Transformation of single-cell three-dimensional genome structure during postnatal development of the mammalian brain

After birth, the mammalian brain undergoes numerous molecular changes that underlie cognitive plasticity and maturation. However, little is known about the dynamics of three-dimensional (3D) genome structure during this period. Here we generated a 3D genome atlas of 1,954 single cells from the developing mouse cortex and hippocampus, using our diploid chromatin conformation capture (Dip-C) method. In adult tissues, genome structure alone delineates major cell types such as cortical excitatory and inhibitory neurons, and hippocampal granule cells. During development, a major transformation was observed between the first and fourth week after birth--coincident with synaptogenesis and de novo DNA methylation, leading to 3D re-organization across multiple genomic scales. Using reciprocal crosses, we systematically examined allele-specific structure of imprinted genes, revealing chromosome-wide difference at the Prader-Willi/Angelman syndrome locus. These findings thus uncover a previously unknown dimension of postnatal brain development.