Transcriptional profiling of isogenic Friedreich ataxia neurons and effect of an HDAC inhibitor on disease signatures

Lai, Jiun-I; Nachun, Daniel; Petrosyan, Lina; Throesch, Benjamin; Campau, Erica; Gao, Fuying; Baldwin, Kristin K.; Coppola, Giovanni; Gottesfeld, Joel M.; Soragni, Elisabetta

doi:10.1074/jbc.ra118.006515

Cited by 32 publications

(44 citation statements)

References 101 publications

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“…These effects may be caused by multiple genes that can be transcriptionally controlled by post-translational modifications in histone and non-histone proteins (36). A-196 demonstrated transcriptional activity that was dose-dependent and substantially reduced compared to a previously-reported HDACi (33). There was no evidence of specific pathway activation, suggesting that the transcriptional effects of A-196 do not result in significant changes in cellular function.…”

Section: Discussionmentioning

confidence: 72%

“…Previous studies of FRDA have focussed on achieving chromatin remodelling by HDACi (24,26,43,44,30,33,(37)(38)(39)(40)(41)(42). As opposed to acetyltransferases, lysine methyltransferases have high specificity, modifying usually one single lysine on a single histone.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, it has been shown that this family of enzymes preferentially methylate histone H4K20 on nucleosomes rather than free histones (20), narrowing down in this way, even more, the epigenetic modification of SUV4-20 genome-wide. The aforementioned characteristics of lysine methyltransferases may be the reason why A-196 used at all tested concentrations, modifies the expression of fewer genes compared to HDACi (33).…”

Section: Discussionmentioning

confidence: 99%

“…All genes considered for differential expression were used as background and an FDR cut-off of 0.01 was used. For comparison between our transcriptomic data and the work by Lai and colleagues (33), raw fastq files were obtained from Sequence Read Archive (SRA) accession PRJNA495860 and processed as described above. The number of replicates per condition was kept constant to minimise differences in statistical power.…”

Section: Rna-sequencingmentioning

confidence: 99%

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Inhibition of the SUV4-20 H1 histone methyltransferase increases frataxin expression in Friedreich’s ataxia patient cells

Vilema-Enríquez

Quinlan

Kilfeather

et al. 2020

Preprint

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The molecular mechanisms of reduced frataxin (FXN) expression in Friedreich's ataxia (FRDA) are linked to epigenetic modification of the FXN locus caused by the disease-associated GAA expansion. Here, we identify that SUV4-20 histone methyltransferases, specifically SUV4-20 H1, play an important role in the regulation of FXN expression and represent a novel therapeutic target. Using a human FXN-GAA-Luciferase repeat expansion genomic DNA reporter model of FRDA, we screened the Structural Genomics Consortium epigenetic probe collection. We found that pharmacological inhibition of the SUV4-20 methyltransferases by the tool compound A-196 increased the expression of FXN by approximately 1.5-fold in the reporter cell line and in several FRDA cell lines and patientderived primary peripheral blood mononuclear cells. SUV4-20 inhibition was accompanied by a reduction in H4K20me2 and H4K20me3 and an increase in H4K20me1, but only modest (1.4-7.8%) perturbation in genome-wide expression was observed. Finally, based on the structural activity relationship and crystal structure of A-196, novel small molecule A-196 analogues were synthesized and shown to give a 20-fold increase in potency for increasing FXN expression. Overall, our results suggest that histone methylation is important in the regulation of FXN expression, and highlight SUV4-20 H1 as a potential novel therapeutic target for FRDA.

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Section: Discussionmentioning

confidence: 72%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Rna-sequencingmentioning

confidence: 99%

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Inhibition of the SUV4-20 H1 histone methyltransferase increases frataxin expression in Friedreich’s ataxia patient cells

Vilema-Enríquez

Quinlan

Kilfeather

et al. 2020

Preprint

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“…We [8][9][10] and others [11][12][13] have characterized the genetic, epigenetic and biochemical phenotype of iPSC-derived "default" neurons, close to immature cortical neurons, showing that they recapitulate essential aspects of FRDA pathogenesis that are at least partially corrected by restoring FXN levels, but no FRDA cell model consisting of human proprioceptors is yet available. Although in some studies iPSC neural differentiation has been cued toward a neural crest-primary sensory neuron fate 14 , or even to primary sensory neurons 11 , they did not specifically enrich for or purified proprioceptors. A rodent cell model consisting in DRG cultures from conditional knock-out mice whose Fxn gene was deleted in Parvalbumin-positive neurons, including proprioceptors, has also been developed, but it has limitations such as the lack of expanded GAA repeats and the postdevelopment induction of FXN deficiency.…”

Section: Introductionmentioning

confidence: 99%

Induced pluripotent stem cell-derived primary proprioceptive neurons as Friedreich ataxia cell model

Dionisi

Rai

Chazalon

et al. 2019

Preprint

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Human induced pluripotent stem cells (iPSCs) are used to generate models of human diseases that recapitulate the pathogenic process as it occurs in affected cells. Many differentiated cell types can currently be obtained from iPSCs, but no validated protocol is yet available to specifically generate primary proprioceptive neurons. Proprioceptors are affected in a number of genetic and acquired diseases, including Friedreich ataxia (FRDA). FRDA is a recessive neurodegenerative and systemic disease due to epigenetic suppression of frataxin (FXN) expression caused by the presence of expanded GAA repeats at the FXN locus. The most characteristic early neuropathologic finding in FRDA is the loss of large primary proprioceptive neurons in the dorsal root ganglia (DRGs), with associated loss of large myelinated fibers in the dorsal roots and in the posterior columns of the spinal cord. Both a developmental deficit and progressive neurodegeneration are thought to underlie the loss of proprioceptors in FRDA, though the relative contribution of these two components is unclear. The basis of the high specific vulnerability of proprioceptors in FRDA is also unknown. In order to address these open questions about FRDA pathogenesis and at the same time develop a cell model that can be applied to other conditions primarily affectingproprioceptors, we set up a protocol to differentiate iPSCs into primary proprioceptive neurons. We modified the dual-SMAD inhibition/WNT activation protocol, previously used to generate nociceptor-enriched cultures of primary sensory neurons from iPSCs, to favor instead the generation of proprioceptors. We succeeded in substantially enriching iPSCderived primary sensory neuron cultures in proprioceptors, largely exceeding the proportion normally represented by these cells in dorsal root ganglia. We also showed that almost pure populations of proprioceptors can be purified from these cultures by fluorescence-activated cell sorting. Finally, we demonstrated that iPSCs from a FRDA patient can generate normal appearing proprioceptors but have subtle differentiation deficits and more limited survival. Corresponding authorCorrespondence to Massimo Pandolfo.

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Blood RNA transcripts reveal similar and differential alterations in fundamental cellular processes in Alzheimer's disease and other neurodegenerative diseases

Huseby

Delvaux

Brokaw

et al. 2022

Alzheimer's & Dementia

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Background Dysfunctional processes in Alzheimer's disease and other neurodegenerative diseases lead to neural degeneration in the central and peripheral nervous system. Research demonstrates that neurodegeneration of any kind is a systemic disease that may even begin outside of the region vulnerable to the disease. Neurodegenerative diseases are defined by the vulnerabilities and pathology occurring in the regions affected. Method A random forest machine learning analysis on whole blood transcriptomes from six neurodegenerative diseases generated unbiased disease‐classifying RNA transcripts subsequently subjected to pathway analysis. Results We report that transcripts of the blood transcriptome selected for each of the neurodegenerative diseases represent fundamental biological cell processes including transcription regulation, degranulation, immune response, protein synthesis, apoptosis, cytoskeletal components, ubiquitylation/proteasome, and mitochondrial complexes that are also affected in the brain and reveal common themes across six neurodegenerative diseases. Conclusion Neurodegenerative diseases share common dysfunctions in fundamental cellular processes. Identifying regional vulnerabilities will reveal unique disease mechanisms. Highlights Transcriptomics offer information about dysfunctional processes. Comparing multiple diseases will expose unique malfunctions within diseases. Blood RNA can be used ante mortem to track expression changes in neurodegenerative diseases. Protocol standardization will make public datasets compatible.

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Transcriptional profiling of isogenic Friedreich ataxia neurons and effect of an HDAC inhibitor on disease signatures

Cited by 32 publications

References 101 publications

Inhibition of the SUV4-20 H1 histone methyltransferase increases frataxin expression in Friedreich’s ataxia patient cells

Inhibition of the SUV4-20 H1 histone methyltransferase increases frataxin expression in Friedreich’s ataxia patient cells

Induced pluripotent stem cell-derived primary proprioceptive neurons as Friedreich ataxia cell model

Blood RNA transcripts reveal similar and differential alterations in fundamental cellular processes in Alzheimer's disease and other neurodegenerative diseases

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