Epigenetics, fragile X syndrome and transcriptional therapy

Abstract

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 ...

Maternal Factors that Induce Epigenetic Changes Contribute to Neurological Disorders in Offspring

“…An increased level of DNA methylation (5mC) and hydroxylmethylation (5hmC) at the transcriptional start site of FMR1 in FXS patients highlights the strong association of epigenetic regulation in FMR1 gene silencing [204]. Hence epigenetic therapeutic strategies using DNA demethylating agents at the transcriptional site to reactivate FMR1 offer promising avenues to treat this currently non-treatable genetic disorder [211]. …”

Targeted Reactivation of FMR1 Transcription in Fragile X Syndrome Embryonic Stem Cells

“…It may be that the underlying repeat size is the critical determinant. Most cases of fully unmethylated full mutation patients described to date have repeat sizes that are less than 400 CGGs (Pietrobono, Tabolacci et al 2005, Tabolacci andChiurazzi 2013). In cases of methylation mosaicism, somatic instability complicates data interpretation, meaning that effects on FMRP production may be cell specific (Jiraanont, Kumar et al 2017).…”

Lysine Acetylation and Deacetylation in Brain Development and Neuropathies

“…The fragile X-linked syndrome is caused by a CGG-triplet repeat expansion in the 5′ UTR of FMR1 , resulting in extensive local methylation, silencing of FMR1 , and loss of fragile X mental retardation protein (FMRP). Given the extensive chromatin rearrangements caused by the CGG-triplet repeat, HDAC inhibitors have been used in different models to reactivate the transcription of FMR1 [155]. Accordingly, treatment with VPA has been reported to ameliorate hyperactivity in fragile X syndrome boys [156].…”