T04B2.1 MS

The conventional notions of pseudogenes being ‘junk DNA’ have largely been offset as research studies have established their role in multiple biological processes. Our studies towards identification of genetic modulators employing C. elegans model, that associate reproductive health and age-related neurodegenerative diseases, led us to identification and functional characterization of a pseudogene T04B2.1, which when knocked out,exacerbates the aggregation of α-Synuclein and β-Amyloid proteins, induces lipid deposition and alters morphometric endpoints in worms. Whole transcriptome analysis of worms under knockdown condition of T04B2.1 revealed an altered expression of 187 sequences, most of these being non-coding RNAs, miRNAs and piRNAs modulating the RNAi regulatory processes. Our gene ontology and pathway enrichment analysis demonstrated the role of T04B2.1 in protein quality control, metabolic pathways and development. We further performed a signature motif search and successfully identified a common motif that is present between all piRNA and miRNA molecules, which are significantly altered upon T04B2.1 silencing. This study unveils the non-conventional regulatory role of pseudogene T04B2.1with respect to effects associated with neurodegenerative diseases and encourages further studies to decipher the regulatory mechanism governed by pseudogenes.

长久以来，学界认为假基因属于‘垃圾DNA’的传统认知已在很大程度上被推翻，诸多研究已证实假基因在多种生物学过程中发挥作用。本研究以秀丽隐杆线虫（Caenorhabditis elegans，简称C. elegans）为模型，筛选与生殖健康及年龄相关性神经退行性疾病相关的遗传调控因子，期间鉴定得到假基因T04B2.1并完成其功能表征。该假基因在被敲除后，会加剧α-突触核蛋白（α-Synuclein）与β-淀粉样蛋白（β-Amyloid）的聚集，诱导脂质沉积，并改变线虫的形态学检测指标。对T04B2.1基因敲低后的线虫进行全转录组分析，结果显示共有187条序列的表达量发生显著改变，其中多数为非编码RNA、微小RNA（miRNA）及PIWI互作RNA（piRNA），这些RNA均参与调控RNA干扰（RNA interference，简称RNAi）相关过程。本研究通过基因本体（Gene Ontology，简称GO）富集分析及通路富集分析，证实T04B2.1参与蛋白质质量控制、代谢通路及发育调控过程。本研究进一步开展特征基序搜索，成功鉴定出一类共有基序，该基序广泛存在于所有表达量受T04B2.1沉默显著改变的piRNA与miRNA分子中。本研究揭示了假基因T04B2.1在神经退行性疾病相关病理过程中的非经典调控作用，并为后续解析假基因介导的调控机制提供了研究方向。