Histone deacetylase knockouts modify transcription, CAG instability and nuclear pathology in Huntington disease mice
- Massachusetts General Hospital, United States
- Massachusetts General Hospital/Broad Institute, United States
- Baylor College of Medicine, United States
- Massachusetts General Hospital, Harvard Medical School, United States
Abstract
Somatic expansion of the Huntington's disease (HD) CAG repeat drives the rate of a pathogenic process ultimately resulting in neuronal cell death. Although mechanisms of toxicity are poorly delineated, transcriptional dysregulation is a likely contributor. To identify modifiers that act at the level of CAG expansion and/or downstream pathogenic processes, we tested the impact of genetic knockout, in HttQ111 mice, of Hdac2 or Hdac3 in medium-spiny striatal neurons that exhibit extensive CAG expansion and exquisite disease vulnerability. Both knockouts moderately attenuated CAG expansion, with Hdac2 knockout decreasing nuclear huntingtin pathology. Hdac2 knockout resulted in a substantial transcriptional response that included modification of transcriptional dysregulation elicited by the HttQ111 allele, likely via mechanisms unrelated to instability suppression. Our results identify novel modifiers of different aspects of HD pathogenesis in MSNs and highlight a complex relationship between the expanded Htt allele and Hdac2 with implications for targeting transcriptional dysregulation in HD.
Data availability
RNA-Seq data is deposited in GEO, under the accession number GSE148440
Article and author information
Author details
Stephen J Haggarty
Funding
Huntington Society of Canada (New Pathways Research Grant)
- Vanessa C Wheeler
National Institutes of Health (NS049206)
- Vanessa C Wheeler
Huntington's Disease Society of America (Berman Topper Career Development Award)
- Ricardo Mouro Pinto
National Institutes of Health (GM38219)
- John H Wilson
National Institutes of Health (EY11731)
- John H Wilson
National Institutes of Health (1F3HG004918)
- Leroy Hubert
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: This study was carried out in accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health under an approved protocol (2009N000216) of the Massachusetts General Hospital Subcommittee on Research Animal Care.
Copyright
© 2020, Kovalenko et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Histone deacetylase knockouts modify transcription, CAG instability and nuclear pathology in Huntington disease mice
eLife 9:e55911.
https://doi.org/10.7554/eLife.55911
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Enhancers and promoters are classically considered to be bound by a small set of transcription factors (TFs) in a sequence-specific manner. This assumption has come under increasing skepticism as the datasets of ChIP-seq assays of TFs have expanded. In particular, high-occupancy target (HOT) loci attract hundreds of TFs with often no detectable correlation between ChIP-seq peaks and DNA-binding motif presence. Here, we used a set of 1003 TF ChIP-seq datasets (HepG2, K562, H1) to analyze the patterns of ChIP-seq peak co-occurrence in combination with functional genomics datasets. We identified 43,891 HOT loci forming at the promoter (53%) and enhancer (47%) regions. HOT promoters regulate housekeeping genes, whereas HOT enhancers are involved in tissue-specific process regulation. HOT loci form the foundation of human super-enhancers and evolve under strong negative selection, with some of these loci being located in ultraconserved regions. Sequence-based classification analysis of HOT loci suggested that their formation is driven by the sequence features, and the density of mapped ChIP-seq peaks across TF-bound loci correlates with sequence features and the expression level of flanking genes. Based on the affinities to bind to promoters and enhancers we detected five distinct clusters of TFs that form the core of the HOT loci. We report an abundance of HOT loci in the human genome and a commitment of 51% of all TF ChIP-seq binding events to HOT locus formation thus challenging the classical model of enhancer activity and propose a model of HOT locus formation based on the existence of large transcriptional condensates.
