Global-run on sequencing identifies Gm11967 as an Akt-dependent long noncoding RNA involved in insulin sensitivity
Dominic Santoleri,
Hee-Woong Lim,
Matthew J. Emmett,
Julian Stoute,
Matthew J. Gavin,
Jaimarie Sostre-Colón,
Kahealani Uehara,
Jaclyn E. Welles,
Kathy Fange Liu,
Mitchell A. Lazar,
Paul M. Titchenell
Affiliations
Dominic Santoleri
Biochemistry and Molecular Biophysics Graduate Group, University of Pennsylvania Biomedical Graduate Studies, Philadelphia, PA 19104, USA; Institute of Diabetes, Obesity and Metabolism, Smilow Center for Translational Research, University of Pennsylvania Perelman School of Medicine, 3400 Civic Center Blvd, Building 421, Philadelphia, PA 19104, USA
Hee-Woong Lim
Division of Biomedical Informatics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA; Department of Pediatrics, University of Cincinnati, Cincinnati, OH 45229, USA
Matthew J. Emmett
Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA
Julian Stoute
Biochemistry and Molecular Biophysics Graduate Group, University of Pennsylvania Biomedical Graduate Studies, Philadelphia, PA 19104, USA; Department of Biochemistry and Biophysics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
Matthew J. Gavin
Institute of Diabetes, Obesity and Metabolism, Smilow Center for Translational Research, University of Pennsylvania Perelman School of Medicine, 3400 Civic Center Blvd, Building 421, Philadelphia, PA 19104, USA
Jaimarie Sostre-Colón
Institute of Diabetes, Obesity and Metabolism, Smilow Center for Translational Research, University of Pennsylvania Perelman School of Medicine, 3400 Civic Center Blvd, Building 421, Philadelphia, PA 19104, USA
Kahealani Uehara
Biochemistry and Molecular Biophysics Graduate Group, University of Pennsylvania Biomedical Graduate Studies, Philadelphia, PA 19104, USA; Institute of Diabetes, Obesity and Metabolism, Smilow Center for Translational Research, University of Pennsylvania Perelman School of Medicine, 3400 Civic Center Blvd, Building 421, Philadelphia, PA 19104, USA
Jaclyn E. Welles
Institute of Diabetes, Obesity and Metabolism, Smilow Center for Translational Research, University of Pennsylvania Perelman School of Medicine, 3400 Civic Center Blvd, Building 421, Philadelphia, PA 19104, USA
Kathy Fange Liu
Biochemistry and Molecular Biophysics Graduate Group, University of Pennsylvania Biomedical Graduate Studies, Philadelphia, PA 19104, USA; Department of Biochemistry and Biophysics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
Mitchell A. Lazar
Institute of Diabetes, Obesity and Metabolism, Smilow Center for Translational Research, University of Pennsylvania Perelman School of Medicine, 3400 Civic Center Blvd, Building 421, Philadelphia, PA 19104, USA; Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
Paul M. Titchenell
Biochemistry and Molecular Biophysics Graduate Group, University of Pennsylvania Biomedical Graduate Studies, Philadelphia, PA 19104, USA; Institute of Diabetes, Obesity and Metabolism, Smilow Center for Translational Research, University of Pennsylvania Perelman School of Medicine, 3400 Civic Center Blvd, Building 421, Philadelphia, PA 19104, USA; Department of Physiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Corresponding author
Summary: The insulin responsive Akt and FoxO1 signaling axis is a key regulator of the hepatic transcriptional response to nutrient intake. Here, we used global run-on sequencing (GRO-seq) to measure the nascent transcriptional response to fasting and refeeding as well as define the specific role of hepatic Akt and FoxO1 signaling in mediating this response. We identified 599 feeding-regulated transcripts, as well as over 6,000 eRNAs, and mapped their dependency on Akt and FoxO1 signaling. Further, we identified several feeding-regulated lncRNAs, including the lncRNA Gm11967, whose expression was dependent upon the liver Akt-FoxO1 axis. Restoring Gm11967 expression in mice lacking liver Akt improved insulin sensitivity and induced glucokinase protein expression, indicating that Akt-dependent control of Gm11967 contributes to the translational control of glucokinase. More broadly, we have generated a unique genome-wide dataset that defines the feeding and Akt/FoxO1-dependent transcriptional changes in response to nutrient availability.
