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Marzi SJ, Leung SK, Ribarska T, Hannon E, Smith AR, Pishva E, Poschmann J, Moore K, Troakes C, Al-Sarraj S, Beck S, Newman S, Lunnon K, Schalkwyk LC, Mill J. A histone acetylome-wide association study of Alzheimer's disease identifies disease-associated H3K27ac differences in the entorhinal cortex. Nat Neurosci. 2018 Nov;21(11):1618-1627. Epub 2018 Oct 22 PubMed.
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An important question in current neuroepigenetics research is to understand whether epigenetics is a cause or a consequence of neurodegenerative diseases. Marzi et al. have led a thorough study to tackle the former hypothesis in Alzheimer’s disease by investigating the epigenetic profile of H3K27ac, a mark of active enhancers (Creyghton et al., 2010; Rada-Iglesias et al., 2011; Zentner et al., 2011) in postmortem AD patient’s brains. They led chromatin immunoprecipitation followed by massive parallel sequencing analyses in the entorhinal cortices of 24 AD patients and 23 age-matched low pathology controls. Out of the 4,162 peaks found differentially acetylated between AD and controls, 2,687 were hypo-acetylated and 1,475 were hyper-acetylated.
A strong result from this study is that the authors demonstrated a significant association of differential H3K27ac peaks with regions in proximity of familial AD genes (APP, PSEN1, PSEN2), the MAPT locus, as well as genomic regions containing GWAS variants or genetic risk factors (e.g. APOE) associated with late-onset AD. Together these results could speak to this mark as a potential cause of AD onset. However, there was no consensus on whether the differentially acetylated H3K27 mark was preferentially hyper- or hypo-acetylated when associated with a given AD-related gene, nor a clear association with deregulation of their gene transcription.
A strength of the study is the number of patients investigated. It is noteworthy that histone acetylation modifications are not stable in postmortem tissues and display a great deal variation depending of the postmortem delay (Barrachina et al., 2012), and that the level of total histone is also modified in some brain regions (Narayan et al., 2015). Therefore, it is of most importance to have sufficient statistical power when leading such studies, as was the case in Marzi et al.
Many questions remain unanswered. Analyses were performed in bulk entorhinal tissue, which can lead to confounding effects with regard to which cell type actually displays hyper- or hypo-acetylated H3K27 enrichment. For example, acetylated H3K27 levels have been consistently found enriched in immune and stimulus-response functions enhancers and promoters and decreased in synapse and learning-associated functions enhancers and promoters in an AD mouse model (Gjoneska et al., 2015). Interestingly, in Marzi’s study, the functional analyses led with GREAT generated the interesting result that hypo-acetylated H3K27 peaks were associated with synaptic genes (e.g. neurotransmission, glutamatergic and GABAergic signaling pathways) and this was not the case with hyper-acetylated peaks.
This is reminiscent of our studies investigating the epigenome of affected brain tissues of mice modelling neurodegenerative diseases, including a mouse model of tauopathy (Chatterjee et al., 2018) and one of Huntington’s disease (Achour 2015; Le Gras 2017). In our very recent study, in addition to H3K27ac, we investigated H2Bac, showing it was decreased from early pathological stage in the hippocampus of tauopathic mice. Interestingly, H2Bac peaks colocalized with subsets of H3K27ac peaks, the latter mark being stable between tau and wild-type mice at this age. The hypo-acetylated genomic regions were enriched in genes involved in synaptic functions and regulatory signaling pathways (cAMP, calcium, MAPK …). Our interpretation was that H2Bac decreased levels were a molecular correlate of decreased plasticity in the Tau mice, thus, reflecting epigenetic dysregulation as a consequence of AD pathology.
In HD mice, H3K27 was found significantly hypo-acetylated at neuronal markers. Given that H3K27ac is also enriched at cell-/tissue-specific gene bodies (Hnisz et al., 2013; Whyte et al., 2013), this possibly translates a loss of striatal neuronal identity during HD pathology (Achour et al., 2015). Interestingly, we were able to restore the H2B acetylome in the hippocampi of tau mice treated with a molecule activating CBP/p300 (KAT3A/B) acetyltransferases (Chatterjee et al., 2013), a treatment which also restored LTD, dendritic spine formation, and long-term memory in tau mice (Chatterjee et al., 2018). Altogether, this gives hope for new therapeutic options targeting the epigenome, especially as Marzi et al. observed a larger number of hypo-acetylated H3K27 peaks than hyper-acetylated ones in human patient’s brains.
Important challenges for the future will be to be able to decipher the epigenome in specific cell types (or at least neurons versus non-neuronal cells; e.g. Benito et al., 2015) and to associate chromosome conformation studies, in order to properly understand functional repercussions of deregulated epigenetics at these specific sites found in the vicinity of AD or disease-associated genes as described here by Marzi et al.
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