Epigenetic Heterogeneity in Friedreich Ataxia Underlies Variable FXN Reactivation

Friedreich ataxia (FRDA) is typically caused by homozygosity for an expanded GAA triplet-repeat in intron 1 of the FXN gene. The expanded repeat induces repressive histone changes and DNA hypermethylation, which result in epigenetic silencing and FXN transcriptional deficiency. A class I histone dea...

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Autores principales:	Layne N. Rodden, Kaitlyn M. Gilliam, Christina Lam, David R. Lynch, Sanjay I. Bidichandani
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	Friedreich ataxia (FRDA) DNA methylation FXN gene histone deacetylase inhibitors (HDACi) somatic heterogeneity epialleles Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571
Acceso en línea:	https://doaj.org/article/c223ce88b32f4ae1b24813a1b5f86a2b
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spelling	oai:doaj.org-article:c223ce88b32f4ae1b24813a1b5f86a2b2021-12-01T00:19:35ZEpigenetic Heterogeneity in Friedreich Ataxia Underlies Variable FXN Reactivation1662-453X10.3389/fnins.2021.752921https://doaj.org/article/c223ce88b32f4ae1b24813a1b5f86a2b2021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fnins.2021.752921/fullhttps://doaj.org/toc/1662-453XFriedreich ataxia (FRDA) is typically caused by homozygosity for an expanded GAA triplet-repeat in intron 1 of the FXN gene. The expanded repeat induces repressive histone changes and DNA hypermethylation, which result in epigenetic silencing and FXN transcriptional deficiency. A class I histone deacetylase inhibitor (HDACi-109) reactivates the silenced FXN gene, although with considerable inter-individual variability, which remains etiologically unexplained. Because HDAC inhibitors work by reversing epigenetic silencing, we reasoned that epigenetic heterogeneity among patients may help to explain this inter-individual variability. As a surrogate measure for epigenetic heterogeneity, a highly quantitative measurement of DNA hypermethylation via bisulfite deep sequencing, with single molecule resolution, was used to assess the prevalence of unmethylated, partially methylated, and fully methylated somatic FXN molecules in PBMCs from a prospective cohort of 50 FRDA patients. Treatment of the same PBMCs from this cohort with HDACi-109 significantly increased FXN transcript to levels seen in asymptomatic heterozygous carriers, albeit with the expected inter-individual variability. Response to HDACi-109 correlated significantly with the prevalence of unmethylated and partially methylated FXN molecules, supporting the model that FXN reactivation involves a proportion of genes that are amenable to correction in non-dividing somatic cells, and that heavily methylated FXN molecules are relatively resistant to reactivation. FXN reactivation is a promising therapeutic strategy in FRDA, and inter-individual variability is explained, at least in part, by somatic epigenetic heterogeneity.Layne N. RoddenLayne N. RoddenKaitlyn M. GilliamChristina LamDavid R. LynchSanjay I. BidichandaniSanjay I. BidichandaniSanjay I. BidichandaniFrontiers Media S.A.articleFriedreich ataxia (FRDA)DNA methylationFXN genehistone deacetylase inhibitors (HDACi)somatic heterogeneityepiallelesNeurosciences. Biological psychiatry. NeuropsychiatryRC321-571ENFrontiers in Neuroscience, Vol 15 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Friedreich ataxia (FRDA) DNA methylation FXN gene histone deacetylase inhibitors (HDACi) somatic heterogeneity epialleles Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571
spellingShingle	Friedreich ataxia (FRDA) DNA methylation FXN gene histone deacetylase inhibitors (HDACi) somatic heterogeneity epialleles Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571 Layne N. Rodden Layne N. Rodden Kaitlyn M. Gilliam Christina Lam David R. Lynch Sanjay I. Bidichandani Sanjay I. Bidichandani Sanjay I. Bidichandani Epigenetic Heterogeneity in Friedreich Ataxia Underlies Variable FXN Reactivation
description	Friedreich ataxia (FRDA) is typically caused by homozygosity for an expanded GAA triplet-repeat in intron 1 of the FXN gene. The expanded repeat induces repressive histone changes and DNA hypermethylation, which result in epigenetic silencing and FXN transcriptional deficiency. A class I histone deacetylase inhibitor (HDACi-109) reactivates the silenced FXN gene, although with considerable inter-individual variability, which remains etiologically unexplained. Because HDAC inhibitors work by reversing epigenetic silencing, we reasoned that epigenetic heterogeneity among patients may help to explain this inter-individual variability. As a surrogate measure for epigenetic heterogeneity, a highly quantitative measurement of DNA hypermethylation via bisulfite deep sequencing, with single molecule resolution, was used to assess the prevalence of unmethylated, partially methylated, and fully methylated somatic FXN molecules in PBMCs from a prospective cohort of 50 FRDA patients. Treatment of the same PBMCs from this cohort with HDACi-109 significantly increased FXN transcript to levels seen in asymptomatic heterozygous carriers, albeit with the expected inter-individual variability. Response to HDACi-109 correlated significantly with the prevalence of unmethylated and partially methylated FXN molecules, supporting the model that FXN reactivation involves a proportion of genes that are amenable to correction in non-dividing somatic cells, and that heavily methylated FXN molecules are relatively resistant to reactivation. FXN reactivation is a promising therapeutic strategy in FRDA, and inter-individual variability is explained, at least in part, by somatic epigenetic heterogeneity.
format	article
author	Layne N. Rodden Layne N. Rodden Kaitlyn M. Gilliam Christina Lam David R. Lynch Sanjay I. Bidichandani Sanjay I. Bidichandani Sanjay I. Bidichandani
author_facet	Layne N. Rodden Layne N. Rodden Kaitlyn M. Gilliam Christina Lam David R. Lynch Sanjay I. Bidichandani Sanjay I. Bidichandani Sanjay I. Bidichandani
author_sort	Layne N. Rodden
title	Epigenetic Heterogeneity in Friedreich Ataxia Underlies Variable FXN Reactivation
title_short	Epigenetic Heterogeneity in Friedreich Ataxia Underlies Variable FXN Reactivation
title_full	Epigenetic Heterogeneity in Friedreich Ataxia Underlies Variable FXN Reactivation
title_fullStr	Epigenetic Heterogeneity in Friedreich Ataxia Underlies Variable FXN Reactivation
title_full_unstemmed	Epigenetic Heterogeneity in Friedreich Ataxia Underlies Variable FXN Reactivation
title_sort	epigenetic heterogeneity in friedreich ataxia underlies variable fxn reactivation
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/c223ce88b32f4ae1b24813a1b5f86a2b
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_version_	1718406046067720192

Epigenetic Heterogeneity in Friedreich Ataxia Underlies Variable FXN Reactivation

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