Transcriptional profiling of isogenic Friedreich ataxia neurons and effect of an HDAC inhibitor on disease signatures.
Jiun-I LaiDaniel NachunLina PetrosyanBenjamin ThroeschErica CampauFuying GaoKristin K BaldwinGiovanni CoppolaJoel M GottesfeldElisabetta SoragniPublished in: The Journal of biological chemistry (2018)
Friedreich ataxia (FRDA) is a neurodegenerative disorder caused by transcriptional silencing of the frataxin (FXN) gene, resulting in loss of the essential mitochondrial protein frataxin. Based on the knowledge that a GAA·TTC repeat expansion in the first intron of FXN induces heterochromatin, we previously showed that 2-aminobenzamide-type histone deacetylase inhibitors (HDACi) increase FXN mRNA levels in induced pluripotent stem cell (iPSC)-derived FRDA neurons and in circulating lymphocytes from patients after HDACi oral administration. How the reduced expression of frataxin leads to neurological and other systemic symptoms in FRDA patients remains unclear. Similar to other triplet-repeat disorders, it is unknown why FRDA affects only specific cell types, primarily the large sensory neurons of the dorsal root ganglia and cardiomyocytes. The combination of iPSC technology and genome-editing techniques offers the unique possibility to address these questions in a relevant cell model of FRDA, obviating confounding effects of variable genetic backgrounds. Here, using "scarless" gene-editing methods, we created isogenic iPSC lines that differ only in the length of the GAA·TTC repeats. To uncover the gene expression signatures due to the GAA·TTC repeat expansion in FRDA neuronal cells and the effect of HDACi on these changes, we performed RNA-seq-based transcriptomic analysis of iPSC-derived central nervous system (CNS) and isogenic sensory neurons. We found that cellular pathways related to neuronal function, regulation of transcription, extracellular matrix organization, and apoptosis are affected by frataxin loss in neurons of the CNS and peripheral nervous system and that these changes are partially restored by HDACi treatment.
Keyphrases
- single cell
- rna seq
- spinal cord
- gene expression
- end stage renal disease
- genome editing
- histone deacetylase
- extracellular matrix
- stem cells
- genome wide
- crispr cas
- newly diagnosed
- ejection fraction
- chronic kidney disease
- oxidative stress
- induced apoptosis
- dna methylation
- blood brain barrier
- binding protein
- early onset
- high glucose
- poor prognosis
- prognostic factors
- spinal cord injury
- copy number
- bone marrow
- depressive symptoms
- cell death
- physical activity
- drug induced
- cerebral ischemia
- mesenchymal stem cells
- small molecule
- sleep quality
- induced pluripotent stem cells
- signaling pathway