# Characterizing enhancers regulating transcription factor expression for cell-type specification across neurodevelopment

> **NIH NIH F99** · ST. JUDE CHILDREN'S RESEARCH HOSPITAL GRADUATE SCHOOL OF BIOMEDICAL SCIENCES, LLC · 2021 · $43,036

## Abstract

Project Summary/Abstract
 Super-enhancers (SEs) are expansive regions of genomic DNA comprised of multiple putative enhancers
that contribute to dynamic gene expression patterns during development. This is particularly important in
neurogenesis because many essential transcription factors have complex developmental stage– and cell–type
specific expression patterns across the central nervous system. In the developing retina, Vsx2 is expressed in
all retinal progenitor cells and is maintained in differentiated bipolar neurons and Müller glia. Mutations in the
Vsx2 gene cause microphthalmia in humans and mice because it is required for retinal progenitor cell
proliferation. Due to this severe early developmental phenotype, it has been difficult to elucidate the role of Vsx2
in bipolar neuron and Müller glia differentiation.
 Victoria Honnell has found that a single SE controls this complex and dynamic pattern of expression in
mice. The deletion of one region disrupts retinal progenitor cell proliferation in early retinal development. The
deletion of another region has no effect on retinal progenitor cell proliferation but instead leads to a complete
loss of bipolar neurons. This prototypical SE may serve as a model for dissecting the complex gene expression
patterns for neurogenic transcription factors during development. Moreover, it provides a unique opportunity to
alter expression of individual transcription factors in distinct cell types at specific stages of development. This
provides a deeper understanding of function that cannot be achieved with traditional gene knockout mouse
approaches.
 In the F99-phase of this proposed research, Victoria will examine the modularity of the Vsx2 SE in human
retinal organoid models. This will inform the field’s understanding of how distinct enhancer regions affect retinal
cell-type specification in a model of human development. In the K00-phase of this proposed research, Victoria
will examine the modularity of other SEs controlling gene expression in the brain. She will characterize the
looping interactions and epigenetic landscape of these SE regions to understand how they influence gene
expression at multiple stages across brain development, and how aberrations in these mechanisms contribute
to neurodevelopmental disorders and neurodegenerative disease.
 This proposed work will yield an innovative approach to uncouple the early and late stage effects of genes
with complex expression patterns and provide an understanding of how the epigenetic landscape of enhancers
affect the expression of neurogenic transcription factors. Ultimately, this will inform the field’s understanding of
enhanceropathies that contribute to disorders and diseases of the central nervous system.

## Key facts

- **NIH application ID:** 10394034
- **Project number:** 1F99NS125819-01
- **Recipient organization:** ST. JUDE CHILDREN'S RESEARCH HOSPITAL GRADUATE SCHOOL OF BIOMEDICAL SCIENCES, LLC
- **Principal Investigator:** Victoria Honnell
- **Activity code:** F99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $43,036
- **Award type:** 1
- **Project period:** 2021-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10394034

## Citation

> US National Institutes of Health, RePORTER application 10394034, Characterizing enhancers regulating transcription factor expression for cell-type specification across neurodevelopment (1F99NS125819-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10394034. Licensed CC0.

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