MODY7 Gene, KLF11, Is a Novel p300-dependent Regulator of Pdx-1 (MODY4) Transcription in Pancreatic Islet β Cells

Abstract

Pdx-1 (pancreatic-duodenal homeobox-1), a MODY4 homeodomain transcription factor, serves as a master regulator in the pancreas because of its importance during organogenesis and in adult islet insulin-producing beta cell activity. Here, we show that KLF11, an SP/Krüppel-like (SP/KLF) transcription factor, mutated in French maturity onset diabetes of the young patients (MODY7), regulates Pdx-1 transcription in beta cells through two evolutionarily conserved GC-rich motifs in conserved Area II, a control region essential to islet beta cell-enriched expression. These regulatory elements, termed GC1 (human base pair -2061/-2055) and GC2 (-2036/-2027), are also nearly identical to the consensus KLF11 binding sequence defined here by random oligonucleotide binding analysis. KLF11 specifically associates with Area II in chromatin immunoprecipitation assays, while preventing binding to GC1- and/or GC2-compromised Pdx1-driven reporter activity in beta cell lines. Mechanistically, we find that KLF11 interacts with the coactivator p300 via its zinc finger domain in vivo to mediate Pdx-1 activation. Together, our data identified a hierarchical regulatory cascade for these two MODY genes, suggesting that gene regulation in MODY is more complex than anticipated previously. Furthermore, because KLF11 like most MODY-associated transcription factors uses p300, these data further support a role for this coactivator as a critical chromatin link in forms of type 2 diabetes.