A single-cell and spatial 3D multi-omic atlas of developing human basal ganglia and inhibitory neurons

The human basal ganglia (BG), subcortical nuclei fundamental to motor
regulation and cognitive modulation, is constructed from neurons produced
during gestation in the adjacent ganglionic eminences (GEs). GEs are
transient structures in the ventral prenatal brain that also generate
GABAergic inhibitory neurons, which migrate to destinations in the BG,
cortex, and other destinations. 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), highly-multiplexed spatial transcriptomics, and
chromatin+RNA single-molecule imaging. Our multi-modal data support a
heterogeneous temporal progression across GE subregions, with the lateral
GE (LGE) showing declining neurogenic activity in mid-gestation and caudal
GE (CGE) exhibiting ongoing developmental progression through infancy. We
identified regulatory programs that specify subtypes of BG principal
cells, medium spiny neurons (MSN), via synchronized maturation of the
3D-epigenome. In infant brains, we found a transient short-range enriched
(SE) chromatin conformation during the transition between oligodendrocyte
progenitors (OPCs) and oligodendrocytes (ODCs), and a temporary shift
toward Long-range Enriched (LE) chromatin conformation in projection
neurons, extending previous works showing the differentiation of neurons
and glial cells is associated with permanent SE and LE conformation,
respectively. Lastly, we found that gene regulatory regions active in MSNs
were enriched in loci associated with genetic risk for neuropsychiatric
disease. Our study delineates the highly complex, lineage-specific 3D
genomic dynamics in ventral progenitors and basal ganglia populations of
the perinatal human brain.