Sciaraffa Nicolina, Santoni Daniele, Li Greci Andrea, Genovese Swonild Ilenia, Coronnello Claudia, Arancio Walter
Advanced Data Analysis Group, Ri. MED Foundation, Palermo, Italy.
Institute for System Analysis and Computer Science "Antonio Ruberti", National Research Council of Italy (IASI-CNR), Rome, Italy.
Front Bioinform. 2025 Apr 9;5:1532981. doi: 10.3389/fbinf.2025.1532981. eCollection 2025.
Autism spectrum disorder (ASD) is a brain developmental disability with a not-fully clarified etiogenesis. Current ASD research largely focuses on coding regions of the genome, but up to date much less is known about the contribution of non-coding elements to ASD risk. The non-coding genome is largely made of DNA repetitive sequences (RS). Although RS were considered slightly more than "junk DNA", today RS have a recognized role in almost every aspect of human biology, especially in developing human brain. Our aim was to test if RS transcription may play a role in ASD.
Global RS transcription was firstly investigated in dorsolateral prefrontal cortex of 13 ASD patients and 39 matched controls. Results were validated in independent datasets.
AmnSINE1 was the only RS significantly downregulated in ASD specimens. The role of AmnSINE1 in ASD has been investigated at multiple levels, showing that the 1,416 genes containing AmnSINE1 are associated with nervous system development and autism susceptibility. This has been confirmed in a different experimental setting, such as in organoid models of the human cerebral cortex, harboring different ASD causative mutations. AmnSINE1 related genes are transcriptionally co-regulated and are involved not only in brain formation but can specifically be involved in ASD development. Looking for a possible direct role of AmnSINE1 non-coding transcripts in ASD, we report that AmnSINE1 transcripts may alter the miRNA regulatory landscape for genes involved in neurogenesis.
Our findings provide preliminary evidence supporting a role for AmnSINE1 in ASD development.
自闭症谱系障碍（ASD）是一种脑发育障碍，其病因尚未完全阐明。目前ASD研究主要集中在基因组的编码区域，但对于非编码元件对ASD风险的贡献，迄今所知甚少。非编码基因组主要由DNA重复序列（RS）组成。尽管RS曾被认为只不过是“垃圾DNA”，但如今RS在人类生物学的几乎每个方面都发挥着公认的作用，尤其是在人类大脑发育过程中。我们的目的是测试RS转录是否在ASD中起作用。
首先在13例ASD患者和39例匹配对照的背外侧前额叶皮质中研究全局RS转录。结果在独立数据集中得到验证。
AmnSINE1是ASD样本中唯一显著下调的RS。已在多个层面研究了AmnSINE1在ASD中的作用，结果表明含有AmnSINE1的1416个基因与神经系统发育和自闭症易感性相关。这在不同的实验环境中得到了证实，比如在携带不同ASD致病突变的人类大脑皮质类器官模型中。与AmnSINE1相关的基因在转录上共同调控，不仅参与大脑形成，还可能特别参与ASD的发展。在寻找AmnSINE1非编码转录本在ASD中可能的直接作用时，我们发现AmnSINE1转录本可能会改变参与神经发生的基因的miRNA调控格局。
我们的研究结果提供了初步证据，支持AmnSINE1在ASD发展中起作用。
