obstetrics and Gynecology Department, Tangshan Gongren Hospital, Tangshan, Hebei 063000, P. R. China.
Lihua
L
Yang
Department of Obstetrics, Gynecology and Reproductive Sciences, Yale Stem Cell Center, Yale University School of Medicine, New Haven, CT 06510, USA Department of Obstetrics and Gynecology, University Hospital, 3012 Bern, Switzerland.
Martin
M
Mueller
Department of Obstetrics, Gynecology and Reproductive Sciences, Yale Stem Cell Center, Yale University School of Medicine, New Haven, CT 06510, USA Department of Immunology and Pathogenic Biology, School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P. R. China.
Xiao-Bo
XB
Zhou
Department of Genetics and Development, Institut Cochin, U1016 Paris, France.
Luisa
L
Dandolo
Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research, 40225 Dusseldorf, Germany Department of Metabolic Diseases, Heinrich Heine University, 40225 Dusseldorf, Germany.
Julia
J
Szendroedi
Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research, 40225 Dusseldorf, Germany Department of Metabolic Diseases, Heinrich Heine University, 40225 Dusseldorf, Germany.
Michael
M
Roden
Department of Obstetrics, Gynecology and Reproductive Sciences, Yale Stem Cell Center, Yale University School of Medicine, New Haven, CT 06510, USA.
Clare
C
Flannery
Department of Obstetrics, Gynecology and Reproductive Sciences, Yale Stem Cell Center, Yale University School of Medicine, New Haven, CT 06510, USA.
Hugh
H
Taylor
Department of Genetics and Developmental Biology, University of Connecticut Health Center, Farmington, CT 06030, USA.
Gordon G
GG
Carmichael
Howard Hughes Medical Institute and Departments of Internal Medicine, Cellular & Molecular Physiology, Yale University School of Medicine, New Haven, CT 06510, USA.
Gerald I
GI
Shulman
Department of Obstetrics, Gynecology and Reproductive Sciences, Yale Stem Cell Center, Yale University School of Medicine, New Haven, CT 06510, USA yingqun.huang@yale.edu.
Yingqun
Y
Huang
D000818:Animals; D015536:Down-Regulation; D025461:Feedback, Physiological; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D006946:Hyperinsulinism / Q000235:genetics / Q000378:metabolism; D007328:Insulin / Q000494:pharmacology; D008297:Male; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000378:metabolism*; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism*; D062085:RNA, Long Noncoding / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000502:physiology; D015398:Signal Transduction; D015534:Trans-Activators / Q000502:physiology
C094335:H19 long non-coding RNA; D007328:Insulin; C507913:Khsrp protein, mouse; D035683:MicroRNAs; D062085:RNA, Long Noncoding; D016601:RNA-Binding Proteins; D015534:Trans-Activators; C487931:mirnlet7 microRNA, human; C542687:mirnlet7 microRNA, mouse; D005947:Glucose