Chulalongkorn Autism Research and Innovation Center of Excellence (Chula ACE), Department of Clinical Chemistry, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok, 10330, Thailand.
Department of Biotechnology and Biomedicine (DTU Bioengineering), Technical University of Denmark, 2800, Kongens Lyngby, Denmark.
Sci Rep. 2024 Sep 19;14(1):21889. doi: 10.1038/s41598-024-72334-x.
LINE-1 and Alu retrotransposons are components of the human genome and have been implicated in many human diseases. These elements can influence human transcriptome plasticity in various mechanisms. Chimeric transcripts derived from LINE-1 and Alu can also impact the human transcriptome, such as exonization and post-transcriptional modification. However, its specific role in ASD neuropathology remains unclear, particularly in the cerebellum tissues. We performed RNA-sequencing of post-mortem cerebellum tissues from ASD and unaffected individuals for transposable elements profiling and chimeric transcript identification. The majority of free transcripts of transposable elements were not changed in the cerebellum tissues of ASD compared with unaffected individuals. Nevertheless, we observed that chimeric transcripts derived from LINE-1 and Alu were embedded in the transcripts of differentially expressed genes in the cerebellum of ASD, and these genes were related to developments and abnormalities of the cerebellum. In addition, the expression levels of these genes were correlated with the significantly decreased thickness of the molecular layer in the cerebellum of ASD. We also found that global methylation and expression of LINE-1 and Alu elements were not changed in ASD, but observed in the ASD sub-phenotypes. Our findings showed associations between transposable elements and cerebellar abnormalities in ASD, particularly in distinct phenotypic subgroups. Further investigations using appropriate models are warranted to elucidate the structural and functional implications of LINE-1 and Alu elements in ASD neuropathology.
LINE-1 和 Alu 逆转录转座子是人类基因组的组成部分，与许多人类疾病有关。这些元件可以通过多种机制影响人类转录组的可塑性。源自 LINE-1 和 Alu 的嵌合转录本也会影响人类转录组，例如外显子化和转录后修饰。然而，其在 ASD 神经病理学中的具体作用仍不清楚，尤其是在小脑组织中。我们对 ASD 和无影响个体的死后小脑组织进行了 RNA 测序，以进行转座元件分析和嵌合转录本鉴定。与无影响个体相比，ASD 小脑组织中转座元件的游离转录本大多数没有改变。然而，我们观察到，源自 LINE-1 和 Alu 的嵌合转录本嵌入了 ASD 小脑中转录本中差异表达基因的转录本中，这些基因与小脑的发育和异常有关。此外，这些基因的表达水平与 ASD 小脑分子层厚度明显减少呈正相关。我们还发现，LINE-1 和 Alu 元件的整体甲基化和表达在 ASD 中没有改变，但在 ASD 的亚表型中观察到。我们的研究结果表明，转座元件与 ASD 中小脑异常之间存在关联，尤其是在不同的表型亚组中。需要进一步使用适当的模型进行研究，以阐明 LINE-1 和 Alu 元件在 ASD 神经病理学中的结构和功能意义。
