Maps can tell you where to go and what landmarks you’ll find along the way. In the same way, a new multiomic map describes how DNA methylation and 3D chromatin conformation changes in the prefrontal cortex and hippocampus as the human brain develops. The map could help researchers determine the heritability of neuropsychiatric conditions, such as schizophrenia and bipolar disorder.
The talented teams of Chongyuan Luo and Mercedes Paredes (University of California, Los Angeles and San Francisco) had previously charted the adult brain, but they wanted to focus on the developing brain for this trip. They analyzed prenatal and adult single cells at many stages with single-nucleus methyl-3C sequencing (snm3C-seq3). Snm3C-seq3 produced maps of DNA methylation and chromatin conformation that organized 139 distinct cell populations into 10 groups. Here’s what they found:
- Excitatory neurons are epigenetically distinct in the hippocampus and prefrontal cortex, whereas non-neuronal cells and inhibitory neurons have shared modifications and conformations
- Neurons and glial cells have noticeable epigenetic differences throughout development, but non-neural cells are similar during this time
- At mid-gestation, methylation occurs first, then conformational changes happen in a neuronal/glial progenitor population
- Methylation patterns emerge earlier in the hippocampus than in the prefrontal cortex
- Neuronal cells are enriched in short-range chromatin interactions, but glial and non-neuronal cells are enriched in long-range interactions
- Neuronal short-range interactions are established at mid-gestation and are associated with H3K9me3 and transcription
- A variant associated with schizophrenia overlaps with a loop-connected differentially methylated region with reduced methylation
- The third trimester and infancy are most important periods for heritability of schizophrenia and bipolar disorder
Overall, the map of neuronal methylome and chromatin conformation remodeling during brain development could provide even more insights by showing researchers studying development and neuropsychiatric diseases where to go. Senior author Chongyuan Luo shares, “Our map offers a baseline to compare against genetic studies of disease-affected brains and pinpoint when and where molecular changes occur.”
Check out the roadmap for yourself at Nature, October 2024.