The impact of proinflammatory cytokines on the beta-cell regulatory landscape provides insights into the genetics of type 1 diabetes
Por:
Ramos-Rodriguez, M, Raurell-Vila, H, Colli, ML, Alvelos, MI, Subirana-Granes, M, Juan-Mateu, J, Norris, R, Turatsinze, JV, Nakayasu, ES, Webb-Robertson, BJM, Inshaw, JRJ, Marchetti, P, Piemonti, L, Esteller, M, Todd, JA, Metz, TO, Eizirik, DL and Pasquali, L
Publicada:
1 nov 2019
Ahead of Print:
1 nov 2019
Categoría:
Genetics
Resumen:
The early stages of type 1 diabetes (T1D) are characterized by local autoimmune inflammation and progressive loss of insulin-producing pancreatic beta cells. Here we show that exposure to proinflammatory cytokines reveals 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 three-dimensional chromatin structure. Our data indicate that the beta-cell response to cytokines is mediated by the induction of new regulatory regions as well as the activation of primed regulatory elements prebound by islet-specific transcription factors. We find that T1D-associated loci are enriched with 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 proinflammatory environment and implicate a role for stimulus response islet enhancers in T1D.
Filiaciones:
:
Germans Trias & Pujol Univ Hosp & Res Inst, Endocrine Regulatory Genom Lab, Badalona, Spain
:
Germans Trias & Pujol Univ Hosp & Res Inst, Endocrine Regulatory Genom Lab, Badalona, Spain
Colli, ML:
Univ Libre Bruxelles, Ctr Diabet Res & Welbio, Med Fac, Brussels, Belgium
Alvelos, MI:
Univ Libre Bruxelles, Ctr Diabet Res & Welbio, Med Fac, Brussels, Belgium
:
Germans Trias & Pujol Univ Hosp & Res Inst, Endocrine Regulatory Genom Lab, Badalona, Spain
Juan-Mateu, J:
Univ Libre Bruxelles, Ctr Diabet Res & Welbio, Med Fac, Brussels, Belgium
:
Germans Trias & Pujol Univ Hosp & Res Inst, Endocrine Regulatory Genom Lab, Badalona, Spain
Turatsinze, JV:
Univ Libre Bruxelles, Ctr Diabet Res & Welbio, Med Fac, Brussels, Belgium
Nakayasu, ES:
Pacific Northwest Natl Lab, Biol Sci Div, Richland, WA 99352 USA
Webb-Robertson, BJM:
Pacific Northwest Natl Lab, Biol Sci Div, Richland, WA 99352 USA
Inshaw, JRJ:
Univ Oxford, Wellcome Ctr Human Genet, NIHR Oxford Biomed Res Ctr, Nuffield Dept Med,JDRF Wellcome Diabet & Inflamma, Oxford, England
Marchetti, P:
Univ Pisa, Dept Clin & Expt Med, Pisa, Italy
Piemonti, L:
Ist Sci San Raffaele, Diabet Res Inst, Milan, Italy
:
Josep Carreras Leukaemia Res Inst, Barcelona, Spain
Ctr Invest Biomed Red Canc, Madrid, Spain
Inst Catalana Recerca & Estudis Avancats, Barcelona, Spain
Univ Barcelona, Sch Med & Hlth Sci, Physiol Sci Dept, Barcelona, Spain
Todd, JA:
Univ Oxford, Wellcome Ctr Human Genet, NIHR Oxford Biomed Res Ctr, Nuffield Dept Med,JDRF Wellcome Diabet & Inflamma, Oxford, England
Metz, TO:
Pacific Northwest Natl Lab, Biol Sci Div, Richland, WA 99352 USA
Eizirik, DL:
Univ Libre Bruxelles, Ctr Diabet Res & Welbio, Med Fac, Brussels, Belgium
:
Germans Trias & Pujol Univ Hosp & Res Inst, Endocrine Regulatory Genom Lab, Badalona, Spain
Josep Carreras Leukaemia Res Inst, Barcelona, Spain
CIBER Diabet & Enfermedades Metabol Asociadas, Barcelona, Spain
Green Submitted, Green Accepted
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