Some say that all babies look the same – small, warm bags of tears and mayhem – with significant differences only appearing as we grow older and grow apart from our newborn brethren (and sistren!). Our burgeoning epigenome may react to aging in a very similar manner, with age-related losses and gains of DNA methylation combining to create widespread variation in CpG methylation. However, we know less regarding how the levels of histone modifications vary with age.
Researchers from the laboratories of Paul J. Utz, Purvesh Khatri, and Alex J. Kuo (Stanford University, USA) knew that the high-throughput study of histone modifications in single cells represented a difficult task. To overcome this technological obstacle, the team put their differences aside to create EpiTOF (or epigenetic landscape profiling using cytometry by time-of-flight) to measure variations in the levels of eight classes of histone modifications and four histone variants in twenty-two major types of human immune cells.
In their latest study, the talented team now reports on how their highly multiplexed mass cytometry analysis has aided the understanding of the profound impact of aging on the chromatin landscape.
Here are the highlights from this fantastic new study:
- Distinct histone modification profiles characterize immune cell subtypes of the healthy human immune system
- Cell-type-specific profiles indicate the hematopoietic lineages from which individual populations derive
- ChIP-Seq analysis indicates drastic changes to profiles associated with gene expression reprogramming during hematopoietic lineage determination
- Overall, unique single-cell profiles form a molecular signature that predicts immune cell identity, including T cell functional subsets
- Comparisons between young and old cells demonstrated that levels of a wide range of histone modification increase in diverse immune cell types with age
- Importantly, an increase in cell-to-cell variability in histone modification profiles within each immune cell subtype represents a molecular signature of aging
- Elevated epigenomic “noise” derived from increased polycomb repressive complex-mediated H3K27me3 deposition leads to varying histone modification profiles in single cells and higher transcriptional noise during aging
- Finally, twin cohort analysis suggested that non-heritable influences majorly drive aging-related variations in histone modification profiles (~70%) and demonstrate that profile divergence widens with age
Taken together, the findings from this new technological breakthrough highlights the profound impact of aging on histone modification at the single cell level, suggesting that while our cells may begin in a similar state, they soon grow apart as we age (disgracefully or not!). Next, the authors hope to apply EpiTOF to identify histone modifications dysregulated in immune-mediated diseases and cancer to facilitate the development of therapeutic agents targeting histone-modifying enzymes.
For all the details on EpiTOF and more on how out chromatin landscape changes with age, see Cell, March 2018.