PDF(Pubmed)
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.
摘要：
明确的细胞命运承诺的巩固依赖于转录因子（TFs）对复杂遗传网络进行组织特异性调节的能力。然而,TFs对基因表达建立这种精确控制的机制仍然难以捉摸-尤其是在单个TF在两个或更多个离散细胞系统中运行的情况下。在这项研究中,我们证明了NKX2.2的β细胞特异性功能是由高度保守的NK2特异性结构域（SD）驱动的。内源性NKX2.2SD的突变阻止了β细胞前体向成熟的发育进程。胰岛素表达β细胞，导致明显的新生儿糖尿病。在成人β细胞内，SD通过激活和抑制对β细胞功能至关重要的NKX2.2调节的转录物的子集来刺激β细胞性能。β细胞基因表达中的这些不规则性可能是通过与染色质重塑剂和核孔复合物的成分的SD-cincordinate相互作用来介导的。然而,与这些胰腺表型形成鲜明对比的是，SD对于CNS内NKX2.2依赖性细胞类型的发展是完全不必要的。一起,这些结果揭示了一种先前未确定的机制，NKX2.2通过该机制在胰腺和神经上皮中指导不同的转录程序。
