HDAC Inhibitors Can Partially Reverse Genetic Signature Linked to FA, Study Shows
Treatment with histone deacetylase inhibitors (HDACi) can restore the cellular pathways that become impaired upon loss of functional frataxin protein in Friedreich’s ataxia, a study using stem cells shows.
The study, “Transcriptional profiling of isogenic Friedreich ataxia neurons and effect of an HDAC inhibitor on disease signatures,” appeared in the Journal of Biological Chemistry.
The genetic mutation known to cause Friedreich’s ataxia consists of repeat stretches of a GAA DNA sequence, found in the part of the FXN gene that codes for the frataxin protein.
Studies have shown that the DNA repeats trigger changes that prevent the gene from being active. Such changes include epigenetic mechanisms — a cell-based system that regulates which genes are active and ready to produce a protein.
Studies have suggested that the Friedreich’s ataxia-associated mutations can change the way the DNA is folded and packed, also contributing to the regulation of genes’ readout.
The use of HDACi has been previously proposed as a strategy to treat Friedreich’s ataxia, as it increased the amount of FXN gene available to produce the frataxin protein. However, it remains poorly understood how these therapeutic agents work in Friedreich’s ataxia.
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Researchers developed three patient-derived induced pluripotent stem cell (iPSC) lines that differed exclusively in the number of GAA repeats in the FXN gene. They chemically induced these lines to be transformed into mature nerve cells of the central nervous system as well as sensory nerve cells.
By using the iPSC technology, it becomes possible to re-create in the lab the cellular and molecular conditions “of diseases that involve inaccessible human tissue,” researchers stated.
After comparing these lines with one that had been genetically altered to restored frataxin production, the team found that reduced FXN gene was linked to altered epigenetic landscape.
When comparing Friedreich’s ataxia and unaffected cells, the team found 855 genes that differed in iPSCs. In contrast, 4,886 genes were present in different amounts in Friedreich’s ataxia-derived sensory neurons compared to controls.
“This could represent an expansion of the Friedreich’s ataxia signature [genetic profile] in a relevant cell type, but also be the result of differentiation-induced variability in the two lines,” researchers said.
They identified 2,431 genes that were downregulated (less active, producing less protein) and 2,455 genes that were upregulated in Friedreich’s ataxia-derived sensory neurons. Among these, 678 and 737 genes were common to iPSC-derived central nervous system neurons.
Further analysis of the altered genes showed that many were involved in cellular pathways related to neuronal function, regulation of protein production, extracellular matrix organization, and cell death. Also, the identified gene level changes could be partially restored with HDACi treatment.
“Genes that are specifically dysregulated in sensory neurons but not in central nervous system neurons could represent a true disease signature rather than the result of changes that compensate for frataxin deficit in cell types that do not appear to be affected in the disease,” they stated.
Still, “the question remains whether and how any of the identified changes in gene” levels contribute to progression of the disease.
