Temporally distinct 3D multi-omic dynamics in the developing human brain.
Publication Year:
2024
PubMed ID:
39385032
Funding Grants:
Public Summary:
The hippocampus and prefrontal cortex are key parts of the brain involved in memory and thinking, but how they develop at the molecular level is still not well understood. In this study, scientists looked at over 53,000 individual brain cells to understand how their DNA is organized and regulated during development.
They found that changes in DNA structure and chemical tags (called methylation) happen at different times. Neurons (nerve cells) showed more local DNA interactions, while glial cells (support cells) and other tissues had more long-distance ones. They also discovered that certain genetic risk factors for schizophrenia are located in specific DNA regions that control brain cell development.
This research gives new insights into how the brain forms and how mental health conditions may arise, offering valuable tools for future studies.
Scientific Abstract:
The human hippocampus and prefrontal cortex play critical roles in learning and cognition(1,2), yet the dynamic molecular characteristics of their development remain enigmatic. Here we investigated the epigenomic and three-dimensional chromatin conformational reorganization during the development of the hippocampus and prefrontal cortex, using more than 53,000 joint single-nucleus profiles of chromatin conformation and DNA methylation generated by single-nucleus methyl-3C sequencing (snm3C-seq3)(3). The remodelling of DNA methylation is temporally separated from chromatin conformation dynamics. Using single-cell profiling and multimodal single-molecule imaging approaches, we have found that short-range chromatin interactions are enriched in neurons, whereas long-range interactions are enriched in glial cells and non-brain tissues. We reconstructed the regulatory programs of cell-type development and differentiation, finding putatively causal common variants for schizophrenia strongly overlapping with chromatin loop-connected, cell-type-specific regulatory regions. Our data provide multimodal resources for studying gene regulatory dynamics in brain development and demonstrate that single-cell three-dimensional multi-omics is a powerful approach for dissecting neuropsychiatric risk loci.
