Journal Article

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 and Justin R. Fallon

in Human Molecular Genetics

Volume 14, issue 14, pages 2027-2034
Published in print July 2005 | ISSN: 0964-6906
Published online June 2005 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddi207
AP-2α selectively regulates fragile X mental retardation-1 gene transcription during embryonic development

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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.

Journal Article.  4896 words.  Illustrated.

Subjects: Genetics and Genomics

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