# Describing the Networks of Disease-associated Transcription Factors in the Brain.

> **NIH NIH F30** · UNIVERSITY OF MARYLAND BALTIMORE · 2020 · $31,865

## Abstract

PROJECT SUMMARY
Schizophrenia is a serious psychiatric disorder that affects up to one percent of the world's population. While it
has been shown that this disease may be associated with molecular changes during neurodevelopment, the
drivers of these changes remains unknown. Transcription factors (TFs) are attractive candidates for further
study; they control the expression of entire networks of genes, and extensive TF-driven networks govern the
development of neurons and other brain cell types. Our previous work leverages a publicly available GWAS of
schizophrenia and an atlas of accessible chromatin in the brain to establish a regulome-wide association mod-
el of this disease. This model uses DNAse-seq “footprints” to determine likely binding sites of TFs and uses
these sites to predict target genes. TFs with many targets associated with risk in GWAS are considered asso-
ciated with risk themselves. This has allowed us to identify TFs that may be involved in the pathogenesis of
schizophrenia, as well as the individual target genes of these TFs. Many of the top TFs identified in our model
are known to be involved in cell-fate decisions, including a neurodevelopmental TF known as EMX1. We have
independently observed increases in EMX1 binding activity in schizophrenia cases versus controls, and shown
that EMX1 target expression is increased in excitatory neuron lineages. This work aims to validate our model
and test the hypothesis that schizophrenia is associated with changes in a transcriptional network governed by
EMX1 that pushes neural precursors towards premature differentiation into excitatory neurons. In silico ap-
proaches using high-quality ATAC-seq and single cell RNA-seq datasets (Aim 1) will be used to confirm our
previous findings that EMX1 shows increased binding activity and show that its binding targets are involved in
the development of excitatory neurons. An embryonic stem cell-derived neural induction system (Aim 2) will be
used to validate targets of EMX1 predicted by our model and demonstrate how EMX1 overexpression inter-
feres with cortex formation. This aim will test the hypothesis that the overexpression of EMX1 activates a net-
work of target genes that causes premature excitatory neuron formation during corticogenesis, resulting in later
deficits in cortical structure and thickness. These experiments will demonstrate the utility of our model in identi-
fying TF networks that mediate risk for schizophrenia, and demonstrate the role of the EMX1 network in neural
cell type determination. This project is a part of a larger training plan designed to train me in the skills and
techniques necessary for a career as a physician-scientist in neuropsychiatric systems biology. I will carry out
this proposal under the guidance of my primary sponsor, Dr. Seth Ament, and my co-sponsor Dr. Margaret
McCarthy. Dr. Ament is an expert in the systems biology of neuropsychiatric disease and has published more
than 27 papers on the subject. Dr...

## Key facts

- **NIH application ID:** 9987964
- **Project number:** 1F30MH120910-01A1
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** Alex Casella
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $31,865
- **Award type:** 1
- **Project period:** 2020-03-01 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9987964

## Citation

> US National Institutes of Health, RePORTER application 9987964, Describing the Networks of Disease-associated Transcription Factors in the Brain. (1F30MH120910-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9987964. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*