Structurally Conserved Primate LncRNAs Are Transiently Expressed during Human Cortical Differentiation and Influence Cell-Type-Specific Genes
Structurally Conserved Primate LncRNAs Are Transiently Expressed during Human Cortical Differentiation and Influence Cell-Type-Specific Genes
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DOI：
10.1016/j.stemcr.2018.12.006
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发表时间：
2019-02-12
影响因子：
5.9
通讯作者：
Haussler, David
中科院分区：
文献类型：
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作者：
Field, Andrew R.;Jacobs, Frank M. J.;Haussler, David
灵长类动物的大脑皮层的大小和复杂性有所扩大，但实现灵长类动物特有的大脑属性的分子创新仍然不清楚。我们从人类、黑猩猩、猩猩和恒河猴的多能干细胞中生成了大脑皮层类器官，并在每周的时间点对它们的转录组进行了测序，以进行比较分析。我们利用转录结构和表达保守性来发现基因调控长非编码 RNA (lncRNA)。在 2,975 个人类多外显子 lncRNA 中，有 2,472 个在至少一个其他物种中结构保守，总共有 920 个。 386 个人类 lncRNA 被瞬时表达 (TrEx)，其中许多在类人猿 (46%) 和恒河猴 (31%) 中也是 TrEx。通过单细胞 RNA 测序，许多 TrEx lncRNA 在特定细胞类型中表达。根据细胞类型特异性、基因结构和表达模式保守性选择的四种 TrEx lncRNA 通过 CRISPRa 在 HEK293 细胞中异位表达。所有诱导的转基因表达变化均与神经基因调节活性一致。
The cerebral cortex has expanded in size and complexity in primates, yet the molecular innovations that enabled primate-specific brain attributes remain obscure. We generated cerebral cortex organoids from human, chimpanzee, orangutan, and rhesus pluripotent stem cells and sequenced their transcriptomes at weekly time points for comparative analysis. We used transcript structure and expression conservation to discover gene regulatory long non-coding RNAs (lncRNAs). Of 2,975 human, multi-exonic lncRNAs, 2,472 were structurally conserved in at least one other species and 920 were conserved in all. Three hundred eighty-six human lncRNAs were transiently expressed (TrEx) and many were also TrEx in great apes (46%) and rhesus (31%). Many TrEx lncRNAs are expressed in specific cell types by single-cell RNA sequencing. Four TrEx lncRNAs selected based on cell-type specificity, gene structure, and expression pattern conservation were ectopically expressed in HEK293 cells by CRISPRa. All induced trans gene expression changes were consistent with neural gene regulatory activity.