Brooks Elliott P, Casey McKenna R, Wells Kristen L, Liu Tsung-Yun, Van Orman Madeline, Sussel Lori
Barbara Davis Center for Diabetes, University of Colorado Anschutz Medical Campus, Aurora, Colorado 80045, USA.
Barbara Davis Center for Diabetes, University of Colorado Anschutz Medical Campus, Aurora, Colorado 80045, USA
Genes Dev. 2025 Feb 3;39(3-4):242-260. doi: 10.1101/gad.352193.124.
Transcription factors (TFs) are indispensable for maintaining cell identity through regulating cell-specific gene expression. Distinct cell identities derived from a common progenitor are frequently perpetuated by shared TFs, yet the mechanisms that enable these TFs to regulate cell-specific targets are poorly characterized. We report that the TF NKX2.2 is critical for the identity of pancreatic islet α cells by directly activating α-cell genes and repressing alternate islet cell fate genes. When compared with the known role of NKX2.2 in islet β cells, we demonstrate that NKX2.2 regulates α-cell genes, facilitated in part by α-cell-specific DNA binding at gene promoters. Furthermore, we have identified the reprogramming factor KLF4 as having enriched expression in α cells, where it co-occupies NKX2.2-bound α-cell promoters, is necessary for NKX2.2 promoter occupancy in α cells, and coregulates many NKX2.2 α-cell transcriptional targets. Overexpression of in β cells is sufficient to manipulate chromatin accessibility, increase binding of NKX2.2 at α-cell-specific promoter sites, and alter expression of NKX2.2-regulated cell-specific targets. This study identifies KLF4 as a novel α-cell factor that cooperates with NKX2.2 to regulate α-cell identity.
转录因子（TFs）对于通过调节细胞特异性基因表达来维持细胞身份至关重要。源自共同祖细胞的不同细胞身份常常由共享的转录因子得以延续，然而使这些转录因子调节细胞特异性靶标的机制却鲜有明确阐述。我们报告称，转录因子NKX2.2通过直接激活α细胞基因并抑制其他胰岛细胞命运基因，对胰岛α细胞的身份至关重要。与NKX2.2在胰岛β细胞中的已知作用相比，我们证明NKX2.2调节α细胞基因，部分是通过在基因启动子处的α细胞特异性DNA结合来实现的。此外，我们已确定重编程因子KLF4在α细胞中表达丰富，它与NKX2.2结合的α细胞启动子共同占据，对NKX2.2在α细胞中的启动子占据是必需的，并且共同调节许多NKX2.2 α细胞转录靶标。在β细胞中过表达足以操纵染色质可及性，增加NKX2.2在α细胞特异性启动子位点的结合，并改变NKX2.2调节的细胞特异性靶标的表达。这项研究确定KLF4是一种与NKX2.2协同调节α细胞身份的新型α细胞因子。
