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Inhibition of pancreatic EZH2 restores progenitor insulin in T1D donor
Type 1 diabetes (T1D) is an autoimmune disease that selectively destroys insulin-producing β-cells in the pancreas. An unmet need in diabetes management, current therapy is focussed on transplantation. While the reprogramming of progenitor cells into functional insulin-producing β-cells has also bee...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9304326/ https://www.ncbi.nlm.nih.gov/pubmed/35864094 http://dx.doi.org/10.1038/s41392-022-01034-7 |
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author | Al-Hasani, Keith Khurana, Ishant Mariana, Lina Loudovaris, Thomas Maxwell, Scott Harikrishnan, K. N. Okabe, Jun Cooper, Mark E. El-Osta, Assam |
author_facet | Al-Hasani, Keith Khurana, Ishant Mariana, Lina Loudovaris, Thomas Maxwell, Scott Harikrishnan, K. N. Okabe, Jun Cooper, Mark E. El-Osta, Assam |
author_sort | Al-Hasani, Keith |
collection | PubMed |
description | Type 1 diabetes (T1D) is an autoimmune disease that selectively destroys insulin-producing β-cells in the pancreas. An unmet need in diabetes management, current therapy is focussed on transplantation. While the reprogramming of progenitor cells into functional insulin-producing β-cells has also been proposed this remains controversial and poorly understood. The challenge is determining why default transcriptional suppression is refractory to exocrine reactivation. After the death of a 13-year-old girl with established insulin-dependent T1D, pancreatic cells were harvested in an effort to restore and understand exocrine competence. The pancreas showed classic silencing of β-cell progenitor genes with barely detectable insulin (Ins) transcript. GSK126, a highly selective inhibitor of EZH2 methyltransferase activity influenced H3K27me3 chromatin content and transcriptional control resulting in the expression of core β-cell markers and ductal progenitor genes. GSK126 also reinstated Ins gene expression despite absolute β-cell destruction. These studies show the refractory nature of chromatin characterises exocrine suppression influencing β-cell plasticity. Additional regeneration studies are warranted to determine if the approach of this n-of-1 study generalises to a broader T1D population. |
format | Online Article Text |
id | pubmed-9304326 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-93043262022-07-23 Inhibition of pancreatic EZH2 restores progenitor insulin in T1D donor Al-Hasani, Keith Khurana, Ishant Mariana, Lina Loudovaris, Thomas Maxwell, Scott Harikrishnan, K. N. Okabe, Jun Cooper, Mark E. El-Osta, Assam Signal Transduct Target Ther Article Type 1 diabetes (T1D) is an autoimmune disease that selectively destroys insulin-producing β-cells in the pancreas. An unmet need in diabetes management, current therapy is focussed on transplantation. While the reprogramming of progenitor cells into functional insulin-producing β-cells has also been proposed this remains controversial and poorly understood. The challenge is determining why default transcriptional suppression is refractory to exocrine reactivation. After the death of a 13-year-old girl with established insulin-dependent T1D, pancreatic cells were harvested in an effort to restore and understand exocrine competence. The pancreas showed classic silencing of β-cell progenitor genes with barely detectable insulin (Ins) transcript. GSK126, a highly selective inhibitor of EZH2 methyltransferase activity influenced H3K27me3 chromatin content and transcriptional control resulting in the expression of core β-cell markers and ductal progenitor genes. GSK126 also reinstated Ins gene expression despite absolute β-cell destruction. These studies show the refractory nature of chromatin characterises exocrine suppression influencing β-cell plasticity. Additional regeneration studies are warranted to determine if the approach of this n-of-1 study generalises to a broader T1D population. Nature Publishing Group UK 2022-07-22 /pmc/articles/PMC9304326/ /pubmed/35864094 http://dx.doi.org/10.1038/s41392-022-01034-7 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Al-Hasani, Keith Khurana, Ishant Mariana, Lina Loudovaris, Thomas Maxwell, Scott Harikrishnan, K. N. Okabe, Jun Cooper, Mark E. El-Osta, Assam Inhibition of pancreatic EZH2 restores progenitor insulin in T1D donor |
title | Inhibition of pancreatic EZH2 restores progenitor insulin in T1D donor |
title_full | Inhibition of pancreatic EZH2 restores progenitor insulin in T1D donor |
title_fullStr | Inhibition of pancreatic EZH2 restores progenitor insulin in T1D donor |
title_full_unstemmed | Inhibition of pancreatic EZH2 restores progenitor insulin in T1D donor |
title_short | Inhibition of pancreatic EZH2 restores progenitor insulin in T1D donor |
title_sort | inhibition of pancreatic ezh2 restores progenitor insulin in t1d donor |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9304326/ https://www.ncbi.nlm.nih.gov/pubmed/35864094 http://dx.doi.org/10.1038/s41392-022-01034-7 |
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