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

doi:10.1016/j.isci.2022.104410

Global-run on sequencing identifies Gm11967 as an Akt-dependent long noncoding RNA involved in insulin sensitivity

iScience. 2022 May 16;25(6):104410. doi: 10.1016/j.isci.2022.104410. eCollection 2022 Jun 17.

Authors

Dominic Santoleri^{1

2}, Hee-Woong Lim^{3

4}, Matthew J Emmett⁵, Julian Stoute^{1

6}, Matthew J Gavin², Jaimarie Sostre-Colón², Kahealani Uehara^{1

2}, Jaclyn E Welles², Kathy Fange Liu^{1

6}, Mitchell A Lazar^{2

7}, Paul M Titchenell^{1

2

8}

Affiliations

¹ Biochemistry and Molecular Biophysics Graduate Group, University of Pennsylvania Biomedical Graduate Studies, Philadelphia, PA 19104, USA.
² 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.
³ Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
⁴ Department of Pediatrics, University of Cincinnati, Cincinnati, OH 45229, USA.
⁵ Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
⁶ Department of Biochemistry and Biophysics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
⁷ Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
⁸ Department of Physiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.

Abstract

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.

Keywords: Molecular Physiology; Omics; Physiology; Transcriptomics.

Abstract

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