Epigenetic analysis reveals a euchromatic configuration in the FMR1 unmethylated full mutations

Tabolacci, Elisabetta; Moscato, Umberto; Zalfa, Francesca; Bagni, Claudia; Chiurazzi, Pietro; Neri, Giovanni

doi:10.1038/ejhg.2008.130

Cited by 88 publications

(94 citation statements)

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“…These epigenetic changes, induced by 5-azadC, appeared to restore a euchromatic configuration of the FMR1 promoter in treated FXS cells (see Fig. 2), effectively transforming a methylated full mutation into an unmethylated full mutation (UFM) Tabolacci et al, 2008a]. 5-azadC effects increased with dose and treatment time [Chiurazzi et al, 1999;Pietrobono et al, 2002], but 4 weeks after treatment was discontinued we observed regain of DNA methylation in the FMR1 promoter and loss of transcription [Pietrobono et al, 2002].…”

Section: Transcriptional Therapy Of Fragile X and Other "Epigenetic" mentioning

confidence: 72%

“…Kumari and Usdin [2010] also reported increased methylation of lysine 20 on histone 4 (H4K20) near the CGG expansion. All these epigenetic changes result in heterochromatinization of the FMR1 locus [Coffee et al, 2002;Tabolacci et al, 2005Tabolacci et al, , 2008a, preventing transcription and resulting in absence of the FMRP protein. An exhaustive overview of FMRP functions is provided by Bagni and Oostra [2013] in this same issue.…”

Section: Fragile X Syndromementioning

confidence: 99%

“…Very few FXS patients have deletions or point mutations of the FMR1 gene [DeBoulle et al, 1993;Collins et al, 2010], resulting anyhow in FMRP loss-of-function. Finally, a rare class of FMR1 alleles is represented by unmethylated full mutations (UFM) that have been exceptionally reported in phenotypically normal males who have a CGG expansion over 200 repeats completely devoid of cytosine methylation [Smeets et al, 1995;Pietrobono et al, 2005;Tabolacci et al, 2008a]. The characterization of cell lines derived from these individuals has revealed that FMR1 promoter DNA is completely unmethylated (in both the CGG expansion and the FMR1 CpG island), transcription is increased (as in premutation carriers), FMRP levels are approximately 30-40% compared to normal (due to ribosome stalling on the expanded FMR1 mRNA [Feng et al, 1995]) and histone marks are similar to those of euchromatin (acetylation of histones 3 and 4, methylation of lysine 4 on histone 3 and di-methylation of lysine 27 on histone 3) with the exception for partial methylation of lysine 9 of histone 3 (H3K9).…”

Section: Fragile X Syndromementioning

confidence: 99%

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Epigenetics, fragile X syndrome and transcriptional therapy

Tabolacci

Chiurazzi

2013

American J of Med Genetics Pt A

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Epigenetics refers to the study of heritable changes in gene expression that occur without a change in DNA sequence. Epigenetic mechanisms therefore include all transcriptional controls that determine how genes are expressed during development and differentiation, but also in individual cells responding to environmental stimuli. The purpose of this review is to examine the basic principles of epigenetic mechanisms and their contribution to human disorders with a particular focus on fragile X syndrome (FXS), the most common monogenic form of developmental cognitive impairment. FXS represents a prototype of the so-called repeat expansion disorders due to "dynamic" mutations, namely the expansion (known as "full mutation") of a CGG repeat in the 5 0 UTR of the FMR1 gene. This genetic anomaly is accompanied by epigenetic modifications (mainly DNA methylation and histone deacetylation), resulting in the inactivation of the FMR1 gene. The presence of an intact FMR1 coding sequence allowed pharmacological reactivation of gene transcription, particularly through the use of the DNA demethylating agent 5 0 -aza-2 0 -deoxycytydine and/or inhibitors of histone deacetylases. These treatments suggested that DNA methylation is dominant over histone acetylation in silencing the FMR1 gene. The importance of DNA methylation in repressing FMR1 transcription is confirmed by the existence of rare unaffected males carrying unmethylated full mutations. Finally, we address the potential use of epigenetic approaches to targeted treatment of other genetic conditions. Ó 2013 Wiley Periodicals, Inc.Key words: fragile X syndrome; epigenetics; transcriptional therapy INTRODUCTION When in 1942 Conrad H. Waddington coined the term "epigenetics," the exact nature of genes and their role in heredity and in transcriptional regulation was not known; he used it as a conceptual model of how genes might interact with their surroundings to produce a phenotype [Waddington, 1942]. The term is a portmanteau of the words epigenesis (differentiation of cells from their initial totipotent state in embryonic development) and genetics. Only in 2008 at a Cold Spring harbor meeting, consensus was reached on the definition of epigenetic trait, as "stably heritable phenotype resulting from changes in a chromosome without alterations in the DNA sequence" [Berger et al., 2009]. The greek prefix epi-refers to features that are "on top of" genetics, that is, all those stable but reversible changes to DNA, RNA and proteins that regulate gene expression and allow cells with the same DNA to do different things at different times.Broadly speaking, epigenetic mechanisms include all transcriptional controls that regulate gene expression, whether during development and differentiation or in mature cells responding to the environment. Epigenetic changes can be inherited (e.g., imprinting) and be relatively stable (e.g., chromosome X inactivation), but are often rapidly imposed or removed on a given locus according to cell needs. Four major layers of epigenetic controls have ...

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Section: Transcriptional Therapy Of Fragile X and Other "Epigenetic" mentioning

confidence: 72%

Section: Fragile X Syndromementioning

confidence: 99%

Section: Fragile X Syndromementioning

confidence: 99%

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Epigenetics, fragile X syndrome and transcriptional therapy

Tabolacci

Chiurazzi

2013

American J of Med Genetics Pt A

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“…In 1991 Verkerk et al identify the FMR1 gene locus Xq27.3, corresponding to the fragile site sensitive to folate deficiency (FRAXA). Its mutation is described as the cause of fragile X syndrome and it is characterized by the presence of a CGG trinucleotide repeat in the in the promoter region of the FMR1 gene (14,15,16 (17,18,19).…”

Section: Discussionmentioning

confidence: 99%

Fragile X Syndrome in a Colombian Family

Saldarriaga¹,

Hagerman

Salcedo-Arellano³

et al. 2018

iatreia

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SUMMARYA study was performed on a family from Cali, Colombia in which nine patients were evaluated, three of which presented with intellectual disability with no previous etiological diagnosis.The proband was diagnosed with Fragile X syndrome by DNA molecular testing and, cascade testing, performed on all available family members, identifying two additional individuals with the full mutation and four carriers of a premutation allele.With this report we seek to contribute to Colombian epidemiology of the syndrome and emphasize the importance of diagnosis to provide a comprehensive and specific treatment to those affected. Further we seek to identify premutation carriers in their families or women with a full mutation without the classic phenotype for genetic counseling and education about potential associated pathologies. KEY WORDSFMRP; Fragile X Syndrome; Genetic Counseling; Intellectual Disability IATREIA Vol 31(1) enero-marzo 2018 77 RESUMEN Sindrome X frágil en una Familia ColombianaSe realizó un estudio descriptivo a una familia de Cali, Colombia, en el cual se evaluaron nueve pacientes, tres de los cuales presentaban discapacidad intelectual sin diagnóstico etiológico anterior. El caso índice fue diagnosticado con el síndrome X frágil mediante pruebas moleculares de ADN. Se realizaron pruebas en cascada a todos los miembros de la familia disponibles, identificando dos individuos adicionales con la mutación completa y cuatro portadores del alelo con pre mutación. Con este informe pretendemos contribuir a la epidemiología colombiana del síndrome y destacamos la importancia del diagnóstico etiológico de la discapacidad intelectual y proporcionar un tratamiento integral y específico a las personas afectadas. Además se busca identificar a los portadores de la pre mutación o mujeres con mutación completa sin fenotipo clásico para el asesoramiento genético y la educación sobre posibles patologías asociadas.

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“…Levels of FMR1 transcription are slightly increased compared with controls, but translational efficiency of the corresponding mRNA is reduced. 6,7 These studies demonstrated that CGG expansion in the range of FM per se does not prevent FMR1 transcription, DNA methylation being …”

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confidence: 99%

Defining the role of the CGGBP1 protein in FMR1 gene expression

et al. 2015

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Fragile X syndrome is the most common heritable form of intellectual disability and is caused by the expansion over 200 repeats and subsequent methylation of the CGG triplets at the 5′ UTR of the FMR1 gene, leading to its silencing. The epigenetic and molecular mechanisms responsible for FMR1 gene silencing are not fully clarified. To identify structure-specific proteins that could recruit components of the silencing machinery we investigated the role of CGGBP1 in FMR1 gene transcription. CGGBP1 is a highly conserved protein that binds specifically to unmethylated CGG tracts. Its role on FMR1 transcription is yet to be defined. Sequencing analysis and expression studies through quantitative PCR of CGGBP1 were performed in cell lines with different allele expansions: wild type, premutation, methylated full mutation and unmethylated full mutation, demonstrating no differences between them. ChIP assays clearly demonstrated that CGGBP1 binds to unmethylated CGG triplets of the FMR1 gene, but not to methylated CGGs. We also observed that CGGBP1 binding to the FMR1 locus was restored after pharmacological demethylation, with 5-azadC, of alleles, carriers of methylated full mutation, suggesting a possible role for CGGBP1 in FMR1 expression. CGGBP1 silencing with shRNAs (reaching~98% of CGGBP1-mRNA depletion) did not affect FMR1 transcription and CGG expansion stability in expanded alleles. Although the strong binding to the CGG tract could suggest a relevant role of CGGBP1 on FMR1 gene expression, our results demonstrate that CGGBP1 has no direct effect on FMR1 transcription and CGG repeat stability. INTRODUCTIONFragile X syndrome (FXS, OMIM #300624) is the leading cause of heritable intellectual disability and autism, belonging to the group of the so-called FRAXopathies. 1,2 FXS affects~1 in 4000 males and 1 in 9000 females. 3,4 It is almost invariably due to a large expansion (full mutation, FM) of an instable CGG repeat in the 5′ untranslated region (5′-UTR) of the FMR1 gene (in Xq27.3). CGG expansion over 200 repeats (FM) is followed by epigenetic modifications of the 5′-UTR of the FMR1 gene, including primarily DNA methylation in both the expanded CGG tract and in the neighboring CpG island, as well as other heterochromatic histone modifications (ie, methylation of H3K9, trimethylation of H3K27, H3 and H4 hypoacetylation). These epigenetic modifications cause the transcriptional silencing of the FMR1 gene and consequently the lack of the FMRP protein. [5][6][7] FMRP is an RNA-binding protein that is involved in multiple pathways of mRNA metabolism, essentially as an inhibitor of translation particularly at synaptic level. 8 Several years ago have been described rare individuals of normal intelligence, carrying a transcriptionally active unmethylated full mutation (UFM). 9 The epigenetic characterization of these rare UFM cell lines showed histone marks similar to euchromatin with absence of DNA methylation in both the CpG island of the promoter region and the CGG repeat itself. Levels of FMR1 transcription are sl...

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Epigenetic analysis reveals a euchromatic configuration in the FMR1 unmethylated full mutations

Cited by 88 publications

References 50 publications

Epigenetics, fragile X syndrome and transcriptional therapy

Epigenetics, fragile X syndrome and transcriptional therapy

Fragile X Syndrome in a Colombian Family

Defining the role of the CGGBP1 protein in FMR1 gene expression

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