# Defining gene regulatory networks driving cortical evolution and brain development

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2022 · $712,187

## Abstract

PROJECT SUMMARY/ABSTRACT
Neuropsychiatric disorders often affect our most distinguishing cognitive and social capabilities, which are
thought to have developed as a result of the expansion of the human neocortex. The unique mechanisms
orchestrating cortical neurogenesis and differentiation in the developing human neocortex forming the basis of
this expansion are beginning to be described. However, although genetic variation in non-coding gene-regulatory
regions, rather than in protein coding genes, drives these evolutionary changes, the cis gene regulatory elements
(GREs), including promoters and enhancers, and the transcription factors (TFs) governing cortical neurogenesis
remain to be characterized. To begin to investigate this understudied mechanism, we and others have leveraged
next generation sequencing approaches to profile chromatin accessibility and interaction in parallel with gene
expression to create GRE maps of varying levels of spatiotemporal specificity. We previously identified
thousands of developmentally dynamic GREs and their putative gene targets by contrasting GRE activity in
progenitor versus neuron-enriched laminae of mid-gestation human neocortex, and functionally validated the
role of select GREs in cortical neurogenesis using primary human neural progenitor cells. Further, we found that
human-gained enhancers (HGEs), a subset of GREs more active in the human than the macaque or mouse
neocortex, regulate genes enriched in outer radial glia (oRG), a neural progenitor with prominent roles in cortical
gyrification. This work supports the hypothesis that human developmentally dynamic GREs and HGEs direct
gene expression programs controlling the proliferation and differentiation of progenitor pools key to cortical
expansion. In this proposal, we seek to test this hypothesis and move from a tissue- and gene-level resolution
atlas to a cellular- and gene isoform-level resolution atlas. We will perform single nucleus ATAC-seq to identify
cell-specific GREs and leverage a novel single-cell isoform sequencing (scIso-seq) technology to investigate a
previously understudied mechanism of gene regulation – alternative promoter usage. This new atlas will inform
our work to functionally define the GREs impacting cortical neurogenesis at scale using CRISPR interference
(CRISPRi) libraries containing capture tags enabling simultaneous reading of transcriptome and sgRNA at the
single-cell level. Finally, we will define and characterize the TFs directing the balance of proliferation versus
differentiation of progenitors. These results will enable us identify the cellular basis of genomic variation causing
risk for neuropsychiatric disease, and influencing cognition and brain structure. Together this work will create a
robust single cell-resolution functional annotation of non-coding GREs and TFs acting in developing human
neocortex and elucidate evolutionary mechanisms driving cortical expansion. Broadly, this work will provide a
blueprint fo...

## Key facts

- **NIH application ID:** 10440238
- **Project number:** 5R01MH124018-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Luis de la Torre-Ubieta
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $712,187
- **Award type:** 5
- **Project period:** 2021-07-01 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10440238

## Citation

> US National Institutes of Health, RePORTER application 10440238, Defining gene regulatory networks driving cortical evolution and brain development (5R01MH124018-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10440238. Licensed CC0.

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