Transcriptional signature of islet neogenesis-associated protein peptide-treated rat pancreatic islets reveals induction of novel long non-coding RNAs

Frontiers in Endocrinology

Endocrinology

Juan J. Gagliardino¹  Bárbara Maiztegui¹  Luis E. Flores¹  Macarena Algañarás¹  Carolina L. Román¹  Ezequiel Nazer²  Santiago A. Rodríguez-Seguí³  Agustín Romero³  Ana C. Heidenreich³ 

[1] Centro de Endocrinología Experimental y Aplicada (CENEXA) - Universidad Nacional de La Plata (UNLP) - CONICET- Centro Asociado a la Comisión de Investigaciones Científicas de la Provincia de Buenos Aires (CeAs CICPBA), Facultad de Ciencias Médicas UNLP, La Plata, Argentina;Instituto de Fisiología, Biología Molecular y Neurociencias (IFIBYNE), CONICET-Universidad de Buenos Aires, Ciudad Universitaria, Buenos Aires, Argentina;Instituto de Fisiología, Biología Molecular y Neurociencias (IFIBYNE), CONICET-Universidad de Buenos Aires, Ciudad Universitaria, Buenos Aires, Argentina;Departamento de Fisiología, Biología Molecular y Celular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina;

关键词: INGAP;    islet;    rat;    pancreas;    beta cell (β-cell);    regeneration;    long noncoding RNA (IncRNA);    Ri-lnc1;   

DOI  :  10.3389/fendo.2023.1226615

 received in 2023-05-21, accepted in 2023-09-06,  发布年份 2023

来源: Frontiers

【 摘 要 】

BackgroundDiabetes mellitus is characterized by chronic hyperglycemia with loss of β-cell function and mass. An attractive therapeutic approach to treat patients with diabetes in a non-invasive way is to harness the innate regenerative potential of the pancreas. The Islet Neogenesis-Associated Protein pentadecapeptide (INGAP-PP) has been shown to induce β-cell regeneration and improve their function in rodents. To investigate its possible mechanism of action, we report here the global transcriptional effects induced by the short-term INGAP-PP in vitro treatment of adult rat pancreatic islets.Methods and findingsRat pancreatic islets were cultured in vitro in the presence of INGAP-PP for 4 days, and RNA-seq was generated from triplicate treated and control islet samples. We performed a de novo rat gene annotation based on the alignment of RNA-seq reads. The list of INGAP-PP-regulated genes was integrated with epigenomic data. Using the new gene annotation generated in this work, we quantified RNA-seq data profiled in INS-1 cells treated with IL1β, IL1β+Calcipotriol (a vitamin D agonist) or vehicle, and single-cell RNA-seq data profiled in rat pancreatic islets. We found 1,669 differentially expressed genes by INGAP-PP treatment, including dozens of previously unannotated rat transcripts. Genes differentially expressed by the INGAP-PP treatment included a subset of upregulated transcripts that are associated with vitamin D receptor activation. Supported by epigenomic and single-cell RNA-seq data, we identified 9 previously unannotated long noncoding RNAs (lncRNAs) upregulated by INGAP-PP, some of which are also differentially regulated by IL1β and vitamin D in β-cells. These include Ri-lnc1, which is enriched in mature β-cells.ConclusionsOur results reveal the transcriptional program that could explain the enhancement of INGAP-PP-mediated physiological effects on β-cell mass and function. We identified novel lncRNAs that are induced by INGAP-PP in rat islets, some of which are selectively expressed in pancreatic β-cells and downregulated by IL1β treatment of INS-1 cells. Our results suggest a relevant function for Ri-lnc1 in β-cells. These findings are expected to provide the basis for a deeper understanding of islet translational results from rodents to humans, with the ultimate goal of designing new therapies for people with diabetes.

【 授权许可】

Unknown   
Copyright © 2023 Romero, Heidenreich, Román, Algañarás, Nazer, Gagliardino, Maiztegui, Flores and Rodríguez-Seguí