Islet β-cell-specific MafA transcription requires the 5′-Flanking conserved region 3 control domain

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

Research output: Contribution to journalArticle

30 Scopus citations

Abstract

MafA is a key transcriptional activator of islet β cells, and its exclusive expression within β cells of the developing and adult pancreas is distinct among pancreatic regulators. Region 3 (base pairs -8118 to -7750 relative to the transcription start site), one of six conserved 5′ cis domains of the MafA promoter, is capable of directing β-cell-line-selective expression. Transgenic reporters of region 3 alone (R3), sequences spanning regions 1 to 6 (R1-6; base pairs -10428 to +230), and R1-6 lacking R3 (R1-6 ΔR3) were generated. Only the R1-6 transgene was active in MafA+ insulin+ cells during development and in adult cells. R1-6 also mediated glucose-induced MafA expression. Conversely, pancreatic expression was not observed with the R3 or R1-6ΔR3 line, although much of the nonpancreatic expression pattern was shared between the R1-6 and R1-6ΔR3 lines. Further support for the importance of R3 was also shown, as the islet regulators Nkx6.1 and Pax6, but not NeuroD1, activated MafA in gel shift, chromatin immunoprecipitation (ChIP), and transfection assays and in vivo mouse knockout models. Lastly, ChIP demonstrated that Pax6 and Pdx-1 also bound to R1 and R6, potentially functioning in pancreatic and nonpancreatic expression. These data highlight the nature of the cis- and trans-acting factors controlling the β-cell-specific expression of MafA.

Original languageEnglish (US)
Pages (from-to)4234-4244
Number of pages11
JournalMolecular and cellular biology
Volume30
Issue number17
DOIs
StatePublished - Sep 2010

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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