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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2023
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.
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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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