Scientists create first map of DNA modification in the developing human brain

Amazing stuff!

"Key takeaways

• A UCLA-led study has created a map of DNA modification in two regions of the brain critical to learning, memory and emotional regulation. The map offers a benchmark for ensuring stem cell-based models accurately replicate human brain development. 
• ... researchers were able to simultaneously analyze two epigenetic mechanisms – DNA methylation and chromatin conformation – that control gene expression on a single-cell basis. 
• Understanding how these regulatory elements act on genes that affect development will help elucidate where genetic variants connect with certain genes, helping to pinpoint the cell types and developmental periods most vulnerable to disorders and diseases.

...
It created the first map of DNA modification in the hippocampus and prefrontal cortex — two regions of the brain critical to learning, memory and emotional regulation. These areas are also frequently involved in disorders like autism and schizophrenia. ...

To produce the map, the research team used a cutting-edge sequencing approach ... called single nucleus methyl-seq and chromatin conformation capture, or snm3C-seq.

This technique enables researchers to simultaneously analyze two epigenetic mechanisms that control gene expression on a single-cell basis: chemical changes to DNA known as methylation and chromatin conformation, the 3D structure of how chromosomes are tightly folded to fit into nuclei. ...

The research team analyzed more than 53,000 brain cells from donors spanning mid-gestation to adulthood, revealing significant changes in gene regulation during critical developmental windows. In capturing such a broad spectrum of developmental phases, the researchers were able to assemble a remarkably comprehensive picture of the massive genetic rewiring that occurs during critical timepoints in human brain development. ..."

From the abstract:

"The human hippocampus and prefrontal cortex play critical roles in learning and cognition, 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). 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."

Scientists create first map of DNA modification in the developing human brain | UCLA "Findings could help pinpoint cell types most vulnerable to conditions like schizophrenia, autism spectrum disorder"

Temporally distinct 3D multi-omic dynamics in the developing human brain (open access)

Fig. 1 Fig. 1: Profiling of epigenomic and chromatin conformation dynamics during human brain development using snm3C-seq3.