A novel gene, FAM11A, associated with the FRAXF CpG island is transcriptionally silent in FRAXF full mutation

Shaw, Marie; Chiurazzi, Pietro; Romain, D R; Neri, Giovanni; Gécz, Jozef

doi:10.1038/sj.ejhg.5200881

Cited by 23 publications

(18 citation statements)

References 24 publications

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“…We have shown that in vitro treatment with 5-azadC of fragile X cells leads to reactivation of FMR1 transcription (Chiurazzi et al, 1998), after causing passive DNA demethylation (Pietrobono et al, 2002). Furthermore, we recently proved that treating cell lines of FRAXF individuals with 5-azadC also causes transcriptional reactivation of the FAM11A gene (Shaw et al, 2002).…”

Section: Reactivation Of Genes With a Methylated Cpg Islandmentioning

confidence: 95%

Reactivation of silenced genes and transcriptional therapy

Chiurazzi¹,

Neri²

2003

Cytogenet Genome Res

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The purpose of this review is to discuss the potential role of “transcriptional therapy” to modulate the expression of target genes in order to treat monogenic as well as multifactorial disorders. In vitro and in vivo experiments with DNA demethylating and histone hyperacetylating drugs are currently performed in several laboratories on a variety of genes. In attempting to place these results into perspective, we divided the target genes into four major categories: (1) single genes with a hypermethylated CpG island; (2) single genes without a CpG island; (3) groups of genes silenced by aberrant DNA methylation; and (4) groups of genes silenced by lack of histone acetylation. We discuss the latest advances in the field of chromatin regulation and, in particular, the role of histone methylation and that of RNA interference in gene silencing. We can expect that in the future regulation of transcription will become an effective treatment for several genetic conditions.

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Section: Reactivation Of Genes With a Methylated Cpg Islandmentioning

confidence: 95%

Reactivation of silenced genes and transcriptional therapy

Chiurazzi¹,

Neri²

2003

Cytogenet Genome Res

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“…MAGEA11 encodes a highly conserved protein that modulates the androgen receptor and may have an important role in phenotypic sex determination and prostate cancer [Jurk et al, 1998;Chomez et al, 2001;Bai et al, 2005]. The TMEM185A promoter contains the FRAXF fragile site and its transcription is completely eliminated by full expansion of FRAXF [Shaw et al, 2002]. However, no physiological defect was observed in a male with this gene silencing, so it appears that neither an increase (as seen here) nor decrease (as reported by Shaw et al [2002]) of one copy of TMEM185A causes an obvious phenotype.…”

Section: Pathological E¡ect Of the Double Complex Mutationsmentioning

confidence: 99%

Double complex mutations involvingF8andFUNDC2caused by distinct break-induced replication

et al. 2007

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Genomic rearrangements are a well-recognized cause of genetic disease and can be formed by a variety of mechanisms. We report a complex rearrangement causing severe hemophilia A, identified and further characterized using a range of PCR-based methods, and confirmed using array-comparative genomic hybridization (array-CGH). This rearrangement consists of a 15.5-kb deletion/16-bp insertion located 0.6 kb from a 28.1-kb deletion/263-kb insertion at Xq28 and is one of the most complex rearrangements described at a DNA sequence level. We propose that the rearrangement was generated by distinct but linked cellular responses to double strand breakage, namely break-induced replication (BIR) and a novel model of break-induced serial replication slippage (SRS). The copy number of several genes is affected by this rearrangement, with deletion of part of the Factor VIII gene (F8, causing hemophilia A) and the FUNDC2 gene, and duplication of the TMEM185A, HSFX1, MAGEA9, and MAGEA11 genes. As the patient exhibits no clinically detectable phenotype other than hemophilia A, it appears that the biological effects of the other genes involved are not dosage-dependent. This investigation has provided novel insights into processes of DNA repair including BIR and the first description of SRS during repair in a pathological context.

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“…Other genes that, like the fully mutated FMR1, have a methylated CpG island, require also DNA demethylation in order to resume transcription. We have actually shown that 5-azadC treatment is also effective in turning on the FAM11A gene associated with the Xq28 folate-sensitive fragile site, that is transcriptionally silent in FRAXF full mutations [Shaw et al, 2002]. The same effect might be expected for the other fragile sites due to a CGG repeat expansion followed by DNA methylation (e.g., FRAXE, FRA16A, etc.)…”

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

confidence: 73%

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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A novel gene, FAM11A, associated with the FRAXF CpG island is transcriptionally silent in FRAXF full mutation

Cited by 23 publications

References 24 publications

Reactivation of silenced genes and transcriptional therapy

Reactivation of silenced genes and transcriptional therapy

Double complex mutations involvingF8andFUNDC2caused by distinct break-induced replication

Epigenetics, fragile X syndrome and transcriptional therapy

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