Timely advances have demonstrated that significant changes to DNA methylation levels accompany the creaking knees, failing eyes, and changing tastes in music (!) associated with the human aging process. A well-timed study now builds upon these past studies to describe a multiomic-based approach with the potential to forge links between epigenetic aging and the gene expression changes that induce the all-too-familiar signs of aging. So, let’s hear more about the “tick-tock” of this new multiomic “epigenetic clock”!
The identification of site-specific DNA methylation alterations over time supported the creation of epigenetic clocks that accurately reflect human aging; however, a lack of robust changes in associated gene expression hampered our understanding of how epigenetic aging negatively impacts cell function. Moving from past to present, a time-traveling team led by Alejandro Ocampo (University of Lausanne, Switzerland) combined chromatin accessibility profiling, a readout integrating multiple epigenetic mechanisms, and transcriptomics to create the first multiomic epigenetic clock that may, in the future, help to decipher how epigenetic aging impacts cell function.
Let’s hear more from Rechsteiner and colleagues on the construction of this novel multiomic epigenetic clock:
- Chromatin accessibility profiling of peripheral blood mononuclear cells from human donors aged between 20 and 74 using assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) supports the construction of a novel epigenetic clock integrating multiple epigenetic mechanisms
- An elastic net regression model predicts age from chromatin accessibility profiles with reasonable accuracy (5.69-year median absolute error in prediction) from both sexes
- Changes in chromatin accessibility during aging do not reflect global changes; instead, these profiles reflect the specific “opening” of genomic sites related to inflammation and the “closing” of sites linked to adaptive immunity
- Investigating links between gene transcription (as measured by RNA-seq) and chromatin accessibility at regulatory elements demonstrates that accessibility changes at promoters, but not enhancers, primarily drive transcriptional responses during aging
- The integration of chromatin accessibility and transcriptome features finally supports the development of the first multiomic epigenetic clock
- Comparisons between clocks trained on matching ATAC-seq and RNA-seq profiles demonstrate that the chromatin accessibility clock performs significantly better than the transcriptomic counterpart
- The multiomic clock performs similarly to the accessibility clock, relying on accessibility features more than gene expression features
Overall, this time-traversing team has reported novel and accurate multiomic epigenetic clocks that will support future explorations into how age-associated changes to epigenetic states negatively impact cell function to a greater degree than current single omic-based clocks.
For more on how this novel multiomic epigenetic clock may help to decipher how the aging process impacts cell function (and your changing tastes in music!), see the preprint article at bioRxiv, August 2022.