NKX2.2 and KLF4 cooperate to regulate alpha cell identity

Abstract

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 cells by directly activating cell genes and repressing alternate islet cell fate genes. When compared to the known role of NKX2.2 in islet {beta} cells, we demonstrate that NKX2.2 regulates cell genes, facilitated in part by cell specific DNA binding at gene promoters. Furthermore, we have identified the reprogramming factor KLF4 as having enriched expression in cells, where it co-occupies NKX2.2-bound cell promoters, is necessary for NKX2.2 promoter occupancy in cells and co-regulates many NKX2.2 cell transcriptional targets. Misexpression of Klf4 in {beta} cells is sufficient to manipulate chromatin accessibility, increase binding of NKX2.2 at cell specific promoter sites, and alter expression of NKX2.2-regulated cell-specific targets. This study identifies KLF4 is a novel cell factor that cooperates with NKX2.2 to regulate cell identity.