Single-cell multiomic human brain atlas reveals regulatory drivers of cortical regionality

Abstract

Distinct regional functionality of the human cortex is orchestrated by diverse cellular and molecular processes, yet the underlying regulatory mechanisms remain poorly understood. We performed multiomic single-cell and spatial characterization of nine regions of the human cortex to define the gene regulatory networks and transcription factors that govern cell-type and region specificity. With the combined data of over three million cells, two striking patterns of cortical neuron specialization were uncovered: a rostral-caudal gradient of calcium regulatory machinery, and subunit switching of multiple signaling receptor families across the transmodal-sensory axis. Gene regulatory network analysis revealed putative transcriptional regulators of cortical neuron specialization with cell-type- and region-specific gene regulation patterns. While regionalization was observed in gene expression, chromatin accessibility, and spatial distributions, these modalities exhibited distinct cortical patterns. Our findings illuminate critical neuronal pathways that vary throughout the cortex and the gene regulatory networks that establish cortical regionalization in the human brain.