A Single-Cell and Spatial 3D-Epigenomic Atlas of Developing Human Basal Ganglia and Inhibitory Neurons

These regions generate inhibitory projection neurons and interneurons that populate diverse brain regions, yet the developmental programs underlying this cellular diversity remain incompletely understood. This study aims to elucidate the epigenomic and 3D-genomic dynamics involved in the specification and maturation of GEs and GE-derived neurons, using single-nucleus methyl-3C sequencing (snm3C-seq), chromatin+RNA single-molecule imaging, and highly-multiplexed spatial transcriptomics.

The multi-modal data support a heterogeneous temporal progression across GEs, with LGE showing declining neurogenic activity in mid-gestation and CGE exhibiting prolonged activity in infancy. We reconstructed the regulatory programs of MSN subtype specification and revealed an unusually synchronized maturation of the 3D-Epigenome across individual MSN cells. The differentiation of neurons and glial cells is associated with permanent Short-range Enriched (SE) and Long-range Enriched (LE) chromatin conformation, respectively 1.