Epigenetic analysis reveals a euchromatic configuration in the FMR1 unmethylated full mutations
Open accessAbstract
Fragile X syndrome (FXS) is caused by the expansion of a CGG repeat in the 5'UTR of the FMR1 gene and the subsequent methylation of all CpG sites in the promoter region. We recently identified, in unrelated FXS families, two rare males with an unmethylated full mutation, that is, with an expanded CGG repeat (>200 triplets) lacking the typical CpG methylation in the FMR1 promoter. These individuals are not mentally retarded and do not appear to be mosaic for premutation or methylated full mutation alleles. We established lymphoblastoid and fibroblast cell lines that showed essentially normal levels of the FMR1-mRNA but reduced translational efficiency of the corresponding mRNA. Epigenetic analysis of the FMR1 gene demonstrated the lack of DNA methylation and a methylation pattern of lysines 4 and 27 on histone H3 similar to that of normal controls, in accordance with normal transcription levels and consistent with a euchromatic configuration. On the other hand, histone H3/H4 acetylation and lysine 9 methylation on histone H3 were similar to those of typical FXS cell lines, suggesting that these epigenetic changes are not sufficient for FMR1 gene inactivation. These findings demonstrate remarkable consistency and suggest a common genetic mechanism causing this rare FMR1 epigenotype. The discovery of such a mechanism may be important in view of therapeutic attempts to convert methylated into unmethylated full mutations, restoring the expression of the FMR1 gene.
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Fragile X alleles show deacetylation of histones H3 and H4, reduced methylation of lysine 4, and increased methylation of lysine 9 on histone H3.
“In addition to altered methylation status, FXS alleles show deacetylation of histones H3 and H4, reduced methylation of lysine 4 (K4), and increased methylation of lysine 9 (K9) on histone H3 (18).”
From Fragile X syndrome: causes, diagnosis, mechanisms, and therapeutics (2012) · cites this paper as [18]
In unmethylated full mutation alleles, H3 and H4 acetylation and H3K9 methylation resemble full mutation alleles, while H3K4 and H3K27 methylation resemble normal alleles.
“acetylation of histones H3 and H4 and methylation of lysine 9 on H3 of UFM alleles are more similar to those of FM alleles, while the level of methylation of lysines 4 and 27 on H3 are more similar to that of normal alleles (18,22).”
From Fragile X syndrome: causes, diagnosis, mechanisms, and therapeutics (2012) · cites this paper as [18]
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Self-citation
- Authors
- Tabolacci, E., Moscato, U., Zalfa, F., Bagni, C., Chiurazzi, P., & Neri, G.
- Affiliations
- Università Cattolica del Sacro Cuore (IT)
- University of Rome Tor Vergata (IT)
- Corresponding author
- Neri, Giovanni
- ORCID
- Venue
- European Journal of Human Genetics
- Published
- 2008-07-16
- Volume
- 16
- Issue
- 12
- Pages
- 1487-1498
- ISSN
- 1018-4813 (ISSN-L)
- 1476-5438
- OpenAlex
- W2047362927
- Cited by
- 91
- References
- 48
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 3 · 2021: 5 · 2020: 6 · 2019: 7 · 2018: 4 · 2017: 5 · 2016: 11 · 2015: 6 · 2014: 9 · 2013: 8 · 2012: 8
- FWCI
- 3.05
- Type
- journal article
- Language
- en
- Open access
- green
- lirias.kuleuven.be
- Licence
- other-oa
- www.springer.com/tdm (tdm)
- Locations
- European Journal of Human Genetics (publishedVersion)
- PubMed (publishedVersion)
- Lirias (submittedVersion, other-oa)
- Cineca Institutional Research Information System (Tor Vergata University) (submittedVersion)
- 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 › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Keywords
- fragile X syndrome, FMR1 gene, CGG repeat expansion, full mutation, DNA methylation, histone H3 lysine 4 methylation, histone H3 lysine 27 methylation, euchromatin, epigenetic silencing
- MeSH terms
- Cell Line, Cells, Cultured, DNA Mutational Analysis, Family, Female, Fibroblasts, Fragile X Syndrome, Humans, Male, Models, Biological, Mutation, DNA Methylation, Euchromatin, Epigenesis, Genetic, Fragile X Mental Retardation Protein, Fragile X Messenger Ribonucleoprotein 1
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