MODY7 gene, KLF11, is a novel p300-dependent regulator of Pdx-1 (MODY4) transcription in pancreatic islet beta cells.
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.
Fernandez-Zapico
Martin E
ME
Schulze Center for Novel Therapeutics, Mayo Clinic, Rochester, Minnesota 55905.
van Velkinburgh
Jennifer C
JC
Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, Tennessee 37232.
Gutiérrez-Aguilar
Ruth
R
CNRS, Unite Mixte de Recherche 8090, Institute of Biology, Institute Pasteur de Lille, F-59019 Lille, France.
Neve
Bernadette
B
CNRS, Unite Mixte de Recherche 8090, Institute of Biology, Institute Pasteur de Lille, F-59019 Lille, France; Genomic Medicine, Hammersmith Hospital, Imperial College London, London SW7 2AZ, United Kingdom.
Froguel
Philippe
P
CNRS, Unite Mixte de Recherche 8090, Institute of Biology, Institute Pasteur de Lille, F-59019 Lille, France; Genomic Medicine, Hammersmith Hospital, Imperial College London, London SW7 2AZ, United Kingdom.
Urrutia
Raul
R
Gastroenterology Research Unit, Mayo Clinic, Rochester, Minnesota 55905.
Stein
Roland
R
Schulze Center for Novel Therapeutics, Mayo Clinic, Rochester, Minnesota 55905. Electronic address: roland.stein@vanderbilt.edu.
D051017:Apoptosis Regulatory Proteins; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000235:genetics; D018398:Homeodomain Proteins / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D017434:Protein Structure, Tertiary / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D020218:Response Elements; D015534:Trans-Activators / Q000096:biosynthesis* / Q000235:genetics; D014158:Transcription, Genetic; D016335:Zinc Fingers / Q000235:genetics; D050880:p300-CBP Transcription Factors / Q000235:genetics / Q000378:metabolism*
D051017:Apoptosis Regulatory Proteins; D018797:Cell Cycle Proteins; D002843:Chromatin; D018398:Homeodomain Proteins; C115117:KLF11 protein, human; D012097:Repressor Proteins; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein; D050880:p300-CBP Transcription Factors