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Major β cell-specific functions of NKX2.2 are mediated via the NK2-specific domain
The consolidation of unambiguous cell fate commitment relies on the ability of transcription factors (TFs) to exert tissue-specific regulation of complex genetic networks. However, the mechanisms by which TFs establish such precise control over gene expression have remained elusive—especially in ins...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Cold Spring Harbor Laboratory Press
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10393193/ https://www.ncbi.nlm.nih.gov/pubmed/37364986 http://dx.doi.org/10.1101/gad.350569.123 |
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author | Abarinov, Vladimir Levine, Joshua A. Churchill, Angela J. Hopwood, Bryce Deiter, Cailin S. Guney, Michelle A. Wells, Kristen L. Schrunk, Jessica M. Guo, Yuchun Hammelman, Jennifer Gifford, David K. Magnuson, Mark A. Wichterle, Hynek Sussel, Lori |
author_facet | Abarinov, Vladimir Levine, Joshua A. Churchill, Angela J. Hopwood, Bryce Deiter, Cailin S. Guney, Michelle A. Wells, Kristen L. Schrunk, Jessica M. Guo, Yuchun Hammelman, Jennifer Gifford, David K. Magnuson, Mark A. Wichterle, Hynek Sussel, Lori |
author_sort | Abarinov, Vladimir |
collection | PubMed |
description | The consolidation of unambiguous cell fate commitment relies on the ability of transcription factors (TFs) to exert tissue-specific regulation of complex genetic networks. However, the mechanisms by which TFs establish such precise control over gene expression have remained elusive—especially in instances in which a single TF operates in two or more discrete cellular systems. In this study, we demonstrate that β cell-specific functions of NKX2.2 are driven by the highly conserved NK2-specific domain (SD). Mutation of the endogenous NKX2.2 SD prevents the developmental progression of β cell precursors into mature, insulin-expressing β cells, resulting in overt neonatal diabetes. Within the adult β cell, the SD stimulates β cell performance through the activation and repression of a subset of NKX2.2-regulated transcripts critical for β cell function. These irregularities in β cell gene expression may be mediated via SD-contingent interactions with components of chromatin remodelers and the nuclear pore complex. However, in stark contrast to these pancreatic phenotypes, the SD is entirely dispensable for the development of NKX2.2-dependent cell types within the CNS. Together, these results reveal a previously undetermined mechanism through which NKX2.2 directs disparate transcriptional programs in the pancreas versus neuroepithelium. |
format | Online Article Text |
id | pubmed-10393193 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Cold Spring Harbor Laboratory Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-103931932023-08-02 Major β cell-specific functions of NKX2.2 are mediated via the NK2-specific domain Abarinov, Vladimir Levine, Joshua A. Churchill, Angela J. Hopwood, Bryce Deiter, Cailin S. Guney, Michelle A. Wells, Kristen L. Schrunk, Jessica M. Guo, Yuchun Hammelman, Jennifer Gifford, David K. Magnuson, Mark A. Wichterle, Hynek Sussel, Lori Genes Dev Research Papers The consolidation of unambiguous cell fate commitment relies on the ability of transcription factors (TFs) to exert tissue-specific regulation of complex genetic networks. However, the mechanisms by which TFs establish such precise control over gene expression have remained elusive—especially in instances in which a single TF operates in two or more discrete cellular systems. In this study, we demonstrate that β cell-specific functions of NKX2.2 are driven by the highly conserved NK2-specific domain (SD). Mutation of the endogenous NKX2.2 SD prevents the developmental progression of β cell precursors into mature, insulin-expressing β cells, resulting in overt neonatal diabetes. Within the adult β cell, the SD stimulates β cell performance through the activation and repression of a subset of NKX2.2-regulated transcripts critical for β cell function. These irregularities in β cell gene expression may be mediated via SD-contingent interactions with components of chromatin remodelers and the nuclear pore complex. However, in stark contrast to these pancreatic phenotypes, the SD is entirely dispensable for the development of NKX2.2-dependent cell types within the CNS. Together, these results reveal a previously undetermined mechanism through which NKX2.2 directs disparate transcriptional programs in the pancreas versus neuroepithelium. Cold Spring Harbor Laboratory Press 2023-06-01 /pmc/articles/PMC10393193/ /pubmed/37364986 http://dx.doi.org/10.1101/gad.350569.123 Text en © 2023 Abarinov et al.; Published by Cold Spring Harbor Laboratory Press https://creativecommons.org/licenses/by/4.0/This article, published in Genes & Development, is available under a Creative Commons License (Attribution 4.0 International), as described at http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Research Papers Abarinov, Vladimir Levine, Joshua A. Churchill, Angela J. Hopwood, Bryce Deiter, Cailin S. Guney, Michelle A. Wells, Kristen L. Schrunk, Jessica M. Guo, Yuchun Hammelman, Jennifer Gifford, David K. Magnuson, Mark A. Wichterle, Hynek Sussel, Lori Major β cell-specific functions of NKX2.2 are mediated via the NK2-specific domain |
title | Major β cell-specific functions of NKX2.2 are mediated via the NK2-specific domain |
title_full | Major β cell-specific functions of NKX2.2 are mediated via the NK2-specific domain |
title_fullStr | Major β cell-specific functions of NKX2.2 are mediated via the NK2-specific domain |
title_full_unstemmed | Major β cell-specific functions of NKX2.2 are mediated via the NK2-specific domain |
title_short | Major β cell-specific functions of NKX2.2 are mediated via the NK2-specific domain |
title_sort | major β cell-specific functions of nkx2.2 are mediated via the nk2-specific domain |
topic | Research Papers |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10393193/ https://www.ncbi.nlm.nih.gov/pubmed/37364986 http://dx.doi.org/10.1101/gad.350569.123 |
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