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NKX2.2 and KLF4 cooperate to regulate α-cell identity
Genes & Development ( IF 7.5 ) Pub Date : 2024-12-20 , DOI: 10.1101/gad.352193.124 Elliott P. Brooks, McKenna R. Casey, Kristen L. Wells, Tsung-Yun Liu, Madeline Van Orman, Lori Sussel
Genes & Development ( IF 7.5 ) Pub Date : 2024-12-20 , DOI: 10.1101/gad.352193.124 Elliott P. Brooks, McKenna R. Casey, Kristen L. Wells, Tsung-Yun Liu, Madeline Van Orman, Lori Sussel
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 Klf4 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.
更新日期：2024-12-20
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