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Single-Cell Study Finds Chromatin Epigenetic Variability Rises with Age

NEW YORK (GenomeWeb) – By following chromatin modification patterns with a single-cell mass cytometry approach in a wide range of immune cell types, a Stanford University-led team has identified a rise in epigenetic variability in aging individuals.

The researchers began by using an "epigenetic landscape profiling using cytometry by time-of-flight," or EpiTOF, approach to profile eight histone modification types and four histone variants in nearly two dozen primary immune cell subtypes — an analysis that uncovered variable chromatin patterns depending on the cell type and blood cell lineage considered.

When the team assessed a range of cell types from 24 seemingly healthy individuals and 19 twin pairs, meanwhile, it saw a rise in cell chromatin modification variability and enhanced chromatin modification heterogeneity in samples from older individuals, though much of this variation appeared to be non-heritable. The findings were published today in Cell.

"Comparative analysis of younger and older adults reveals that increased variations between individuals and elevated cell-to-cell variability in chromatin marks are signatures of aging," according to the authors, led by Alex Kuo, Purvesh Khatri, and Paul Utz, all based at Stanford's Institute for Immunity, Transplantation, and Infection, among other affiliations.

The phosphorylation, acetylation, methylation, and other diverse modifications appended to histone proteins are known for making contributions to everything from chromatin architecture to genetic regulation, the team explained. Even so, it has been tricky to comprehensively profile the suite of post-translational histone modifications and histone variants that impact human traits and disease.

"While recent technologic breakthroughs have allowed investigations of chromatin dynamics using a small number of cells or even single cells," the authors wrote, "a high-throughput method to measure the overall cellular levels of chromatin marks in individuals cells has not been described."

With that in mind, the researchers began by developing a multiplexed, single-cell EpiTOF mass cytometry pipeline for interrogating histone modifications and variants. Starting from a panel of more than 150 commercially available antibodies, they narrowed in on 40 antibodies for EpiTOF panels used to assess immune cell subtypes.

From there, the team went on to profile chromatin modifications in peripheral blood mononuclear cells from a dozen healthy, cytomegalovirus-free individuals, including six individuals younger than 25 years and six individuals in the over-65 group.

Along with cell type-specific chromatin marks, the researchers' analyses suggest that histone variation tends to rise in immune cells as individuals age — patterns they verified through EpiTOF testing on samples for another 12 individuals.

"Comparative analysis of younger and older adults reveals that increased variations between individuals and elevated cell-to-cell variability in chromatin marks are signatures of aging," the authors wrote.

In addition to analyses on cell type clusters based on the chromatin profiling, the team brought in available chromatin immunoprecipitation sequencing and gene expression data to get a look at the consequences of the regulatory reprogramming that occurs as chromatin marks shift.

The study also delved into the heritability of the histone variability detected with age, by profiling 40 chromatin marks using samples from 19 identical twin pairs. Based on patterns in those samples, the researchers estimated that some 70 percent of the chromatin modification variability documented in aging individuals is a product of environmental exposures and influences rather than inherited genetic features. 

"Our data provide insights about how aging affects the epigenomics landscape and the relative contribution of nature and nurture to chromatin dynamics in aging human cells," the authors wrote, noting that the EpiTOF approach may also prove useful for tracing chromatin contributions to human disease.

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