Hancock Melody B, Ruby Dana R, Bieler Rachael A, Cole David C, Marsden Kurt C
North Carolina State University.
bioRxiv. 2025 Jul 29:2025.07.28.666396. doi: 10.1101/2025.07.28.666396.
CHARGE syndrome is a developmental disorder that affects 1 in 10,000 births, and patients exhibit both physical and behavioral characteristics. mutations in cause 67% of CHARGE syndrome cases. CHD7 is a DNA-binding chromatin remodeler with thousands of predicted binding sites in the genome, making it challenging to define molecular pathways linking loss of to CHARGE phenotypes. To address this problem, here we used a previously characterized zebrafish CHARGE model to generate transcriptomic and proteomic datasets from larval zebrafish head tissue at two developmental time points. By integrating these datasets with differential expression, pathway, and upstream regulator analyses, we identified multiple consistently dysregulated pathways and defined a set of candidate genes that link loss of with disease-related phenotypes. Finally, to functionally validate the roles of these genes, CRISPR/Cas9-mediated knockdown of , , or phenocopies behavioral defects seen in mutants. Our data provide a resource for further investigation of molecular mediators of CHD7 and a template to reveal functionally relevant therapeutic targets to alleviate specific aspects of CHARGE syndrome.
CHARGE综合征是一种发育障碍疾病，每10000例出生中就有1例受其影响，患者同时表现出身体和行为特征。67%的CHARGE综合征病例是由 突变引起的。CHD7是一种DNA结合染色质重塑因子，在基因组中有数千个预测的结合位点，因此很难确定将 缺失与CHARGE表型联系起来的分子途径。为了解决这个问题，我们使用之前表征的斑马鱼CHARGE模型，在两个发育时间点从斑马鱼幼体头部组织生成转录组和蛋白质组数据集。通过将这些数据集与差异表达、通路和上游调节因子分析相结合，我们确定了多个持续失调的通路，并定义了一组将 缺失与疾病相关表型联系起来的候选基因。最后，为了在功能上验证这些基因的作用，利用CRISPR/Cas9介导的 、 或 的敲低模拟了 突变体中出现的行为缺陷。我们的数据为进一步研究CHD7的分子介质提供了资源，并为揭示功能相关的治疗靶点以缓解CHARGE综合征的特定方面提供了模板。
