Role of Mismatch Repair Enzymes in GAA·TTC Triplet-repeat Expansion in Friedreich Ataxia Induced Pluripotent Stem Cells

Du, Jintang; Campau, Erica; Soragni, Elisabetta; Ku, Sherman; Puckett, James W.; Dervan, Peter B.; Gottesfeld, Joel M.

doi:10.1074/jbc.m112.391961

Cited by 104 publications

(146 citation statements)

References 46 publications

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“…6). Moreover, an average expansion of 1.6-2.5 GAAs per replication cycle together with bias toward greater expansion rate in the longer of the two GAA tracts (GAA2), matches very well with results of previous studies [32,56]. Remarkably, the increase of the repeat size correlates extremely well with passage number (R 2 = 0.95-0.99; Fig.…”

Section: Figsupporting

confidence: 77%

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Alleviating GAA Repeat Induced Transcriptional Silencing of the Friedreich's Ataxia Gene During Somatic Cell Reprogramming

Polak

Butler

et al. 2016

Stem Cells and Development

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Friedreich's ataxia (FRDA) is the most common autosomal recessive ataxia. This severe neurodegenerative disease is caused by an expansion of guanine-adenine-adenine (GAA) repeats located in the first intron of the frataxin (FXN) gene, which represses its transcription. Although transcriptional silencing is associated with heterochromatin-like changes in the vicinity of the expanded GAAs, the exact mechanism and pathways involved in transcriptional inhibition are largely unknown. As major remodeling of the epigenome is associated with somatic cell reprogramming, modulating chromatin modification pathways during the cellular transition from a somatic to a pluripotent state is likely to generate permanent changes to the epigenetic landscape. We hypothesize that the epigenetic modifications in the vicinity of the GAA repeats can be reversed by pharmacological modulation during somatic cell reprogramming. We reprogrammed FRDA fibroblasts into induced pluripotent stem cells (iPSCs) in the presence of various small molecules that target DNA methylation and histone acetylation and methylation. Treatment of FRDA iPSCs with two compounds, sodium butyrate (NaB) and Parnate, led to an increase in FXN expression and correction of repressive marks at the FXN locus, which persisted for several passages. However, prolonged culture of the epigenetically modified FRDA iPSCs led to progressive expansions of the GAA repeats and a corresponding decrease in FXN expression. Furthermore, we uncovered that differentiation of these iPSCs into neurons also results in resilencing of the FXN gene. Taken together, these results demonstrate that transcriptional repression caused by long GAA repeat tracts can be partially or transiently reversed by altering particular epigenetic modifications, thus revealing possibilities for detailed analyses of silencing mechanism and development of new therapeutic approaches for FRDA.

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Section: Figsupporting

confidence: 77%

“…7B). The expansion rates varied from 1.6 to 2.5 GAA repeats per replication cycle, which is very similar to the rate of 1.7-2.3 repeats/ replication cycle reported earlier [56].…”

Section: Differentiation To Neuronal Lineage Restores Silencing Of Thsupporting

confidence: 59%

Alleviating GAA Repeat Induced Transcriptional Silencing of the Friedreich's Ataxia Gene During Somatic Cell Reprogramming

Polak

Butler

et al. 2016

Stem Cells and Development

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“…16 Neurospheres were dissociated to single cells with accutase and plated on Matrigel (BDBiosciences) at 50,000 cells/cm 2 and passaged every 4–5 days for expansion. Cells were centrifuged, and cell pellets were collected and washed with PBS buffer.…”

Section: Methodsmentioning

confidence: 99%

Quantitative Proteomic Analysis Identifies Targets and Pathways of a 2-Aminobenzamide HDAC Inhibitor in Friedreich’s Ataxia Patient iPSC-Derived Neural Stem Cells

Shan

Zhang

et al. 2014

J. Proteome Res.

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Members of the 2-aminobenzamide class of histone deacetylase (HDAC) inhibitors show promise as therapeutics for the neurodegenerative diseases Friedreich’s ataxia (FRDA) and Huntington’s disease (HD). While it is clear that HDAC3 is one of the important targets of the 2-aminobenzamide HDAC inhibitors, inhibition of other class I HDACs (HDACs 1 and 2) may also be involved in the beneficial effects of these compounds in FRDA and HD, and other HDAC interacting proteins may be impacted by the compound. To this end, we synthesized activity-based profiling probe (ABPP) versions of one of our HDAC inhibitors (compound 106), and in the present study we used a quantitative proteomic method coupled with multidimensional protein identification technology (MudPIT) to identify the proteins captured by the ABPP 106 probe. Nuclear proteins were extracted from FRDA patient iPSC-derived neural stem cells, and then were reacted with control and ABPP 106 probe. After reaction, the bound proteins were digested on the beads, and the peptides were modified using stable isotope-labeled formaldehyde to form dimethyl amine. The selectively bound proteins determined by mass spectrometry were subjected to functional and pathway analysis. Our findings suggest that the targets of compound 106 are involved not only in transcriptional regulation but also in posttranscriptional processing of mRNA.

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“…None of these studies have yet successfully recapitulated the specific cerebellar neuronal dysfunction and degeneration known to characterize these conditions. In human iPSC-based studies of FRDA, which is caused by an intronic repeat expansion in the FXN gene encoding Frataxin, disease-relevant phenotypes such as reduced Frataxin mRNA and protein levels as well as mitochondrial defects were observed in cardiomyocytes and peripheral sensory neurons, two of the affected cell types in FRDA [33][34][35][36] . In the case of A-T, chromosomal instability and cell cycle checkpoint defects, resulting from mutations in the ATM gene encoding ataxia-telangiectasia mutated (ATM) protein, have been found to reduce the efficiency of the reprogramming of A-T iPSCs 37 .…”

Section: Disease Modelling Of Cerebellar Ataxiasmentioning

confidence: 99%

Recent advances in modelling of cerebellar ataxia using induced pluripotent stem cells

Wong

Watson

Becker

2017

J Neurol Neuromedicine

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The cerebellar ataxias are a group of incurable brain disorders that are caused primarily by the progressive dysfunction and degeneration of cerebellar Purkinje cells. The lack of reliable disease models for the heterogeneous ataxias has hindered the understanding of the underlying pathogenic mechanisms as well as the development of effective therapies for these devastating diseases. Recent advances in the field of induced pluripotent stem cell (iPSC) technology offer new possibilities to better understand and potentially reverse disease pathology. Given the neurodevelopmental phenotypes observed in several types of ataxias, iPSC-based models have the potential to provide significant insights into disease progression, as well as opportunities for the development of early intervention therapies. To date, however, very few studies have successfully used iPSC-derived cells to model cerebellar ataxias. In this review, we focus on recent breakthroughs in generating human iPSC-derived Purkinje cells. We also highlight the future challenges that will need to be addressed in order to fully exploit these models for the modelling of the molecular mechanisms underlying cerebellar ataxias and the development of effective therapeutics.

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Role of Mismatch Repair Enzymes in GAA·TTC Triplet-repeat Expansion in Friedreich Ataxia Induced Pluripotent Stem Cells

Cited by 104 publications

References 46 publications

Alleviating GAA Repeat Induced Transcriptional Silencing of the Friedreich's Ataxia Gene During Somatic Cell Reprogramming

Alleviating GAA Repeat Induced Transcriptional Silencing of the Friedreich's Ataxia Gene During Somatic Cell Reprogramming

Quantitative Proteomic Analysis Identifies Targets and Pathways of a 2-Aminobenzamide HDAC Inhibitor in Friedreich’s Ataxia Patient iPSC-Derived Neural Stem Cells

Recent advances in modelling of cerebellar ataxia using induced pluripotent stem cells

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