Major β cell-specific functions of NKX2.2 are mediated via the NK2-specific domain
- Vladimir Abarinov1,2,
- Joshua A. Levine1,
- Angela J. Churchill1,
- Bryce Hopwood2,
- Cailin S. Deiter2,
- Michelle A. Guney2,
- Kristen L. Wells2,
- Jessica M. Schrunk2,
- Yuchun Guo3,
- Jennifer Hammelman3,
- David K. Gifford3,
- Mark A. Magnuson4,
- Hynek Wichterle5,6,7 and
- Lori Sussel1,2
- 1Department of Genetics and Development, Columbia University, New York, New York 10032, USA;
- 2Barbara Davis Center for Diabetes, University of Colorado Anschutz Medical Campus, Aurora, Colorado 80045, USA;
- 3Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA;
- 4Department of Molecular Physiology and Biophysics, Center for Stem Cell Biology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA;
- 5Department of Pathology and Cell Biology, Columbia University, New York, New York 10032, USA;
- 6Department of Neurology, Columbia University, New York, New York 10032, USA;
- 7Department of Neuroscience, Columbia University, New York, New York 10032, USA
- Corresponding author: lori.sussel{at}cuanschutz.edu
Abstract
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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Footnotes
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Supplemental material is available for this article.
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Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.350569.123.
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Freely available online through the Genes & Development Open Access option.
- Received February 25, 2023.
- Accepted June 6, 2023.
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/.