Investigating the role of the chromatin remodeller CHD3 during human cranial neural crest cell specification
File(s)
Author(s)
Mitchell, Zoe
Type
Thesis
Abstract
CHD3 is a component of the NuRD chromatin remodelling complex. Pathogenic CHD3 variants cause Snijders Blok-Campeau Syndrome, a neurodevelopmental disorder with variable features including developmental delays, intellectual disability, speech/language difficulties, and craniofacial anomalies. I therefore hypothesised that CHD3 may be involved in human craniofacial development. In this thesis, I sought to unveil the role of CHD3 in craniofacial development and shed light on how CHD3 variants impair this process. To address this, I utilised homozygous and heterozygous CHD3 knockout induced pluripotent stem cells (iPSCs), along with iPSCs derived from individuals with Snijders Blok-Campeau syndrome and control lines, and differentiated these into cranial neural crest cells (CNCCs). I show that CHD3 expression is low in wild-type iPSCs and neuroectoderm, but is upregulated during CNCC specification, where it opens the chromatin at BMP-responsive enhancers, to allow binding of DLX5 and other factors. CHD3 loss leads to repression of BMP target genes and an imbalance between BMP and Wnt signalling, which ultimately results in the adoption of an aberrant mesodermal fate. Consequently, CNCC specification fails, and is replaced by early-mesoderm identity, which can be partially rescued by titrating Wnt levels. I also demonstrate that heterozygous CHD3 variants underlying Snijders Blok-Campeau syndrome impair CNCC specification through the interruption of epithelial-to-mesenchymal transition (EMT), a key process in the formation of migratory CNCCs. My findings highlight a novel role for CHD3 as a pivotal regulator of BMP signalling, essential for proper neural crest specification and craniofacial development. My findings also begin to uncover the mechanisms underlying the facial phenotype of Snijders Blok-Campeau syndrome, furthering our understanding of both this syndrome and of human craniofacial development.
Version
Open Access
Date Issued
2025-12-22
Date Awarded
2026-05-01
Copyright Statement
Attribution-NonCommercial 4.0 International Licence (CC BY-NC)
License URL
Advisor
Trizzino, Marco
Publisher Department
Department of Life Sciences
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)