Department of Pathology, Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, United States.
Department of Bioengineering, Stanford University, Stanford, United States.
Elife. 2019 Jan 10;8:e41770. doi: 10.7554/eLife.41770.
Long noncoding RNAs (lncRNAs) have been shown to act as important cell biological regulators including cell fate decisions but are often ignored in human genetics. Combining differential lncRNA expression during neuronal lineage induction with copy number variation morbidity maps of a cohort of children with autism spectrum disorder/intellectual disability versus healthy controls revealed focal genomic mutations affecting several lncRNA candidate loci. Here we find that a t(5:12) chromosomal translocation in a family manifesting neurodevelopmental symptoms disrupts specifically . We further show that is an evolutionarily conserved lncRNA functionally enhances induced neuronal cell maturation and directly occupies and regulates transcription of neuronal genes including autism-associated genes. Thus, integrating human genetics and functional testing in neuronal lineage induction is a promising approach for discovering candidate lncRNAs involved in neurodevelopmental diseases.
长链非编码 RNA（lncRNAs）已被证明是重要的细胞生物学调节剂，包括细胞命运决定，但在人类遗传学中经常被忽视。将神经元谱系诱导过程中的差异 lncRNA 表达与自闭症谱系障碍/智力障碍患儿队列与健康对照的拷贝数变异发病率图谱相结合，揭示了影响几个 lncRNA 候选基因座的局部基因组突变。在这里，我们发现一个表现出神经发育症状的家族中的 t（5:12）染色体易位特异性地破坏了 。我们进一步表明， 是一种进化上保守的 lncRNA，可增强诱导的神经元细胞成熟，并直接占据和调节包括自闭症相关基因在内的神经元基因的转录。因此，将人类遗传学和神经元谱系诱导中的功能测试相结合是发现参与神经发育疾病的候选 lncRNA 的一种很有前途的方法。
