Single-Cell Sequencing Atlas Maps Epigenetic Diversity Across Human Tissues

Every human cell carries the same three billion DNA letters, yet cells such as neurons, heart muscle cells, and pancreatic beta cells perform entirely different jobs. That difference comes down to epigenetics: chemical tags and three-dimensional structures that determine which genes are active in a given cell.

In a study published in Science, researchers at the Salk Institute, the Arc Institute, and collaborators presented the first body-wide single-cell atlas combining two epigenetic systems, three-dimensional genome folding and DNA methylation, measured simultaneously in the same cells. The atlas spans 86,689 cells from 16 human tissues, covering 35 major cell types and 206 subtypes, and is freely available online. The work is part of the NIH’'s 4D Nucleome program, which studies how genome organization regulates gene expression in health and disease. 

“There has been an appreciation for trying to understand, at the individual cell level, how the genome is organized, so that we can get a better idea of how genetic variants impact disease,” said co-corresponding author Joseph Ecker. “Some cell types may be more vulnerable than others to genetic variants, because the genome is organized differently in different cell types.”

Most disease-linked genetic variants sit in non-coding DNA, making it hard to link them to genes or cell types. The team identified more than 1.36 million differentially methylated regions and 283,606 differential chromatin loops, and found disease variants clustered in expected cell types, such as blood-glucose variants in endocrine cells and bipolar disorder and schizophrenia variants in neurons. “By adding in the 3D genome aspect, we can potentially bridge that gap,” said co-corresponding author Jesse Dixon.

The two epigenetic layers didn't always agree. In skeletal muscle, some fibers showed mature 3D genome folding but retained the methylation signature of muscle stem cells, suggesting 3D architecture updates before methylation during cell transitions. Similar mismatches appeared in Schwann cells and placental trophoblasts. The atlas also found that non-CG methylation, once thought largely confined to brain and stem cells, carries cell-identity information across many tissues.

The team built an interactive web browser with 195 billion methylation measurements and 18 billion chromatin contacts. In a companion Science paper, Bing Ren of the New York Genome Center and Columbia University used the atlas to show that many brain microglia are replaced by monocyte-like cells between ages 50 and 75, challenging the view that microglia persist from embryonic development throughout life.