Mining the transcriptome of target tissues of autoimmune and degenerative pancreatic β-cell and brain diseases to discover therapies
Xiaoyan Yi,
Bianca Marmontel de Souza,
Toshiaki Sawatani,
Florian Szymczak,
Lorella Marselli,
Piero Marchetti,
Miriam Cnop,
Decio L. Eizirik
Affiliations
Xiaoyan Yi
ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels 1070, Belgium
Bianca Marmontel de Souza
ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels 1070, Belgium
Toshiaki Sawatani
ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels 1070, Belgium
Florian Szymczak
ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels 1070, Belgium; Interuniversity Institute of Bioinformatics in Brussels, Université Libre de Bruxelles-Vrije Universiteit Brussel, Brussels 1050, Belgium
Lorella Marselli
Department of Clinical and Experimental Medicine, AOUP Cisanello University Hospital, University of Pisa, Pisa 56126, Italy
Piero Marchetti
Department of Clinical and Experimental Medicine, AOUP Cisanello University Hospital, University of Pisa, Pisa 56126, Italy
Miriam Cnop
ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels 1070, Belgium; Division of Endocrinology, Erasmus Hospital, Université Libre de Bruxelles, Brussels 1070, Belgium
Decio L. Eizirik
ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels 1070, Belgium; WELBIO, Université Libre de Bruxelles, Brussels 1070, Belgium; Corresponding author
Summary: Target tissues of autoimmune and degenerative diseases show signals of inflammation. We used publicly available RNA-seq data to study whether pancreatic β-cells in type 1 and type 2 diabetes and neuronal tissue in multiple sclerosis and Alzheimer’s disease share inflammatory gene signatures. We observed concordantly upregulated genes in pairwise diseases, many of them related to signaling by interleukins and interferons. We next mined these signatures to identify therapies that could be re-purposed/shared among the diseases and identified the bromodomain inhibitors as potential perturbagens to revert the transcriptional signatures. We experimentally confirmed in human β-cells that bromodomain inhibitors I-BET151 and GSK046 prevent the deleterious effects of the pro-inflammatory cytokines interleukin-1β and interferon-γ and at least some of the effects of the metabolic stressor palmitate. These results demonstrate that key inflammation-induced molecular mechanisms are shared between β-cells and brain in autoimmune and degenerative diseases and that these signatures can be mined for drug discovery.
