Mechanism of Action of 2-Aminobenzamide HDAC Inhibitors in Reversing Gene Silencing in Friedreich's Ataxia

Frontiers in Neurology
Elisabetta SoragniJoel M Gottesfeld

Abstract

The genetic defect in Friedreich's ataxia (FRDA) is the hyperexpansion of a GAA•TTC triplet in the first intron of the FXN gene, encoding the essential mitochondrial protein frataxin. Histone post-translational modifications near the expanded repeats are consistent with heterochromatin formation and consequent FXN gene silencing. Using a newly developed human neuronal cell model, derived from patient-induced pluripotent stem cells, we find that 2-aminobenzamide histone deacetylase (HDAC) inhibitors increase FXN mRNA levels and frataxin protein in FRDA neuronal cells. However, only compounds targeting the class I HDACs 1 and 3 are active in increasing FXN mRNA in these cells. Structural analogs of the active HDAC inhibitors that selectively target either HDAC1 or HDAC3 do not show similar increases in FXN mRNA levels. To understand the mechanism of action of these compounds, we probed the kinetic properties of the active and inactive inhibitors, and found that only compounds that target HDACs 1 and 3 exhibited a slow-on/slow-off mechanism of action for the HDAC enzymes. HDAC1- and HDAC3-selective compounds did not show this activity. Using siRNA methods in the FRDA neuronal cells, we show increases in FXN mRNA upon silencing of ...Continue Reading

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Citations

Feb 21, 2016·Nucleic Acids Research·Yogesh K ChutakeSanjay I Bidichandani
Aug 26, 2017·Journal of Neurogenetics·Oliver EdenharterJuan A Navarro
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Jan 18, 2021·The Journal of Biological Chemistry·Gabriela Vilema-EnríquezRichard Wade-Martins
Aug 17, 2021·Investigative Ophthalmology & Visual Science·Heather M SchmittRobert W Nickells

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Datasets Mentioned

BETA
GM04878
GSE65399

Methods Mentioned

BETA
histone acetylation
acetylation
histone
transgenic
transfection
immunoprecipitation
PCR
ChIP

Software Mentioned

DAVID
Database for Annotation , Visualization , and Integrated Disco...
KaleidaGraph

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