Two new single-cell multi-omics efforts provided direct links between epigenetic architecture and gene regulation. Salk Institute and Arc Institute researchers reported a body-wide single-cell atlas that measures 3D genome organization and DNA methylation simultaneously across 86,689 cells from 16 human tissues. In the atlas, the researchers show that the two epigenetic layers do not always tell the same story about cell identity and disease-relevant programs, underlining the value of integrated measurement when interpreting epigenetic “signals.” The work was published in Science alongside multiple NIH 4D Nucleome papers. Separately, researchers studying Alzheimer’s disease used single-cell approaches to connect genome folding changes with disrupted gene regulation in specific brain cell types. In postmortem prefrontal cortex tissue, the study reported altered genome architecture—including changes consistent with weakened compartment segregation—and mapped these structural shifts to disease-associated regulatory programs. Together, the studies strengthen a mechanistic framework for neurodegeneration and cell-state biology by linking spatial genome features to transcriptional outcomes at single-cell resolution.