Human Molecular Genetics Advance Access published online on November 24, 2004
Human Molecular Genetics, doi:10.1093/hmg/ddi024
© 2004 by Oxford University Press
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1 Istituto di Genetica Medica, Università Cattolica, Rome, Italy
* To whom correspondence should be addressed. The analysis of a lymphoblastoid cell line (5106), derived from a rare individual of normal intelligence with an unmethylated full mutation of the FMR1 gene, allowed us to reconstruct the chain of molecular events leading to the FMR1 inactivation and to fragile X syndrome. We found that lack of DNA methylation of the entire promoter region, including the expanded CGG repeat, correlates with methylation of lysine 4 residue on the N-tail of histone H3 (H3-K4), as in normal controls. Normal levels of FMR1 mRNA were detected by real-time fluorescent RT-PCR (0.8 to 1.4 times compared to a control sample), but mRNA translation was less efficient (-40%), as judged by polysome profiling, resulting in reduced levels of FMRP protein (
Article
Molecular dissection of the events leading to inactivation of the FMR1 gene
2 Dipartimento di Biologia, Università di Roma "Tor Vergata", Rome, Italy; Istituto di Farmacologia, Fondazione Santa Lucia IRCCS, Rome, Italy
3 Istituto di Igiene, Università Cattolica, Rome, Italy
4 Department of Clinical Genetics, Erasmus Medical Center, Erasmus University, Rotterdam, The Netherlands
5 Istituto di Genetica Medica, Università Cattolica, largo F. Vito 1, 00168 Roma, Italy
Giovanni Neri, E-mail: gneri{at}rm.unicatt.it
Abstract 
30% of a normal control). These results underline once more that CGG repeat amplification per se does not prevent FMR1 transcription and FMRP production in the absence of DNA methylation. Surprisingly, we found by chromatin immunoprecipitation (ChIP) that cell line 5106 has deacetylated histones H3 and H4, as well as methylated lysine 9 on histone H3 (H3-K9), like fragile X cell lines, in both the promoter and exon 1. This indicates that these two epigenetic marks (i.e. histone deacetylation and H3-K9 methylation) can be established in the absence of DNA methylation and do not interfere with active gene transcription, contrary to expectation. Our results also suggest that the molecular pathways regulating DNA and H3-K4 methylation are independent from those regulating histone acetylation and H3-K9 methylation.
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