A preprint using cells from 77 donors links hematopoietic cell aging to the vulnerability of complex gene programs
A preprint using cells from 77 donors links hematopoietic cell aging to the vulnerability of complex gene programs
On June 4, Harlan Stevens's team posted a preprint describing 385 509 paired single-cell profiles from the cells of 77 healthy donors aged 17–81 years. In each cell, the authors measured gene activity and the accessibility of DNA regions.
Hematopoietic stem cells and early progenitor cells continuously replenish the blood and immune system. With age, programs involved in stress responses and myeloid cell production become more active in these cells. Myeloid cells comprise part of the blood and innate immune system. At the same time, programs involved in self-renewal and lymphocyte development become less active. The authors looked for a common framework that could connect these changes.
They compared cells of the same type from people of different ages. This allowed them to distinguish age-related changes within cells from changes in the proportions of the cell types themselves. Using data on gene activity and the accessibility of DNA regions, the researchers computationally reconstructed gene programs. In each program, a regulatory protein is linked to DNA regions and genes whose activity it is thought to regulate.
In a thread discussing the study, Stevens summarized its premise:
“Entropy is random. Its effects on aging are not.”
The authors use “regulatory entropy” as a working term for several consistent observations. Cells of the same type show greater variation in gene activity. The association between an accessible DNA region and the gene it is thought to control becomes weaker. Accessible DNA regions lose their well-defined boundaries. In networks constructed separately for individual donors, the number of regulatory proteins also decreases with age. Together, these measurements describe a loss of regulatory coordination.
Programs whose regulatory regions were closer to the gene were more likely to remain stable or become more active with age. Programs that maintain cell identity were more likely to weaken when their regulation depended on distal enhancers, which are DNA regions that affect a gene from a distance. The same association appeared when the researchers compared regulatory proteins with similar roles in hematopoiesis.
The authors propose that the stress response, myeloid bias, and loss of cell identity may be related consequences of instability in the regulatory network. Their map of cells from people of different ages suggests a testable question: does the structure of a gene program predict how much that program will weaken with age within a single hematopoietic lineage?