The impact of pro-inflammatory cytokines on the β-cell regulatory landscape provides new insights into the genetics of type 1 diabetes

Ramos-Rodriguez, M.; Raurell-Villa, H.; Colli, M. L.; Alvelos, M. I.; Subirana-Granes, M.; Juan-Mateu, J.; Norris, R.; Turatsinze, J.-V.; Nakayasu, E.; Webb-Robertson, B.-J.; Inshaw, J. R.; Marchetti, P.; Piemonti, L.; Esteller, M.; Todd, J. A.; Metz, T. O.; Eizirik, D. L.; Pasquali, L.

doi:10.1101/560193

bioRxiv · 10.1101/560193

The impact of pro-inflammatory cytokines on the β-cell regulatory landscape provides new insights into the genetics of type 1 diabetes

Ramos-Rodriguez, M.·Raurell-Villa, H.·Colli, M. L.·Alvelos, M. I.·Subirana-Granes, M.·Juan-Mateu, J.·Norris, R.·Turatsinze, J.-V.·Nakayasu, E.·Webb-Robertson, B.-J.·Inshaw, J. R.·Marchetti, P.·Piemonti, L.·Esteller, M.·Todd, J. A.·Metz, T. O.·Eizirik, D. L.·Pasquali, L.

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Abstract

Early stages of type 1 diabetes (T1D) are characterized by local autoimmune inflammation and progressive loss of insulin-producing pancreatic {beta} cells. We show here that exposure to pro-inflammatory cytokines unmasks a marked plasticity of the {beta}-cell regulatory landscape. We expand the repertoire of human islet regulatory elements by mapping stimulus-responsive enhancers linked to changes in the {beta}-cell transcriptome, proteome and 3D chromatin structure. Our data indicates that the {beta} cell response to cytokines is mediated by the induction of novel regulatory regions as well as the activation of primed regulatory elements pre-bound by islet-specific transcription factors. We found that T1D-associated loci are enriched of the newly mapped cis-regulatory regions and identify T1D-associated variants disrupting cytokine-responsive enhancer activity in human {beta} cells. Our study illustrates how {beta} cells respond to a pro-inflammatory environment and implicate a role for stimulus-response islet enhancers in T1D.

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Ramos-Rodriguez, M., Raurell-Villa, H., Colli, M. L., Alvelos, M. I., Subirana-Granes, M., Juan-Mateu, J., Norris, R., Turatsinze, J.-V., Nakayasu, E., Webb-Robertson, B.-J., Inshaw, J. R., Marchetti, P., Piemonti, L., Esteller, M., Todd, J. A., Metz, T. O., Eizirik, D. L., Pasquali, L.. 2019-02-25. The impact of pro-inflammatory cytokines on the β-cell regulatory landscape provides new insights into the genetics of type 1 diabetes. https://doi.org/10.1101/560193

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