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

## TL;DR

This study maps gene activity in different parts of the human brain to uncover how neurons specialize in distinct regions.

## Contribution

The paper introduces a multiomic single-cell atlas of the human cortex, revealing gene regulatory networks that drive cortical regionality.

## Key findings

- Two patterns of cortical neuron specialization were identified: a rostral-caudal calcium regulatory pattern and subunit switching of signaling receptors.
- Gene regulatory networks show cell-type- and region-specific gene regulation patterns in the human cortex.
- Regionalization is observed in gene expression, chromatin accessibility, and spatial distributions, but with distinct cortical patterns.

## 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 spatial pattern 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.

The underlying regulatory mechanisms of of human cortical diversity remains poorly understood. Here, authors profiled human brain cells to study how they use different gene programs across cortical regions, revealing molecular rules and specific transcription factors that drive functional specialization of neurons in the brain