Treatment with JQ1, a BET bromodomain inhibitor, is selectively detrimental to R6/2 Huntington’s disease mice.

Treatment with JQ1, a BET bromodomain inhibitor, is selectively detrimental to R6/2 Huntington’s disease mice.

Publication date: Nov 07, 2019

Transcriptional and epigenetic alterations occur early in Huntington’s disease (HD) and treatment with epigenetic modulators are beneficial in several HD animal models. The drug JQ1, which inhibits histone acetyl-lysine reader bromodomains, has shown promise in multiple cancers and in neurodegenerative disease. We tested whether JQ1 could improve behavioral phenotypes in the R6/2 mouse model of HD and modulate HD-associated changes in transcription and epigenomics. R6/2 and non-transgenic (NT) mice were treated with JQ1 daily from 5-11 weeks of age and behavioral phenotypes evaluated over this period. Following the trial, cortex and striatum were isolated and subjected to mRNA-seq and ChIP-seq for the histone marks H3K4me3 and H3K27ac. Initially, JQ1 enhanced motor performance in NT mice. In R6/2 mice, however, JQ1 had no effect on rotarod or grip strength but exacerbated weight loss and worsened performance on the pole test. JQ1-induced gene expression changes in NT mice were distinct from those in R6/2 and primarily involved protein translation and bioenergetics pathways. Dysregulation of HD-related pathways in striatum was exacerbated by JQ1 in R6/2 mice, but not in NTs, and JQ1 caused a corresponding increase in the formation of a mutant huntingtin protein-dependent High Molecular Weight (HMW) species associated with pathogenesis. This study suggests that drugs predicted to be beneficial based on their mode of action and effects in wild-type or in other neurodegenerative disease models may have an altered impact in the HD context. These observations have important implications in the development of epigenetic modulators as therapies for HD.

Kedaigle, A.J., Reidling, J.C., Lim, R.G., Adam, M., Wu, J., Wassie, B., Stocksdale, J.T., Casale, Fraenkel, E., and Thompson, L.M. Treatment with JQ1, a BET bromodomain inhibitor, is selectively detrimental to R6/2 Huntington’s disease mice. 06756. 2019 Hum Mol Genet.

Concepts Keywords
Acetyl Epigenomics
BET H3K27
Bioenergetics Histone
Bromodomain Epigenomics
ChIP JQ1
Cortex Bromodomain
Epigenetic BET inhibitor
Epigenomics Epigenetics
Grip Strength Genetics
Histone Branches of biology
Huntingtin Protein Cancers neurodegenerative disease
Huntington
Inhibitor
Lysine
Mice
MRNA
Mutant
Neurodegenerative
Neurodegenerative Disease
Pathogenesis
Phenotypes
Striatum
Transcription
Transgenic
Weight Loss
Wild Type

Semantics

Type Source Name
disease DOID neurodegenerative disease
disease MESH neurodegenerative disease
disease MESH cancers
drug DRUGBANK L-Lysine
gene UNIPROT DNER
disease MESH development
gene UNIPROT IMPACT
gene UNIPROT HTT
gene UNIPROT NTS
pathway BSID Gene Expression
gene UNIPROT POLE
disease MESH weight loss
gene UNIPROT STUB1

Original Article

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