MafA and MafB regulate Pdx1 transcription through the Area II control region in pancreatic beta cells.
Pancreatic-duodenal homeobox factor-1 (Pdx1) is highly enriched in islet beta cells and integral to proper cell development and adult function. Of the four conserved 5'-flanking sequence blocks that contribute to transcription in vivo, Area II (mouse base pairs -2153/-1923) represents the only mammalian specific control domain. Here we demonstrate that regulation of beta-cell-enriched Pdx1 expression by the MafA and MafB transcription factors is exclusively through Area II. Thus, these factors were found to specifically activate through Area II in cell line transfection-based assays, and MafA, which is uniquely expressed in adult islet beta cells was only bound to this region in quantitative chromatin immunoprecipitation studies. MafA and MafB are produced in beta cells during development and were both bound to Area II at embryonic day 18.5. Expression of a transgene driven by Pdx1 Areas I and II was also severely compromised during insulin+ cell formation in MafB(-/-) mice, consistent with the importance of this large Maf in beta-cell production and Pdx1 expression. These findings illustrate the significance of large Maf proteins to Pdx1 expression in beta cells, and in particular MafB during pancreatic development.
Vanhoose
Amanda M
AM
Department of Molecular Physiology and Biophysics, Vanderbilt Medical School, Nashville, Tennessee 37232, USA.
Samaras
Susan
S
Artner
Isabella
I
Henderson
Eva
E
Hang
Yan
Y
Stein
Roland
R
D016475:3T3 Cells; D000818:Animals; D001483:Base Sequence; D004247:DNA / Q000737:chemistry / Q000235:genetics; D017930:Genes, Reporter; D006367:HeLa Cells; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D050417:Insulin-Secreting Cells / Q000502:physiology*; D007340:Insulinoma / Q000235:genetics; D007668:Kidney / Q000502:physiology; D051473:Maf Transcription Factors, Large / Q000502:physiology*; D051379:Mice; D008969:Molecular Sequence Data; D010190:Pancreatic Neoplasms / Q000235:genetics; D011401:Promoter Regions, Genetic; D051381:Rats; D015534:Trans-Activators / Q000235:genetics*; D014158:Transcription, Genetic
D018398:Homeodomain Proteins; C485159:MAFA protein, human; D051473:Maf Transcription Factors, Large; C485160:Mafa protein, mouse; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein; D004247:DNA