Epigenomic and chromosomal architectural reconfiguration in developing human frontal cortex and hippocampus. Epigenomic and chromosomal architectural reconfiguration in developing human frontal cortex and hippocampus

Human frontal cortex and hippocampus play key roles in learning and cognition, and are representative structures of the six-layer neocortex and the more ancient allocortex, respectively. Here we investigated the epigenomic and 3D-chromatin conformational dynamics of human frontal cortex and hippocampus development using more than 53,000 joint single-nucleus profiles of chromatin conformation and DNA methylation (sn-m3C-seq) generated from mid-gestational, late-gestational, infant and adult human brains. We found that the remodeling of DNA methylation predominantly happens during late-gestational to early-post-natal development, and is temporally uncoupled from the dynamics of chromatin conformation. We reconstructed regulatory hierarchies of cortical and hippocampal cell differentiation and maturation and identified brain regional-specific regulatory signatures. The single-cell 3D-regulatome approach further enabled the cell-type-specific dissection of neuropsychiatric risk loci during key neurodevelopmental stages and in adult human brains. Overall design: Single-nucleus joint profiling of human frontal cortex and hippocampus in developing human brains Raw data will be uploaded to a controlled access database due to patient privacy issues.