Global profiling of Nkx2.2 SD-domain mutant pancreas during development and adulthood compared to transcriptional profiling of SD-domain mutant expressing neural progenitors.

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. The mechanisms by which TFs establish such precise control over gene expression, however, have remained elusive—especially in instances where a single TF operates in two or more discrete cellular systems. In this study, we demonstrate that  cell specific functions of NKX2.2 are driven by the highly conserved NK2-Specific Domain (SD). Mutation of the endogenous NKX2.2 SD domain prevents the developmental progression of beta cell precursors into mature, insulin-expressing beta cells, resulting in overt neonatal diabetes. Within the adult beta cell, the SD domain stimulates beta cell performance through the activation and repression of a subset of NKX2.2-regulated transcripts critical for beta cell function. These irregularities in beta cell gene expression may be mediated via SD domain-contingent interactions with components of the nuclear pore complex. In stark contrast to these pancreatic phenotypes, however, the SD domain 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 vs. neuroepithelium.

ORGANISM(S): Mus musculus

PROVIDER: GSE226345 | GEO | 2024/02/21

REPOSITORIES: GEO