# Epigenomic control of the neural crest cis-regulatory landscape by TGF-beta signaling

> **NIH NIH F99** · CORNELL UNIVERSITY · 2022 · $39,040

## Abstract

The neural crest is a multipotent embryonic cell population that gives rise to most of the craniofacial skeleton,
including cartilage, bone and connective tissue. Misregulation of neural crest development results in the vast
majority of craniofacial malformations and birth defects. Thus, uncovering the molecular and genetic
underpinnings of neural crest formation has important implications for the diagnosis and treatment of these
pathologies. Neural crest development is orchestrated by a multi-level gene regulatory network, in which
progenitor cells are progressively committed to a neural crest fate. This process requires not only shifts in gene
expression but also an extensive remodeling of the epigenomic landscape. The chromatin remodeling events
which occur between two respective stages of neural crest formation, induction and specification, are driven in
part by the action of the pioneer factor TFAP2A. TFAP2A activates distinct sets of genomic regions during
induction and specification of neural crest cells, and its target specificity is dependent upon its dimerization with
paralogous proteins TFAP2C and TFAP2B. This heterodimeric switch between TFAP2A/C and TFAP2A/B acts
to drive the transition from induction to specification, allowing for progressive cell fate commitment of neural
crest cells. Consistent with this idea, TFAP2B expression is both necessary and sufficient to drive the transition
from induction to specification. Analysis of an enhancer of TFAP2B has implicated SMAD2/3 nuclear effectors
as predicted drivers of TFAP2B expression. This observation has led to the hypothesis that TFAP2 pioneer
factors integrate environmental signals into the gene regulatory network to drive the transition from induction to
specification within the neural crest lineage. The F99 phase of this proposal aims to investigate the role of
SMAD nuclear effectors and their upstream signaling systems in the control of TFAP2B expression and
consequently the neural crest specification program. This work will shed light on how environmental stimuli act
to remodel the chromatin landscape within the presumptive neural crest.
Moreover, while much focus has been paid to understand the cis-regulatory control of neural crest cell
formation, we still have very little insight on the molecular mechanisms by which these cells differentiate to
form the bone and cartilage of the face. Single-cell analysis of chromatin accessibility in neural crest
differentiation will allow for the identification of enhancer elements specific to numerous facial compartments.
Furthermore, identification of compartment-specific drivers will reveal how these regulatory factors act to
orchestrate the formation of highly complex and nuanced structures within the craniofacial skeleton. Ultimately,
this data may be used to gain a mechanistic understanding of the etiology of congenital birth defects linked to
the misregulation of craniofacial morphogenesis.

## Key facts

- **NIH application ID:** 10474293
- **Project number:** 5F99DE030326-02
- **Recipient organization:** CORNELL UNIVERSITY
- **Principal Investigator:** Megan Rothstein
- **Activity code:** F99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $39,040
- **Award type:** 5
- **Project period:** 2021-08-21 → 2023-02-06

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10474293

## Citation

> US National Institutes of Health, RePORTER application 10474293, Epigenomic control of the neural crest cis-regulatory landscape by TGF-beta signaling (5F99DE030326-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10474293. Licensed CC0.

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