Specific promoter deacetylation of histone H3 is conserved across mouse models of Huntington's disease in the absence of bulk changes

Sfp1 links TORC1 and cell growth regulation to the yeast SAGA‐complex component Tra1 in response to polyQ proteotoxicity

“…It is reasonable to deduce that impaired Tra1‐regulated transcription has an important role in the toxic phenotype observed in HD models. Indeed, reduced histone acetylation is closely associated with HD and histone deacetylase inhibitors improve the HD phenotype in animal models . Thus, further analysis of the role of the major regulators of chromatin remodeling, gene expression and their specific targets may provide avenues for modulating the toxicity of polyQ expansion in HD.…”

Sfp1 regulates the SAGA component Tra1 in response to proteotoxic stress inSaccharomyces cerevisiae

“…It is reasonable to think that impaired Tra1-regulated transcription has an important role in the toxic phenotype observed in HD models. Indeed, reduced histone acetylation is closely associated with HD and histone deacetylase inhibitors improve the HD phenotype in animal models 23,24,26,27,91,92 . Thus, better characterization of the role of the major regulators of chromatin remodeling and gene expression and their targets provides insight into how modulating acetylation in HD can be beneficial.…”

Understanding histone deacetylation in Huntington’s disease

“…In agreement with this observation, the genome-wide efforts aimed at the identification of HDACi targets in HD models have yielded candidates that are weakly related with the transcriptional dysregulation program or that need to be replicated [1, 4]. In any case, this small subset contained potential relevant genes for synaptic and neuronal functions that also exhibited similar alterations in the striatum and associated cortex of another HD model, the R6/1 strain [8], suggesting the existence of a consistent transcriptional and epigenetic signature across HD mouse models that can be potentially restored by using pharmacological approaches.…”

“…In this follow-up study [8] we also introduced the concept of susceptibility to transcriptional dysregulation that may help to better reconcile alterations at the epigenetic and transcriptional level. In other words, histone H3 deacetylation of TSS may mark genes that become affected at the gene expression level only under specific but still unknown circumstances.…”

“…In this article we provided some examples of genes effectively hypoacetylated at their TSS that showed specific altered patterns of gene expression depending on the mouse model (e.g., Fos ), brain area (e.g., Igfbp5 ) or stage of the disease (e.g., Camk1g and Rasl11b ). In fact, whereas only 12% of the hypoacetylated genes in the hipocampus of N171-82Q was also transcriptionally altered in this brain area and animal model, this percentage was increased to 41% when also considering the genes transcriptionally altered in other datasets generated from diverse HD scenarios (i.e., N171-82Q cerebellum, R6/1 striatum, R6/2 cortex and striatum, and caudate nucleus of early-grade patients) [8]. Taking into account that this meta-analysis can be considered as preliminary, it is expected that further analytical improvements will not only strength the relationship between pathological epigenetics and transcription but also will enhance our understanding of the transcriptional actions of epigenetic restorative approaches.…”