PDF(Pubmed)
Abstract：
Inner ear morphogenesis requires tightly regulated epigenetic and transcriptional control of gene expression. CHD7, an ATP-dependent chromodomain helicase DNA-binding protein, and SOX2, an SRY-related HMG box pioneer transcription factor, are known to contribute to vestibular and auditory system development, but their genetic interactions in the ear have not been explored. Here, we analyzed inner ear development and the transcriptional regulatory landscapes in mice with variable dosages of Chd7 and/or Sox2. We show that combined haploinsufficiency for Chd7 and Sox2 results in reduced otic cell proliferation, severe malformations of semicircular canals, and shortened cochleae with ectopic hair cells. Examination of mice with conditional, inducible Chd7 loss by Sox2CreER reveals a critical period (~E9.5) of susceptibility in the inner ear to combined Chd7 and Sox2 loss. Data from genome-wide RNA-sequencing and CUT&Tag studies in the otocyst show that CHD7 regulates Sox2 expression and acts early in a gene regulatory network to control expression of key otic patterning genes, including Pax2 and Otx2. CHD7 and SOX2 directly bind independently and cooperatively at transcription start sites and enhancers to regulate otic progenitor cell gene expression. Together, our findings reveal essential roles for Chd7 and Sox2 in early inner ear development and may be applicable for syndromic and other forms of hearing or balance disorders.
摘要：
内耳形态发生需要基因表达的紧密调节的表观遗传和转录控制。CHD7，一种ATP依赖性的色结构域解旋酶DNA结合蛋白，和SOX2，一个SRY相关的HMG盒先驱转录因子，已知有助于前庭和听觉系统发育，但是它们在耳朵中的遗传相互作用还没有被探索过。这里,我们分析了Chd7和/或Sox2剂量可变的小鼠的内耳发育和转录调控景观。我们表明，Chd7和Sox2的组合单倍体不足导致减少的耳细胞增殖，严重的半规管畸形，耳蜗有异位毛细胞缩短。有条件的小鼠检查，Sox2CreER引起的Chd7损失揭示了内耳对Chd7和Sox2损失的敏感性的关键时期（〜E9.5）。来自全基因组RNA测序和CUT&Tag研究的数据表明，CHD7调节Sox2表达，并在基因调控网络中早期起作用，以控制关键的耳模式基因的表达。包括Pax2和Otx2。CHD7和SOX2在转录起始位点和增强子处独立且协作地直接结合以调节耳祖细胞基因表达。一起,我们的发现揭示了Chd7和Sox2在早期内耳发育中的重要作用，可能适用于综合征和其他形式的听力或平衡障碍。
