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Title: The impact of proinflammatory cytokines on the ß-cell regulatory landscape provides new insights into the genetics of type 1 diabetes

Abstract

Early stages of type 1 diabetes (T1D) are characterized by local autoimmune inflammation and progressive loss of insulin-producing pancreatic ß cells. We show here that exposure to pro-inflammatory cytokines unmasks a marked plasticity of the ß-cell regulatory landscape. We expand the repertoire of human islet regulatory elements by mapping stimulusresponsive enhancers linked to changes in the ß-cell transcriptome, proteome and 3D chromatin structure. Our data indicates that the ß 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 T1Dassociated variants disrupting cytokine-responsive enhancer activity in human ß cells. Our study illustrates how ß cells respond to a proinflammatory environment and implicate a role for stimulus-response islet enhancers in T1D.

Authors:
 [1];  [2];  [3];  [3];  [2];  [3];  [2];  [4]; ORCiD logo [5];  [5];  [6];  [7];  [8];  [9];  [10]; ORCiD logo [5];  [3];  [11]
  1. IGTP Health Sciences Research Institute of the Germans Trias i Pujol Foundation
  2. Germans Trias i Pujol University Hospital and Research Institute
  3. Université Libre de Bruxelles
  4. ULB Center for Diabetes Research, Université Libre de Bruxelles
  5. BATTELLE (PACIFIC NW LAB)
  6. University of Oxford
  7. Department of Endocrinology and Metabolism
  8. San Raffaele Scientific Institute
  9. University of Barcelona
  10. NIHR Oxford Biomedical Research Centre
  11. Germans Trias i Pujol University
Publication Date:
Research Org.:
Pacific Northwest National Lab. (PNNL), Richland, WA (United States)
Sponsoring Org.:
USDOE
OSTI Identifier:
1574393
Report Number(s):
PNNL-SA-141684
DOE Contract Number:  
AC05-76RL01830
Resource Type:
Journal Article
Journal Name:
Nature Genetics
Additional Journal Information:
Journal Volume: 51; Journal Issue: 11
Country of Publication:
United States
Language:
English

Citation Formats

Romas-Rodriquez, Mireia, Raurell-Vila, Helena, Colli, Maikel L., Alvelos, Maria I., Subirana, Marc, Mateu, Jonas J., Norris, Richard, Turatsinze, Jean-Valery, Nakayasu, Ernesto S., Webb-Robertson, Bobbie-Jo M., Inshaw, Jamie R., Marchetti, Piero, Piemonti, Lorenzo, Esteller, Manel, Todd, John A., Metz, Thomas O., Eizirik, Decio L., and Pasquali, Lorenzo. The impact of proinflammatory cytokines on the ß-cell regulatory landscape provides new insights into the genetics of type 1 diabetes. United States: N. p., 2019. Web. doi:10.1038/s41588-019-0524-6.
Romas-Rodriquez, Mireia, Raurell-Vila, Helena, Colli, Maikel L., Alvelos, Maria I., Subirana, Marc, Mateu, Jonas J., Norris, Richard, Turatsinze, Jean-Valery, Nakayasu, Ernesto S., Webb-Robertson, Bobbie-Jo M., Inshaw, Jamie R., Marchetti, Piero, Piemonti, Lorenzo, Esteller, Manel, Todd, John A., Metz, Thomas O., Eizirik, Decio L., & Pasquali, Lorenzo. The impact of proinflammatory cytokines on the ß-cell regulatory landscape provides new insights into the genetics of type 1 diabetes. United States. doi:10.1038/s41588-019-0524-6.
Romas-Rodriquez, Mireia, Raurell-Vila, Helena, Colli, Maikel L., Alvelos, Maria I., Subirana, Marc, Mateu, Jonas J., Norris, Richard, Turatsinze, Jean-Valery, Nakayasu, Ernesto S., Webb-Robertson, Bobbie-Jo M., Inshaw, Jamie R., Marchetti, Piero, Piemonti, Lorenzo, Esteller, Manel, Todd, John A., Metz, Thomas O., Eizirik, Decio L., and Pasquali, Lorenzo. Fri . "The impact of proinflammatory cytokines on the ß-cell regulatory landscape provides new insights into the genetics of type 1 diabetes". United States. doi:10.1038/s41588-019-0524-6.
@article{osti_1574393,
title = {The impact of proinflammatory cytokines on the ß-cell regulatory landscape provides new insights into the genetics of type 1 diabetes},
author = {Romas-Rodriquez, Mireia and Raurell-Vila, Helena and Colli, Maikel L. and Alvelos, Maria I. and Subirana, Marc and Mateu, Jonas J. and Norris, Richard and Turatsinze, Jean-Valery and Nakayasu, Ernesto S. and Webb-Robertson, Bobbie-Jo M. and Inshaw, Jamie R. and Marchetti, Piero and Piemonti, Lorenzo and Esteller, Manel and Todd, John A. and Metz, Thomas O. and Eizirik, Decio L. and Pasquali, Lorenzo},
abstractNote = {Early stages of type 1 diabetes (T1D) are characterized by local autoimmune inflammation and progressive loss of insulin-producing pancreatic ß cells. We show here that exposure to pro-inflammatory cytokines unmasks a marked plasticity of the ß-cell regulatory landscape. We expand the repertoire of human islet regulatory elements by mapping stimulusresponsive enhancers linked to changes in the ß-cell transcriptome, proteome and 3D chromatin structure. Our data indicates that the ß 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 T1Dassociated variants disrupting cytokine-responsive enhancer activity in human ß cells. Our study illustrates how ß cells respond to a proinflammatory environment and implicate a role for stimulus-response islet enhancers in T1D.},
doi = {10.1038/s41588-019-0524-6},
journal = {Nature Genetics},
number = 11,
volume = 51,
place = {United States},
year = {2019},
month = {11}
}

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