Characterization of frataxin gene network in Friedreich's ataxia fibroblasts using the RNA-Seq technique

Sánchez, Nilda; Chapdelaine, Pierre; Rousseau, Joël; Raymond, Frédéric; Corbeil, Jacques; Tremblay, Jacques P.

doi:10.1016/j.mito.2016.06.003

Cited by 9 publications

(5 citation statements)

References 56 publications

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“…These results suggest that decreased FXN may alter selenometabolism which could explain the translational deficits (cluster 2), and may decrease the activity of antioxidant selenoenzymes (cluster 3), increasing the burden of oxidative stress, and leading to increased apoptosis (cluster 1). Thus, our results further support a more specific formulation of the oxidative stress hypothesis for FA, which has long been hypothesized to be a key mechanism of FA [55].…”

Section: Discussionsupporting

confidence: 85%

Potential biomarker identification for Friedreich’s ataxia using overlapping gene expression patterns in patient cells and mouse dorsal root ganglion

et al. 2019

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Friedreich’s ataxia (FA) is a neurodegenerative disease with no approved therapy that is the result of frataxin deficiency. The identification of human FA blood biomarkers related to disease severity and neuro-pathomechanism could support clinical trials of drug efficacy. To try to identify human biomarkers of neuro-pathomechanistic relevance, we compared the overlapping gene expression changes of primary blood and skin cells of FA patients with changes in the Dorsal Root Ganglion (DRG) of the KIKO FA mouse model. As DRG is the primary site of neurodegeneration in FA, our goal was to identify which changes in blood and skin of FA patients provide a 'window' into the FA neuropathomechanism inside the nervous system. In addition, gene expression in frataxin-deficient neuroglial cells and FA mouse hearts were compared for a total of 5 data sets. The overlap of these changes strongly supports mitochondrial changes, apoptosis and alterations of selenium metabolism. Consistent biomarkers were observed, including three genes of mitochondrial stress (MTIF2, ENO2), apoptosis (DDIT3/CHOP), oxidative stress (PREX1), and selenometabolism (SEPW1). These results prompted our investigation of the GPX1 activity as a marker of selenium and oxidative stress, in which we observed a significant change in FA patients. We believe these lead biomarkers that could be assayed in FA patient blood as indicators of disease severity and progression, and also support the involvement of mitochondria, apoptosis and selenium in the neurodegenerative process.

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Section: Discussionsupporting

confidence: 85%

Potential biomarker identification for Friedreich’s ataxia using overlapping gene expression patterns in patient cells and mouse dorsal root ganglion

et al. 2019

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“…interferon-induced apoptosis (OAS1 and OAS3) were observed and it is consistent with findings reported in FRDA and other neurodegenerative diseases (Nakad and Schumacher, 2016;Sanchez et al, 2016). Stimulation of several interferon induced genes (IFN) such as…”

Section: Signatures Of Inflammation In Both Sca12 Derived Neuronal LIsupporting

confidence: 89%

“…IFN activation also play as inflammatory mediators in neurodegeneration in Alzheimer's disease, Huntington disease and Friedreich Ataxia (FRDA) (Taylor et al, 2014;Miller et al, 2016;Sanchez et al, 2016). Interferon inducible inflammatory responses is frequently linked to interferon-induced apoptosis and DNA damage pathway (Brzostek-Racine et al, 2011).…”

Section: Signatures Of Inflammation In Both Sca12 Derived Neuronal LImentioning

confidence: 99%

Transcriptomic Dynamics of a non-coding trinucleotide repeat expansion disorder SCA12 in iPSC derived neuronal cells: signatures of interferon induced response

Kumar

Dhapola

et al. 2017

Preprint

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Abstract:Spinocerebellar ataxia type-12 (SCA12) is a neurological disorder that exhibits a unique progressive tremor/ataxia syndrome induced by triplet (CAG) repeat expansion in 5' UTR of PPP2R2B. SCA12 is one of the most prominent SCA-subtype in India and till date no appropriate disease models have been described. Our aim was to establish human iPSC derived neuronal cell lines of SCA12 and study transcriptomic level alterations induced by CAG expansion. For translational application, peripheral blood transcriptomics of SCA12 patients was also performed. Lymphoblastoid cell lines of three SCA12 patients were reprogrammed to iPSCs and then re-differentiated into pan-neuronal lineage. RNAsequencing based comparative transcriptomics was performed for disease and control cell lineages. Microarray based transcriptomic profiling of peripheral blood of SCA12 patients was performed in a case/control (n=15/9) design. We have successfully created human neuronal cell lines of SCA12 patient as exhibited by their molecular profiling. Differential expression analysis of RNA-Seq data has shown enrichment for type-I interferon signaling and other relevant cellular processes in SCA12-neurons. At the splice-isoform level, we observed an upregulation of expanded CAG containing non-coding transcript of PPP2R2B.Peripheral blood transcriptomics analysis and targeted validation of RNA-Seq data has allowed us to identify inflammatory signatures as potential markers of molecular pathology in SCA12. Our study has allowed us to establish first iPSC based neuronal cell lines of SCA12.We have identified pro-inflammatory signatures in SCA12-neurons suggestive of a dsRNA mediated activation of interferon signaling and that corroborates with the emerging evidence of neuronal atrophy due to neuro-inflammation in common neurodegenerative diseases. This study involved development of an iPSCs derived neuronal cells of SCA12 and look through signatures of neurodegeneration by whole RNA sequencing. This model sheds light upon key role of RNA mediated induced response in Interferon signaling for neurodegeneration.peer-reviewed)

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“…Our massive parallel-sequencing analysis tool, MassiveSeq, provides an opportunity for researchers and bioinformaticians to easily extract and process meaningful information (such as quantitative gene expression, novel transcripts and their isoforms, alternative splice-site variants, SNPs or copy-number variation) from these large datasets to evaluate the associations between biological processes, gene expression and disease outcomes. MassiveSeq automates downloading and processing of large-scale RNA-seq datasets with the aim of easing computational time and complexity 70– 73 .…”

Section: Project Descriptions and Goalsmentioning

confidence: 99%

“…The MassiveSeq pipeline allows uniform processing of multiple, independent RNAseq datasets, enabling powerful identification of differentially expressed genes and transcripts associated with diseases of interest. We applied MassiveSeq to 99 Friedreich’s Ataxia SRA datasets to identify disease-associated transcripts for Iron Hack 70– 73 .…”

Section: Project Descriptions and Goalsmentioning

confidence: 99%

Iron Hack - A symposium/hackathon focused on porphyrias, Friedreich’s ataxia, and other rare iron-related diseases

et al. 2019

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Background: Basic and clinical scientific research at the University of South Florida (USF) have intersected to support a multi-faceted approach around a common focus on rare iron-related diseases. We proposed a modified version of the National Center for Biotechnology Information’s (NCBI) Hackathon-model to take full advantage of local expertise in building “Iron Hack”, a rare disease-focused hackathon. As the collaborative, problem-solving nature of hackathons tends to attract participants of highly-diverse backgrounds, organizers facilitated a symposium on rare iron-related diseases, specifically porphyrias and Friedreich’s ataxia, pitched at general audiences. Methods: The hackathon was structured to begin each day with presentations by expert clinicians, genetic counselors, researchers focused on molecular and cellular biology, public health/global health, genetics/genomics, computational biology, bioinformatics, biomolecular science, bioengineering, and computer science, as well as guest speakers from the American Porphyria Foundation (APF) and Friedreich’s Ataxia Research Alliance (FARA) to inform participants as to the human impact of these diseases. Results: As a result of this hackathon, we developed resources that are relevant not only to these specific disease-models, but also to other rare diseases and general bioinformatics problems. Within two and a half days, “Iron Hack” participants successfully built collaborative projects to visualize data, build databases, improve rare disease diagnosis, and study rare-disease inheritance. Conclusions: The purpose of this manuscript is to demonstrate the utility of a hackathon model to generate prototypes of generalizable tools for a given disease and train clinicians and data scientists to interact more effectively.

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Characterization of frataxin gene network in Friedreich's ataxia fibroblasts using the RNA-Seq technique

Cited by 9 publications

References 56 publications

Potential biomarker identification for Friedreich’s ataxia using overlapping gene expression patterns in patient cells and mouse dorsal root ganglion

Potential biomarker identification for Friedreich’s ataxia using overlapping gene expression patterns in patient cells and mouse dorsal root ganglion

Transcriptomic Dynamics of a non-coding trinucleotide repeat expansion disorder SCA12 in iPSC derived neuronal cells: signatures of interferon induced response

Iron Hack - A symposium/hackathon focused on porphyrias, Friedreich’s ataxia, and other rare iron-related diseases

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