AP-2α selectively regulates fragile X mental retardation-1 gene transcription during embryonic development

Jae H. Lim, Anne B. Booker, Ting Luo, Trevor Williams, Yasuhide Furuta, Oleg Lagutin, Guillermo Oliver, Thomas D. Sargent, Justin R. Fallon*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

Fragile X syndrome (FXS) is almost always caused by silencing of the FMR1 gene. The defects observed in FXS indicate that the normal FMR1 gene has a range of functions and plays a particularly prominent role during development. However, the mechanisms regulating FMR1 expression in vivo are not known. Here, we have tested the role of the transcription factor AP-2α in regulating Fmr1 expression. Chromatin immunoprecipitation showed that AP-2α associates with the Fmr1 promoter in vivo. Furthermore, Fmr1 transcript levels are reduced >4-fold in homozygous null AP-2α mutant mice at embryonic day 18.5 when compared with normal littermates. Notably, AP-2α exhibits a strong gene dosage effect, with heterozygous mice showing ∼2-fold reduction in Fmr1 levels. Examination of conditional AP-2α mutant mice indicates that this transcription factor plays a major role in regulating Fmr1 expression in embryos, but not in adults. We further investigated the role of AP-2α in the developmental regulation of Fmr1 expression using the Xenopus animal cap assay. Over-expression of a dominant-negative AP-2α in Xenopus embryos led to reduced Fmr1 levels. Moreover, exogenous wild-type AP-2α rescued Fmr1 expression in embryos where endogenous AP-2α had been suppressed. We conclude that AP-2α associates with the Fmr1 promoter in vivo and selectively regulates Fmr1 transcription during embryonic development.

Original languageEnglish (US)
Pages (from-to)2027-2034
Number of pages8
JournalHuman molecular genetics
Volume14
Issue number14
DOIs
StatePublished - Jul 15 2005

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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