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Abstract：
In the last few years, the role of non-coding regulatory elements and their involvement in human disease have received great attention. Among the non-coding regulatory sequences, enhancers are particularly important for the proper establishment of cell type-specific gene-expression programs. Furthermore, the disruption of enhancers can lead to human disease through two main mechanisms: (i) Mutations or copy number variants can directly alter the enhancer sequences and thereby affect expression of their target genes; (ii) structural variants can provoke changes in 3-D chromatin organization that alter neither the enhancers nor their target genes, but rather the physical communication between them. In this review, these pathomechanisms are mostly discussed in the context of neurocristopathies, congenital disorders caused by defects that occur during neural crest development. We highlight why, due to its contribution to multiple tissues and organs, the neural crest represents an important, yet understudied, cell type involved in multiple congenital disorders. Moreover, we discuss currently available resources and experimental models for the study of human neurocristopathies. Last, we provide some practical guidelines that can be followed when investigating human neurocristopathies caused by structural variants. Importantly, these guidelines can be useful not only to uncover the etiology of human neurocristopathies, but also of other human congenital disorders in which enhancer disruption is involved.
摘要：
在过去的几年里，非编码调控元件的作用及其在人类疾病中的参与受到了极大的关注。在非编码调控序列中，增强子对于正确建立细胞类型特异性基因表达程序特别重要。此外，增强子的破坏可以通过两种主要机制导致人类疾病：（i）突变或拷贝数变体可以直接改变增强子序列，从而影响其靶基因的表达；（ii）结构变体可以引起3-D染色质组织的变化，既不改变增强子也不改变其靶基因，而是他们之间的物理交流。在这次审查中,这些病理机制大多是在神经病理学的背景下讨论的，由神经c发育过程中出现的缺陷引起的先天性疾病。我们强调为什么，由于它对多个组织和器官的贡献，神经嵴代表了一个重要的，然而研究不足，涉及多种先天性疾病的细胞类型。此外，我们讨论了人类神经病理学研究的现有资源和实验模型。最后,我们提供了一些实用指南,在研究由结构变异引起的人类神经病理学时可以遵循这些指南.重要的是,这些指南不仅有助于揭示人类神经病变的病因，还有其他涉及增强子破坏的人类先天性疾病。
