Sánchez-Gaya Víctor, Mariner-Faulí Maria, Rada-Iglesias Alvaro
Institute of Biomedicine and Biotechnology of Cantabria (IBBTEC), Consejo Superior de Investigaciones Científicas-University of Cantabria-Sociedad para el Desarrollo de Cantabria, Santander, Spain.
Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
Front Genet. 2020 Jul 20;11:688. doi: 10.3389/fgene.2020.00688. eCollection 2020.
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.
在过去几年中，非编码调控元件的作用及其与人类疾病的关联受到了广泛关注。在非编码调控序列中，增强子对于细胞类型特异性基因表达程序的正确建立尤为重要。此外，增强子的破坏可通过两种主要机制导致人类疾病：（i）突变或拷贝数变异可直接改变增强子序列，从而影响其靶基因的表达；（ii）结构变异可引发三维染色质组织的变化，这种变化既不改变增强子及其靶基因，而是改变它们之间的物理通讯。在本综述中，这些发病机制大多在神经嵴病的背景下进行讨论，神经嵴病是由神经嵴发育过程中出现的缺陷引起的先天性疾病。我们强调，由于神经嵴对多种组织和器官的形成有贡献，它代表了一种重要但尚未得到充分研究的细胞类型，参与多种先天性疾病。此外，我们讨论了目前可用于研究人类神经嵴病的资源和实验模型。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嵴病时可以遵循。重要的是，这些指南不仅有助于揭示人类神经嵴病的病因，也有助于揭示其他涉及增强子破坏的人类先天性疾病的病因。
