NKX2.2 and KLF4 cooperate to regulate α cell identity [aTC_klf4_KD_nkx2.2_ChIPseq]

Transcription factors (TF) 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 facilitate their cell specific regulatory 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 to the known role of NKX2.2 in islet β cells, we demonstrate that NKX2.2 regulates novel α cell target 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 and is necessary for NKX2.2 binding in α cells to co-regulate many NKX2.2 α cell transcriptional targets. Misexpression of Klf4 in β cells is sufficient to manipulate chromatin accessibility, increase binding of NKX2.2 at α cell specific promoters sites, and alter expression of NKX2.2-regulated cell specific targets. This study identifies KLF4 is a novel α cell identity factor that cooperates with NKX2.2 to regulate α cell identity.