Molecular dissection of the events leading to inactivation of the FMR1 gene
Open accessAbstract
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 (0.8-1.4 times compared with a control sample), but mRNA translation was less efficient (-40%), as judged by polysome profiling, resulting in reduced levels of FMRP protein (approximately 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 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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FMR1 silencing is the consequence of complex epigenetic modifications.
“FMR1 silencing is the consequence of rather complex epigenetic modifications (13).”
From Fragile X syndrome: causes, diagnosis, mechanisms, and therapeutics (2012) · cites this paper as [13]
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- Authors
- Pietrobono, R., Tabolacci, E., Zalfa, F., Zito, I., Terracciano, A., Moscato, U., Bagni, C., Oostra, B., Chiurazzi, P., & Neri, G.
- Affiliations
- Università Cattolica del Sacro Cuore (IT)
- University of Rome Tor Vergata (IT)
- Corresponding author
- Pietrobono, Roberta
- ORCID
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2004-11-24
- Volume
- 14
- Issue
- 2
- Pages
- 267-277
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- OpenAlex
- W2136682839
- Cited by
- 130
- References
- 39
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 4 · 2023: 2 · 2022: 1 · 2021: 2 · 2020: 7 · 2019: 4 · 2018: 8 · 2017: 10 · 2016: 12 · 2015: 7 · 2014: 11 · 2013: 10 · 2012: 9
- FWCI
- 2.65
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Human Molecular Genetics (publishedVersion)
- PubMed (publishedVersion)
- Lirias (submittedVersion, other-oa)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- Cineca Institutional Research Information System (Tor Vergata University) (submittedVersion)
- Funders
- Fondazione Telethon
- Ministero dell’Istruzione, dell’Università e della Ricerca (COFIN-2002, FIRB_2001)
- National Institutes of Health
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD038038)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- fragile X syndrome, CGG repeat expansion, DNA methylation, histone H3 lysine 4 methylation, histone deacetylation, histone H3 lysine 9 methylation, FMRP, epigenetic regulation, promoter methylation, normal intelligence
- MeSH terms
- Female, Humans, Male, Mutation, Nerve Tissue Proteins, RNA-Binding Proteins, Gene Silencing, Epigenesis, Genetic, Fragile X Messenger Ribonucleoprotein 1
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