An atlas of 86 thousand cell nuclei from 16 tissues links DNA folding to methylation
An atlas of 86 thousand cell nuclei from 16 tissues links DNA folding to methylation
On 23 July, Science published a study of 86 689 human cell nuclei. In each nucleus, the authors measured DNA methylation together with three-dimensional chromatin contacts, which show how the long DNA molecule folds and which regions come into proximity.
Nerve, muscle, and immune cells have almost the same DNA sequence. Their distinct functions are determined by chemical marks on DNA and by its organization within the nucleus. Methylation marks specific regions, while spatial contacts can bring a regulatory region close to a gene. Previous atlases usually measured these two layers separately or examined them only in individual organs. This study measured both layers in the same nuclei across 16 tissues.
Measuring both layers in the same nucleus helps distinguish a stable cell type from a transitional state. In skeletal muscle, the authors found fibers whose three-dimensional organization already resembled that of mature muscle, while their methylation retained features of muscle stem cells. A GEN analysis attributes this mismatch to differences in how quickly the two epigenetic layers are updated. A cell can therefore appear mature based on DNA organization while retaining a methylation record of its previous state.
The same atlas helps connect a risk variant to the cell type in which it may alter gene activity. Many disease-associated variants lie in noncoding regions of DNA. These regions do not produce proteins, but they can regulate gene activity. The linear DNA sequence alone rarely shows which gene such a region affects. Three-dimensional contacts identify possible connections, while methylation indicates the cell type. When the researchers mapped known risk variants onto the atlas, variants associated with atrial fibrillation were found in cardiac muscle cells, while variants associated with bipolar disorder and schizophrenia were found in excitatory and inhibitory neurons. These results give researchers specific, cell-based hypotheses for experiments on disease mechanisms.