Genomic coordinates of all tested enhancers.

Neurocristopathies such as CHARGE syndrome result from aberrant neural crest development. A large proportion of CHARGE cases are attributed to pathogenic variants in the gene encoding CHD7, chromodomain helicase DNA binding protein 7, which remodels chromatin. While the role for CHD7 in neural crest development is well documented, how this factor is specifically up-regulated in neural crest cells is not understood. Here, we use epigenomic profiling of chick and human neural crest to identify a cohort of enhancers regulating Chd7 expression in neural crest cells and other tissues. We functionally validate upstream transcription factor binding at candidate enhancers, revealing novel epistatic relationships between neural crest master regulators and Chd7, showing tissue-specific regulation of a globally acting chromatin remodeller. Furthermore, we find conserved enhancer features in human embryonic epigenomic data and validate the activity of the human equivalent CHD7 enhancers in the chick embryo. Our findings embed Chd7 in the neural crest gene regulatory network and offer potentially clinically relevant elements for interpreting CHARGE syndrome cases without causative allocation.

神经嵴病（Neurocristopathies）如CHARGE综合征（CHARGE syndrome），均由神经嵴发育异常引发。多数CHARGE综合征病例可归因于编码染色质域解旋酶DNA结合蛋白7（chromodomain helicase DNA binding protein 7，CHD7）的基因发生致病变异，该蛋白负责催化染色质重塑。尽管CHD7在神经嵴发育中的作用已被充分证实，但该因子在神经嵴细胞中特异性上调的具体机制仍未明确。本研究通过对鸡胚及人类神经嵴组织开展表观基因组谱分析，鉴定出一组可调控神经嵴细胞及其他组织中Chd7表达的增强子。我们针对候选增强子的上游转录因子结合位点开展功能验证，揭示了神经嵴主控调控因子与Chd7之间全新的上位性关系，阐明了全局作用型染色质重塑因子的组织特异性调控机制。此外，我们在人类胚胎表观基因组数据中鉴定到保守的增强子特征，并在鸡胚中验证了人类同源CHD7增强子的调控活性。本研究将Chd7纳入神经嵴基因调控网络，同时为尚未明确病因归因的CHARGE综合征病例的临床解读提供了潜在的相关分子元件。