A better understanding of the molecular processes underlying brain ageing is required to develop strategies to promote health in our ageing population. Molecular processes include epigenomics, which refers to mechanisms that regulate gene expression (how much a gene is turned on or off) that are not due to changes in the DNA coding sequence. Epigenomic mechanisms include methylation of the DNA backbone (DNA methylation – the methylome) and non-coding RNAs that do not encode proteins. To date, few studies have investigated the brain methylome and gene expression changes over adulthood.
There is evidence that different brain regions have different gene expression and epigenomic profiles making it vital that studies be conducted in specific brain areas. The posterior cingulate cortex is a small brain region that is implicated in emotional processing, attention, and memory. Although ageing-related changes in the posterior cingulate are observed, few studies have examined gene expression and DNA methylation profiles in this brain region across adulthood.
Dr Mather’s team sought to address this knowledge gap by collecting methylation and non-coding RNA data in the posterior cingulate cortex across the adult lifespan. DNA methylation across the genome was measured and RNA sequencing was undertaken in 60- 62 brain posterior cingulate cortex samples from deceased individuals, ranging in age from 32 to 103 years at the time of death, of which 44% were female. In preliminary epigenetic findings, there were 355 methylation sites across the genome that were significantly associated with ageing. For most of these differentially methylated sites, DNA methylation was positively correlated with age. Many of the results have been previously found in human ageing studies, which predominantly looked at peripheral blood DNA methylation. Of particular interest were differentially methylated sites that were identified in the FHL2 gene. The product of this gene interacts with over 90 proteins influencing their function and is implicated in metabolism, signaling, gene expression regulation and lipid metabolism. Previous work has shown associations with methylation of this gene with not only age but diabetes and cancer. Using the sequencing data, Dr Mather investigated small non-coding RNAs, known as microRNAs, that play important roles in the brain and are involved in synaptic plasticity and neuron growth. Our preliminary results found the expression levels of 43 microRNAs were associated with ageing. Two of the top results are known to influence the production of amyloid beta. Aggregations of this protein are a hallmark of Alzheimer’s disease. Future work will look at the relationships between DNA methylation, gene expression (both non-coding and non-coding) and genetic variation (previously collected), as none of these biological processes act in isolation but instead interact in complex ways.
An outcome of this research has been the development of an internationally significant, unique and comprehensive multi-omics dataset, which will facilitate investigation of gene expression, epigenomic and genetic data from the same brain samples across adulthood. National and international postgraduate students and other researchers will be able to access this data. Ultimately, this work has the potential to benefit our ageing population by revealing the fundamental molecular changes that occur with brain ageing to suggest therapeutic targets and interventions to promote brain health.
