{Reference Type}: Journal Article
{Title}: Major β cell-specific functions of NKX2.2 are mediated via the NK2-specific domain.
{Author}: Abarinov V;Levine JA;Churchill AJ;Hopwood B;Deiter CS;Guney MA;Wells KL;Schrunk JM;Guo Y;Hammelman J;Gifford DK;Magnuson MA;Wichterle H;Sussel L;
{Journal}: Genes Dev
{Volume}: 37
{Issue}: 11
{Year}: 2023 06 1
{Factor}: 12.89
{DOI}: 10.1101/gad.350569.123
{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.