Zarantonello Giulia, Arnoldi Michele, Filosi Michele, Tebaldi Toma, Spirito Giovanni, Barbieri Anna, Gustincich Stefano, Sanges Remo, Domenici Enrico, Di Leva Francesca, Biagioli Marta
Laboratory of Neuroepigenetics, Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, Trento, Italy.
Laboratory of Neurogenomic Biomarkers, Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, Trento, Italy.
Front Genet. 2021 Nov 22;12:745229. doi: 10.3389/fgene.2021.745229. eCollection 2021.
represents one of the highest confidence genetic risk factors implied in Autism Spectrum Disorders, with most mutations leading to haploinsufficiency and the insurgence of specific phenotypes, such as macrocephaly, facial dysmorphisms, intellectual disability, and gastrointestinal complaints. While extensive studies have been conducted on the possible consequences of suppression and protein coding RNAs dysregulation during neuronal development, the effects of transcriptional changes of long non-coding RNAs (lncRNAs) remain unclear. In this study, we focused on a peculiar class of natural antisense lncRNAs, SINEUPs, that enhance translation of a target mRNA through the activity of two RNA domains, an embedded transposable element sequence and an antisense region. By looking at dysregulated transcripts following knock down (KD), we first identified as a potential SINEUP RNA for its domain configuration. Then we demonstrated that such lncRNA is able to increase endogenous RAB11B protein amounts without affecting its transcriptional levels. RAB11B has a pivotal role in vesicular trafficking, and mutations on this gene correlate with intellectual disability and microcephaly. Thus, our study discloses an additional layer of molecular regulation which is altered by suppression. This represents the first experimental confirmation that naturally occurring SINEUP could be involved in ASD pathogenesis and underscores the importance of dysregulation of functional lncRNAs in neurodevelopment.
代表自闭症谱系障碍中暗示的最高置信度遗传风险因素之一，大多数突变导致单倍剂量不足以及特定表型的出现，如巨头畸形、面部畸形、智力残疾和胃肠道不适。虽然已经对神经元发育过程中抑制和蛋白质编码RNA失调的可能后果进行了广泛研究，但长链非编码RNA（lncRNA）转录变化的影响仍不清楚。在本研究中，我们聚焦于一类特殊的天然反义lncRNA，即SINEUPs，它们通过两个RNA结构域（一个嵌入的转座元件序列和一个反义区域）的活性增强靶mRNA的翻译。通过观察敲低（KD）后失调的转录本，我们首先因其结构域配置将其鉴定为一种潜在的SINEUP RNA。然后我们证明这种lncRNA能够增加内源性RAB11B蛋白的量，而不影响其转录水平。RAB11B在囊泡运输中起关键作用，该基因的突变与智力残疾和小头畸形相关。因此，我们的研究揭示了一层因抑制而改变的额外分子调控。这是天然存在的SINEUP可能参与自闭症谱系障碍发病机制的首个实验证据，并强调了功能性lncRNA失调在神经发育中的重要性。
