INGAP and the control of pancreatic β cell mass and function: transcriptional and epigenomic effects

AGUSTÍN ROMERO ; SANTIAGO RODRIGUEZ SEGUÍ; CAROLINA L. ROMÁN; JUAN J. GAGLIARDINO

Bariloche

Congreso; SISTAM 2018; 2018

INGAP and the control of pancreatic β cell mass and function: transcriptional and epigenomic effectsAgustín Romero1,2, Carolina L. Román3, Juan J. Gagliardino3, Bárbara Maiztegui3, Luis E. Flores3, Santiago A. Rodríguez-Seguí1,2*.1 CONICET-Universidad de Buenos Aires, Instituto de Fisiología, Biología Molecular y Neurociencias (IFIBYNE), Buenos Aires, Argentina; 2 Universidad de Buenos Aires, Facultad de Ciencias Exactas y Naturales, Departamento de Fisiología y Biología Molecular y Celular, Buenos Aires, Argentina; 3 CENEXA-Centro de Endocrinología Experimental y Aplicada (UNLP-CONICET LA PLATA-FCM; Centro Asociado a CICPBA), Facultad de Ciencias Médicas UNLP, La Plata, Argentina.* Email: srodriguez@fbmc.fcen.uba.arDiabetes Mellitus is a disease characterized by the loss or reduction of the pancreatic β cell mass, the consequent diminution of insulin production and the incapability of maintain glycaemia in a normal range. Nowadays, one of the most promising therapeutic treatments is trying to leverage the innate regenerative potential of the endocrine pancreas. A pancreatic protein, INGAP (homologous to REG3γ in mouse) increases the β cells mass, vascular neogenesis and insulin secretion. The same effect is achieved with a pentadecapeptide, INGAP-PP, containing an inner sequence of INGAP. Here we will present our ongoing work to characterize the transcriptomic and epigenomic effects of INGAP-PP, as well as the potential effects of INGAP (and more widely REG3 proteins) in other regenerative settings of the pancreas.To profile the transcriptomic response of rat pancreatic islets to the INGAP-PP treatment, we performed RNA-seq assays on INGAP-PP-treated-islets. Our preliminary results suggest that INGAP-PP activates pathways associated with GABA signaling and interacts with cells of the immune system, among others. In this context, INGAP-PP could reduce the immunoregulatory interactions between islet and lymphoid-cells, reducing the activation of cytokine-mediated pathways and leading the tissue regeneration through an anti-inflammatory environment. Interestingly, a re-analysis of public RNA-seq datasets, profiled in purified pancreatic cell populations throughout β cell development, revealed that the expression of genes coding for proteins of the REG3 family is strongly enhanced in 12-day-postnatal β cells. This fact coincides with the expansion and maturation period of these cells, and suggests an important role of REG3 proteins during the neonatal period. Thus, the effects of the REG3/INGAP proteins might have more functions than initially expected, opening new avenues of research. Gaining further insights into the molecular mechanisms through which the INGAP-PP excerpts its effects is expected to help developing improved treatment strategies.