# Architecture and function of the neural crest genome

> **NIH NIH R01** · BOSTON CHILDREN'S HOSPITAL · 2024 · $554,035

## Abstract

ABSTRACT
The neural crest is a migratory stem cell population that is essential for the development of various tissues and
organs during embryogenesis. Disruptions in neural crest development contribute to the pathogenesis of
craniofacial defects and other congenital malformations, imposing a significant burden on individuals and
society. Understanding the molecular mechanisms underlying neural crest formation is crucial for proper
diagnosis of these conditions. While previous research has focused on protein-DNA interactions in activating
neural crest genes, the role of chromatin conformation changes in this process remains poorly understood.
Previous studies characterizing the architecture of the neural crest genome revealed that these cells display a
complex enhancer-promoter interactome characterized by a reliance on long-range interactions. This proposal
aims to investigate the contribution of architectural proteins, specifically CTCF and YY1, in establishing this
unique chromatin organization. We hypothesize that architectural proteins interact with pioneer transcription
factors to assemble the neural crest interactome and promote activation of gene regulatory circuits. We will test
this hypothesis in three specific aims. Aim 1 will define the function of architectural proteins in neural crest
formation by identifying the chromatin loops mediated by CTCF and YY1 through chromatin conformation
capture. We will also target architectural proteins in loss-of-function studies to uncover their relative
contributions to the establishment of the neural crest enhancer interactome. Aim 2 seeks to determine how
tissue-specific enhancer-promoter loops are established during neural crest specification. To accomplish this,
we will investigate the functional and physical interactions between architectural proteins and the pioneer
transcription factors that define the neural crest lineage. Aim 3 will define how disease-linked mutations in
architectural proteins affect neural crest chromatin organization. We will employ genome engineering to
reproduce CTCF/YY1 mutations in embryonic stem cells and drive these cells into adopting a cranial neural
crest fate. By elucidating the function of architectural proteins in neural crest development and their role in the
genesis of craniofacial malformations, this research has the potential to pave the way for future therapeutic
strategies aimed at preventing or treating these debilitating conditions.

## Key facts

- **NIH application ID:** 10857675
- **Project number:** 1R01DE033701-01
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** Marcos Simoes-Costa
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $554,035
- **Award type:** 1
- **Project period:** 2024-04-01 → 2029-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10857675

## Citation

> US National Institutes of Health, RePORTER application 10857675, Architecture and function of the neural crest genome (1R01DE033701-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10857675. Licensed CC0.

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