Exploring Beyond the DNA Sequence: A Review of Epigenomic Studies of DNA and Histone Modifications in Dementia

Abstract

Purpose of Review Although genome-scale studies have identified many genetic variants associated with dementia, these do not account for all of disease incidence and so recently attention has turned to studying mechanisms of genome regulation. Epigenetic processes such as modifications to the DNA and histones alter transcriptional activity and have been hypothesized to be involved in the etiology of dementia. Here, we review the growing body of literature on dementia epigenomics, with a focus on novel discoveries, current limitations, and future directions for the field. Recent Findings It is through advances in genomic technology that large-scale quantification of epigenetic modifications is now possible in dementia. Most of the literature in the field has primarily focussed on exploring DNA modifications, namely DNA methylation, in postmortem brain samples from individuals with Alzheimer’s disease. However, recent studies have now begun to explore other epigenetic marks, such as histone modifications, investigating these signatures in both the brain and blood, and in a range of other dementias. Summary There is still a demand for more epigenomic studies to be conducted in the dementia field, particularly those assessing chromatin dynamics and a broader range of histone modifications. The field faces limitations in sample accessibility with many studies lacking power. Furthermore, the frequent use of heterogeneous bulk tissue containing multiple cell types further hinders data interpretation. Looking to the future, multi-omic studies, integrating many different epigenetic marks, with matched genetic, transcriptomic, and proteomic data, will be vital, particularly when undertaken in isolated cell populations, or ideally at the level of the single cell. Ultimately these studies could identify novel dysfunctional pathways and biomarkers for disease, which could lead to new therapeutic avenues.

A meta-analysis of epigenome-wide association studies in Alzheimer’s disease highlights novel differentially methylated loci across cortex

“…In the future, larger meta-analyses should stratify by the presence of these protein aggregates, particularly given that very few EWAS have been undertaken in other dementias. Indeed, only three DNA methylomic studies have been undertaken in cortical samples of individuals with other dementias to date [27][28][29][30] , with none of these studies utilizing > 15 individuals for EWAS. Further studies exploring common and unique DNA methylation signatures and our classifier in other diseases characterized by dementia will be vital for identifying disease-specific epigenetic signatures that could represent novel therapeutic targets.…”

Epigenetics of Alzheimer’s Disease

“…Acetylation dysregulation has been associated with various impairments in signaling, proliferation, inflammation, immunity, apoptosis, and neuronal plasticity [ 129 ]. So far, two epigenome-wide association studies (EWAS) investigated histone acetylation in postmortem AD brain samples using chromatin immunoprecipitation sequencing (ChIP-seq) [ 130 ]. EWAS conducted by Marzi et al investigated H3K27 histone acetylation in postmortem AD brain samples and identified 4162 differentially acetylated peaks, of which many were located in genes implicated in AD pathology or AD genetic risk variants (APP, PSEN1, PSEN2, and MAPT) [ 118 ].…”

Analyzing Modern Biomolecules: The Revolution of Nucleic-Acid Sequencing – Review

“…In this manner, it has been possible to identify particular cells responsible for expressing genes related to neurodevelopmental diseases [168], as well as changes during learning and memory [169]. Also, epigenetics have been related to dementia, such as Alzheimer's disease [170]. Such epigenetic modifications can be quantified not only in the central nervous system (CNS), but also in the cerebrospinal fluid.…”