Zachariou Margarita, Loizidou Eleni M, Spyrou George M
Bioinformatics Department, The Cyprus Institute of Neurology and Genetics, 6 Iroon Avenue, P.C. 2371, Ayios Dometios, Nicosia, Cyprus.
Bioinformatics Department, The Cyprus Institute of Neurology and Genetics, 6 Iroon Avenue, P.C. 2371, Ayios Dometios, Nicosia, Cyprus; Biobank.cy, Center of Excellence in Biobanking and Biomedical Research, University of Cyprus, Shacolas Educational Centre for Clinical Medicine, P.C. 2029, Aglantzia, Nicosia, Cyprus.
Comput Biol Med. 2025 May;190:110043. doi: 10.1016/j.compbiomed.2025.110043. Epub 2025 Mar 29.
Immediate-early genes (IEGs), a subset of activity-regulated genes (ARGs), are rapidly and transiently activated by neuronal activity independent of protein synthesis. While extensively researched, the role of IEGs within genetic networks and their potential as drug targets for brain diseases remain underexplored. This study aimed to investigate the topological influence of IEGs within genetic networks and explore their relevance to Alzheimer's disease (AD). To achieve this, we employed a multi-step approach: mouse ARG data were analysed and mapped to human genes to identify the topological properties that distinguish IEGs from other ARGs; the involvement of ARGs in biological pathways and diseases and their mutational constraints were examined; ARG-related variants in AD were assessed using genome-wide association study (GWAS) summary statistics and functional analysis; and network and GWAS findings were integrated to identify ARG-AD-associated genes. Our key findings were: (1) IEGs exhibit significantly higher topological influence across human and mouse gene networks compared to other ARGs; (2) ARGs are less frequently involved in diseases and exhibit higher mutational constraint than non-ARGs; (3) Several AD-associated variants are located in ARG regions, particularly in MARK4 near FOSB, with an AD risk eQTL that increases MARK4 expression in cortical areas; (4) MARK4 emerges as a key node in a dense AD multi-omic network and exhibits a high druggability score. These findings underscore the influential role of IEGs within genetic networks, providing valuable insights into their potential as intervention points for diseases characterised by downstream dysregulation, with MARK4 emerging as a promising and underexplored target for AD.
即刻早期基因（IEGs）是活性调节基因（ARGs）的一个子集，可被神经元活动快速且短暂地激活，且不依赖于蛋白质合成。尽管已得到广泛研究，但IEGs在基因网络中的作用及其作为脑部疾病药物靶点的潜力仍未得到充分探索。本研究旨在调查IEGs在基因网络中的拓扑学影响，并探索它们与阿尔茨海默病（AD）的相关性。为实现这一目标，我们采用了多步骤方法：分析小鼠ARG数据并将其映射到人类基因上，以确定区分IEGs与其他ARGs的拓扑学特性；检查ARGs在生物途径和疾病中的参与情况及其突变限制；使用全基因组关联研究（GWAS）汇总统计数据和功能分析评估AD中与ARG相关的变异；整合网络和GWAS研究结果以识别与ARG-AD相关的基因。我们的主要发现如下：（1）与其他ARGs相比，IEGs在人类和小鼠基因网络中表现出显著更高的拓扑学影响；（2）ARGs参与疾病的频率较低，且与非ARGs相比表现出更高的突变限制；（3）几个与AD相关的变异位于ARG区域，特别是在FOSB附近的MARK4中，存在一个AD风险eQTL，可增加MARK4在皮质区域的表达；（4）MARK4在密集的AD多组学网络中成为关键节点，并表现出较高的药物可及性评分。这些发现强调了IEGs在基因网络中的重要作用，为其作为以下游失调为特征的疾病干预点的潜力提供了有价值的见解，其中MARK4成为AD一个有前景且未被充分探索的靶点。
