Human Molecular Genetics, Vol 6, 2051-2060, Copyright © 1997 by Oxford University Press
R Drouin, M Angers, N Dallaire, TM Rose, W Khandjian and F Rousseau
Fragile X mental retardation syndrome is associated with an expansion of a
CGG repeat within the 5'UTR of the first exon of the FMR1 gene, abnormal
methylation of the CpG island in the promoter region, and a transcriptional
silencing of this gene. We studied transcriptional regulation of the FMR1
gene using protein footprint analysis of the active and inactive gene in
vivo . We identified four footprints within the FMR1 promoter region which
correspond to consensus binding sites of known transcription factors,
alpha-PAL/NRF1, Sp1, H4TF1/Sp1-like and c- myc. These footprints were
present in normal cells with a transcriptionally active FMR1 gene. The same
footprints were present in different cell types: primary fibroblasts,
lymphoblastoid cells and peripheral lymphocytes. However, for the 1.1 kb
region analyzed, no footprints were detected in a variety of cell types
derived from patients with fragile X syndrome which have a
transcriptionally inactive FMR1 gene. A BLAST nucleotide search identified
sequence similarities between the region of the FMR1 gene containing the
footprints and an analogous region within the promoter region of the gene
for the heterogeneous nuclear ribonucleoprotein (hnRNP) A2, a member of a
family of ribonucleoproteins implicated in mRNA processing and
nuclear-cytoplasm transport. The nucleotide sequences identified in the
hnRNP-A2 promoter region correspond to the same consensus binding sites
showing DNA-protein interactions in the FMR1 gene. Our previous functional
studies and the studies of others demonstrate that FMR proteins, like
hnRNP-A2, are also ribonucleoproteins which appear to be involved in mRNA
transport. The results from our footprint studies suggest that the
expression of the FMR1 gene is regulated by the binding of specific
transcription factors to sequence elements in the 5' region of the gene and
that this expression may be regulated by elements in common with the
hnRNP-A2 gene. Common regulation of these two genes might play an important
role in the cooperative processing and transport of mRNA from the nucleus
to the translation machinery.
ARTICLES
Structural and functional characterization of the human FMR1 promoter reveals similarities with the hnRNP-A2 promoter region
Unite de Recherche en Genetique Humaine et Moleculaire,Centre de Recherche, Pavillon Saint-Francois d'Assise, Centre Hospitalier Universitaire de Quebec, Canada.
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