Chen Peiwei, Pan Katherine C, Park Eunice H, Luo Yicheng, Lee Yuh Chwen G, Aravin Alexei A
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125.
Department of Ecology and Evolutionary Biology, University of California, Irvine, CA 92697.
Proc Natl Acad Sci U S A. 2025 Jan 14;122(2):e2418541122. doi: 10.1073/pnas.2418541122. Epub 2025 Jan 7.
From RNA interference to chromatin silencing, diverse genome defense pathways silence selfish genetic elements to safeguard genome integrity. Despite their diversity, different defense pathways share a modular organization, where numerous specificity factors identify diverse targets and common effectors silence them. In the PIWI-interacting RNA (piRNA) pathway, target RNAs are first identified by complementary base pairing with piRNAs and then silenced by PIWI-clade nucleases. Such a binary architecture allows the defense systems to be readily adaptable, where new targets can be captured via innovation of specificity factors. Thus, our current understanding of genome defense against lineage-specific selfish genes has been largely limited to specificity factor innovations, while it remains poorly understood whether other types of innovations are required. Here, we describe a new type of innovation, which escalates the genome defense capacity to control a recently expanded selfish gene in . Through a targeted RNAi screen for repressors of -a recently evolved meiotic driver-we identified a defense factor, Trailblazer. Trailblazer is a transcription factor that promotes the expression of two PIWI-clade nucleases, Aub and AGO3, to match in abundance. Recent innovation in the DNA-binding domain of Trailblazer enabled it to elevate Aub and AGO3 expression, thereby escalating the silencing capacity of piRNA pathway to tame expanded and safeguard fertility. As copy-number expansion is a recurrent feature of diverse selfish genes across the tree of life, we envision that augmenting the defense capacity to quantitatively match selfish genes is a repeatedly employed defense strategy in evolution.
从RNA干扰到染色质沉默，多种基因组防御途径使自私的遗传元件沉默，以维护基因组完整性。尽管它们具有多样性，但不同的防御途径共享一种模块化组织，其中众多特异性因子识别不同的靶标，共同效应器使其沉默。在PIWI相互作用RNA（piRNA）途径中，靶标RNA首先通过与piRNA的互补碱基配对被识别，然后被PIWI家族核酸酶沉默。这种二元结构使防御系统易于适应，新的靶标可以通过特异性因子的创新来捕获。因此，我们目前对基因组针对谱系特异性自私基因的防御的理解在很大程度上仅限于特异性因子的创新，而对于是否需要其他类型的创新仍知之甚少。在这里，我们描述了一种新型创新，它提升了基因组防御能力，以控制最近在……中扩展的自私基因。通过针对……（一种最近进化的减数分裂驱动因子）的阻遏物进行靶向RNAi筛选，我们鉴定出一种防御因子，开拓者（Trailblazer）。开拓者是一种转录因子，可促进两种PIWI家族核酸酶Aub和AGO3的表达，使其丰度相匹配。开拓者DNA结合结构域的近期创新使其能够提高Aub和AGO3的表达，从而提升piRNA途径的沉默能力，以驯服扩展的……并保障生育力。由于拷贝数扩展是生命之树中各种自私基因的一个反复出现的特征，我们设想增强防御能力以在数量上匹配自私基因是进化中一种反复采用的防御策略。
