Genome-Wide Histone Acetylation Is Altered in a Transgenic Mouse Model of Huntington's Disease

Abstract

In Huntington's disease (HD; MIM ID #143100), a fatal neurodegenerative disorder, transcriptional dysregulation is a key pathogenic feature. Histone modifications are altered in multiple cellular and animal models of HD suggesting a potential mechanism for the observed changes in transcriptional levels. In particular, previous work has suggested an important link between decreased histone acetylation, particularly acetylated histone H3 (AcH3; H3K9K14ac), and downregulated gene expression. However, the question remains whether changes in histone modifications correlate with transcriptional abnormalities across the entire transcriptome. Using chromatin immunoprecipitation paired with microarray hybridization (ChIP-chip), we interrogated AcH3-gene interactions genome-wide in striata of 12-week old wild-type (WT) and transgenic (TG) R6/2 mice, an HD mouse model, and correlated these interactions with gene expression levels. At the level of the individual gene, we found decreases in the number of sites occupied by AcH3 in the TG striatum. In addition, the total number of genes bound by AcH3 was decreased. Surprisingly, the loss of AcH3 binding sites occurred within the coding regions of the genes rather than at the promoter region. We also found that the presence of AcH3 at any location within a gene strongly correlated with the presence of its transcript in both WT and TG striatum. In the TG striatum, treatment with histone deacetylase (HDAC) inhibitors increased global AcH3 levels with concomitant increases in transcript levels; however, AcH3 binding at select gene loci increased only slightly. This study demonstrates that histone H3 acetylation at lysine residues 9 and 14 and active gene expression are intimately tied in the rodent brain, and that this fundamental relationship remains unchanged in an HD mouse model despite genome-wide decreases in histone H3 acetylation.

Acetyltransferases (HATs) as Targets for Neurological Therapeutics

“…However, the authors observed that an H3ac association at specific gene loci strongly correlated with expressed genes in both wild-type and transgenic striata, suggesting that these changes in histone H3ac, although genome-wide, were not sufficient to trigger the transcriptional dysfunctions associated with HD [96].…”

“…At the level of bulk chromatin, a genome-wide deacetylation of H3 histone (H3K9K14ac) was observed in the striatum of the R6/2 mouse model, but no association with a specific HAT was observed [96]. However, the authors observed that an H3ac association at specific gene loci strongly correlated with expressed genes in both wild-type and transgenic striata, suggesting that these changes in histone H3ac, although genome-wide, were not sufficient to trigger the transcriptional dysfunctions associated with HD [96].…”

“…Increasing the acetylation of histones and non-histone proteins via the use of HDAC inhibitors also counteracts neurodegeneration [8,88,[99][100][101]. Intriguingly, McFarlan et al [96] also demonstrated that HDAC inhibition reestablished altered transcriptional levels in the striatum of the R6/2 mouse model, but only slightly improved H3ac binding to specific promoter, emphasizing the idea that the overall chromatin environment surrounding a gene would be more adapted to therapeutic targeting than simply increasing the acetylation of the histones.…”

Epigenetic Mechanisms of Neurodegeneration in Huntington's Disease

“…Importantly, histone modifications, such as hypo-acetylation and hypermethylation, have been identified in HD patients, HD animal models, and HD cell line models [53][54][55][56]. Interestingly, the hypo-acetylation of histone is correlated with downregulations of genes in HD, and therapeutic inhibition of HDAC restores the acetylation level of histone and improves the neuropathology and the motor symptom in HD [56][57][58][59][60][61].…”

“…Impaired neurogenesis results in cognitive dysfunction and could be an important epigenetic marker of neurodegeneration in HD HAT activity [50,64]. Accordingly, the sequestration of CBP protein by mthtt expression causes the hypermethylation and hypo-acetylation of histone proteins, and the subsequent transcriptional dysfunction of neurons in HD [56,59,61,65,66]. These specific interactions and transcriptional dysfunction are attributable to pathological epigenetic modifications [51].…”