Non-coding RNAs Associated with Prader-Willi Syndrome Regulate Transcription of Neurodevelopmental Genes in Human Induced Pluripotent Stem Cells
Non-coding RNAs Associated with Prader-Willi Syndrome Regulate Transcription of Neurodevelopmental Genes in Human Induced Pluripotent Stem Cells
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与普瑞德-威利综合征相关的非编码 RNA 调节人诱导多能干细胞中神经发育基因的转录
DOI：
10.1101/2021.05.11.443612
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发表时间：
2021
期刊：
影响因子：
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通讯作者：
Sledziowska M
中科院分区：
文献类型：
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作者：
Sledziowska M
细胞分化过程中的突变和异常基因表达导致神经发育障碍，例如Prader-Willi综合征（PWS），其由父系遗传的15号染色体上的印记基因座缺失引起。我们分析了在从PWS中缺失的基因座转录的杂合小核仁长非编码RNA（sno-lncRNA）和5' snoRNA加帽和聚腺苷酸化的长非编码RNA（SPA-lncRNA）耗尽后人类诱导多能细胞（iPSC）中的染色质相关RNA。我们发现这些lncRNA的快速消融影响特定基因类别的转录。下调的基因有助于神经发育和神经元的维持，而上调的基因主要参与细胞代谢和凋亡过程的负调控。我们的数据揭示了SPA-lncRNA和sno-lncRNA在控制iPSCs中基因表达中的重要性，并为PWS研究中的合成实验方法提供了平台。我们的结论是，从PWS基因座转录的ncRNA是转录签名的关键调节因子，这对神经元的分化和发育非常重要。
Mutations and aberrant gene expression during cellular differentiation lead to neurodevelopmental disorders, such as Prader–Willi syndrome (PWS), which results from the deletion of an imprinted locus on paternally inherited chromosome 15. We analyzed chromatin-associated RNA in human induced pluripotent cells (iPSCs) upon depletion of hybrid small nucleolar long non-coding RNAs (sno-lncRNAs) and 5’ snoRNA capped and polyadenylated long non-coding RNAs (SPA-lncRNAs) transcribed from the locus deleted in PWS. We found that rapid ablation of these lncRNAs affects transcription of specific gene classes. Downregulated genes contribute to neurodevelopment and neuronal maintenance, while upregulated genes are predominantly involved in the negative regulation of cellular metabolism and apoptotic processes. Our data reveal the importance of SPA-lncRNAs and sno-lncRNAs in controlling gene expression in iPSCs and provide a platform for synthetic experimental approaches in PWS studies. We conclude that ncRNAs transcribed from the PWS locus are critical regulators of a transcriptional signature, which is important for neuronal differentiation and development.