Cargando…

BET Proteins Are Required for Transcriptional Activation of the Senescent Islet Cell Secretome in Type 1 Diabetes

Type 1 diabetes (T1D) results from the progressive loss of pancreatic beta cells as a result of autoimmune destruction. We recently reported that during the natural history of T1D in humans and the female nonobese diabetic (NOD) mouse model, beta cells acquire a senescence-associated secretory pheno...

Descripción completa

Detalles Bibliográficos
Autores principales: Thompson, Peter J., Shah, Ajit, Apostolopolou, Hara, Bhushan, Anil
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6801956/
https://www.ncbi.nlm.nih.gov/pubmed/31561444
http://dx.doi.org/10.3390/ijms20194776
_version_ 1783460701196517376
author Thompson, Peter J.
Shah, Ajit
Apostolopolou, Hara
Bhushan, Anil
author_facet Thompson, Peter J.
Shah, Ajit
Apostolopolou, Hara
Bhushan, Anil
author_sort Thompson, Peter J.
collection PubMed
description Type 1 diabetes (T1D) results from the progressive loss of pancreatic beta cells as a result of autoimmune destruction. We recently reported that during the natural history of T1D in humans and the female nonobese diabetic (NOD) mouse model, beta cells acquire a senescence-associated secretory phenotype (SASP) that is a major driver of disease onset and progression, but the mechanisms that activate SASP in beta cells were not explored. Here, we show that the SASP in islet cells is transcriptionally controlled by Bromodomain ExtraTerminal (BET) proteins, including Bromodomain containing protein 4 (BRD4). A chromatin analysis of key beta cell SASP genes in NOD islets revealed binding of BRD4 at active regulatory regions. BET protein inhibition in NOD islets diminished not only the transcriptional activation and secretion of SASP factors, but also the non-cell autonomous activity. BET protein inhibition also decreased the extent of SASP induction in human islets exposed to DNA damage. The BET protein inhibitor iBET-762 prevented diabetes in NOD mice and also attenuated SASP in islet cells in vivo. Taken together, our findings support a crucial role for BET proteins in the activation of the SASP transcriptional program in islet cells. These studies suggest avenues for preventing T1D by transcriptional inhibition of SASP.
format Online
Article
Text
id pubmed-6801956
institution National Center for Biotechnology Information
language English
publishDate 2019
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-68019562019-10-31 BET Proteins Are Required for Transcriptional Activation of the Senescent Islet Cell Secretome in Type 1 Diabetes Thompson, Peter J. Shah, Ajit Apostolopolou, Hara Bhushan, Anil Int J Mol Sci Communication Type 1 diabetes (T1D) results from the progressive loss of pancreatic beta cells as a result of autoimmune destruction. We recently reported that during the natural history of T1D in humans and the female nonobese diabetic (NOD) mouse model, beta cells acquire a senescence-associated secretory phenotype (SASP) that is a major driver of disease onset and progression, but the mechanisms that activate SASP in beta cells were not explored. Here, we show that the SASP in islet cells is transcriptionally controlled by Bromodomain ExtraTerminal (BET) proteins, including Bromodomain containing protein 4 (BRD4). A chromatin analysis of key beta cell SASP genes in NOD islets revealed binding of BRD4 at active regulatory regions. BET protein inhibition in NOD islets diminished not only the transcriptional activation and secretion of SASP factors, but also the non-cell autonomous activity. BET protein inhibition also decreased the extent of SASP induction in human islets exposed to DNA damage. The BET protein inhibitor iBET-762 prevented diabetes in NOD mice and also attenuated SASP in islet cells in vivo. Taken together, our findings support a crucial role for BET proteins in the activation of the SASP transcriptional program in islet cells. These studies suggest avenues for preventing T1D by transcriptional inhibition of SASP. MDPI 2019-09-26 /pmc/articles/PMC6801956/ /pubmed/31561444 http://dx.doi.org/10.3390/ijms20194776 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Communication
Thompson, Peter J.
Shah, Ajit
Apostolopolou, Hara
Bhushan, Anil
BET Proteins Are Required for Transcriptional Activation of the Senescent Islet Cell Secretome in Type 1 Diabetes
title BET Proteins Are Required for Transcriptional Activation of the Senescent Islet Cell Secretome in Type 1 Diabetes
title_full BET Proteins Are Required for Transcriptional Activation of the Senescent Islet Cell Secretome in Type 1 Diabetes
title_fullStr BET Proteins Are Required for Transcriptional Activation of the Senescent Islet Cell Secretome in Type 1 Diabetes
title_full_unstemmed BET Proteins Are Required for Transcriptional Activation of the Senescent Islet Cell Secretome in Type 1 Diabetes
title_short BET Proteins Are Required for Transcriptional Activation of the Senescent Islet Cell Secretome in Type 1 Diabetes
title_sort bet proteins are required for transcriptional activation of the senescent islet cell secretome in type 1 diabetes
topic Communication
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6801956/
https://www.ncbi.nlm.nih.gov/pubmed/31561444
http://dx.doi.org/10.3390/ijms20194776
work_keys_str_mv AT thompsonpeterj betproteinsarerequiredfortranscriptionalactivationofthesenescentisletcellsecretomeintype1diabetes
AT shahajit betproteinsarerequiredfortranscriptionalactivationofthesenescentisletcellsecretomeintype1diabetes
AT apostolopolouhara betproteinsarerequiredfortranscriptionalactivationofthesenescentisletcellsecretomeintype1diabetes
AT bhushananil betproteinsarerequiredfortranscriptionalactivationofthesenescentisletcellsecretomeintype1diabetes