Histone deacetylase knockouts modify transcription, CAG instability and nuclear pathology in Huntington disease mice

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.

Modifiers of CAG/CTG Repeat Instability: Insights from Mammalian Models

“…Relationships between HDACs, HATs and repeat instability appear to be complex, however. For example, knockdown of HDAC9 promoted, rather than suppressed, CAG expansion in the cultured astrocyte model [76], and HDAC inhibitors promoted contractions in a selectable human cell-based assay [91]. In S. cerevisiae, loss of function of different HDACs either enhanced or suppressed CAG instability [75,228], with CAG stability being dependent on activities of both HDACs and HATs that control levels of H4 acetylation [228].…”

“…These genetic data are supported by the suppression of instability upon treatment with the Class I/II HDAC inhibitor trichostatin A (TSA) [ 203 ]. Genetic knockout of either Hdac2 or Hdac3 in MSNs of Htt Q111 knock-in mice moderately suppressed striatal expansions [ 91 ]. The impact of Hdac3 knockout in this model is consistent with the expansion-suppressing effect of a selective HDAC3 inhibitor [ 227 ].…”

Identification of genetic modifiers of Huntington’s disease somatic CAG repeat instability by in vivo CRISPR-Cas9 genome editing

“…SETD2 recruits MutSα (MSH2-MSH6) to chromatin (Huang and Li, 2020); however, the opposing directions of effects targeting Setd2 and Msh6 do not obviously support such a role in vivo . CBP, SETD2 and SETDB1 may alternatively act via post-translational modification of DNA repair proteins themselves (Kovalenko et al ., 2020; Williams et al ., 2020).…”

Suppression of Somatic Expansion As a Novel Therapeutic Approach for Huntington Disease and Other Repeat Expansion Disorders

“…30,33 Subsequent analyses revealed that the striatal specific expansions occurred predominantly in the medium spiny neurons that are the primary target of neurodegeneration in HD. 34,35 Given that longer inherited alleles cause an earlier age at onset, and that in nearly all the model systems greater pathologic effects are observed with longer CAGs, it seems logical to assume that somatic expansion of the CAG repeat in HD may contribute toward the progressive nature and tissue specificity of the symptoms. Consistent with this hypothesis, it was shown that in HD individuals with the same inherited repeat length, those with greater somatic expansion in the cortex showed earlier disease onset.…”