Islet {beta}-cell-specific MafA transcription requires the 5'-flanking conserved Region 3 control domain.

Research output: Contribution to journalArticle

Abstract

MafA is a key transcriptional activator of islet beta cells and its exclusive expression within beta cells of the developing and adult pancreas is distinct amongst pancreatic regulators. Region 3 (base pairs -8118/-7750 relative to the transcription start site), one of six conserved 5' cis-domains of the MafA promoter, is capable of directing beta-cell-line-selective expression. Transgenic reporters of Region 3 alone (R3), sequences spanning Regions 1-6 (R1-6; base pairs -10428/+230), and R1-6 lacking Region 3 (R1-6(DeltaR3)) were generated. Only the R1-6 transgene was active in MafA(+) insulin(+) cells during development and in adults. R1-6 also mediated glucose-induced MafA expression. Conversely, pancreatic expression was not observed with the R3 or R1-6(DeltaR3) lines, although much of the non-pancreatic expression pattern was shared between the R1-6 and R1-6(DeltaR3) lines. Further support for the importance of Region 3 was shown as the islet regulators Nkx6.1 and Pax6, but not NeuroD1 activated MafA using gel shift, chromatin immunoprecipitation (ChIP), transfection assays, and in vivo mouse knockout models. Lastly ChIP demonstrated that Pax6 and Pdx-1 bound also to Regions 1 and 6, potentially functioning in pancreatic and non-pancreatic expression. These data highlight the nature of the cis- and trans-acting factors controlling the beta-3cell-specific expression of MafA.

Details

Authors
  • Jeffrey C Raum
  • Chad S Hunter
  • Isabella Artner
  • Eva Henderson
  • Min Guo
  • Lynda Elghazi
  • Beatriz Sosa-Pineda
  • Takeshi Ogihara
  • Raghavendra G Mirmira
  • Lori Sussel
  • Roland Stein
Organisations
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Cell and Molecular Biology
Original languageEnglish
Pages (from-to)4234-4244
JournalMolecular and Cellular Biology
Volume30
Issue number17
Publication statusPublished - 2010
Publication categoryResearch
Peer-reviewedYes