Department of Neurology, Institute of Neuroscience, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China.
Department of Neurology, Institute of Neuroscience, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China.
Pharmacol Res. 2023 Jan;187:106637. doi: 10.1016/j.phrs.2022.106637. Epub 2022 Dec 28.
Cockayne syndrome (CS) is a devastating autosomal recessive genetic disorder, mainly characterized by photosensitivity, growth failure, neurological abnormalities, and premature aging. Mutations in CSB (ERCC6) are associated with almost all clinical phenotypes resembling classic CS. Using RNA-seq approach in multiple cell types, we identified Necdin (NDN) as a target of the CSB protein. Supportive of the RNA-seq results, CSB directly binds to NDN and manipulates the remodeling of active histone marks and DNA 5C methylation on the regulatory elements of the NDN gene. Intriguingly, hyperactivation of NDN due to CSB deficiency does not interfere with nucleotide excision repair (1), but greatly affects neuronal cell differentiation. Inhibition of NDN can partially rescue the motor neuron defects in CSB mouse models. In addition to shedding light on cellular mechanisms underlying CS and pointing to future avenues for intervention, these data substantiate a reciprocal communication between CSB and NDN in the context of general transcription regulation.
科凯恩综合征（CS）是一种破坏性的常染色体隐性遗传疾病，主要表现为光敏感性、生长发育迟缓、神经异常和早衰。CSB（ERCC6）基因突变与几乎所有类似经典 CS 的临床表型相关。我们在多种细胞类型中使用 RNA-seq 方法，鉴定出 Necdin（NDN）是 CSB 蛋白的靶标。支持 RNA-seq 结果，CSB 直接与 NDN 结合，并调节 NDN 基因调控元件上的活性组蛋白标记和 DNA 5C 甲基化的重塑。有趣的是，由于 CSB 缺陷导致的 NDN 过度激活不会干扰核苷酸切除修复（1），但会极大地影响神经元细胞分化。抑制 NDN 可以部分挽救 CSB 小鼠模型中的运动神经元缺陷。除了阐明 CS 的细胞机制，并为干预提供未来的途径外，这些数据证实了 CSB 和 NDN 在一般转录调节背景下的相互交流。
