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

ROMERO AGUSTIN; ROMAN CL; GAGLIARDINO JJ; MAIZTEGUI B; FLORES LE; RODRIGUEZ-SEGUÍ SA

San Carlos de Bariloche, Río Negro

Simposio; SISTAM 2018 IUBMB focused meeting; 2018

SISTAM

Diabetes 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.