Department of Biostatistics, Harvard School of Public Health, Boston, MA, USA.
Institute of Biomedical Informatics, National Yang-Ming University, Taipei, Taiwan.
Cell Rep. 2020 Jun 23;31(12):107795. doi: 10.1016/j.celrep.2020.107795.
Sex differences manifest in many diseases and may drive sex-specific therapeutic responses. To understand the molecular basis of sex differences, we evaluated sex-biased gene regulation by constructing sample-specific gene regulatory networks in 29 human healthy tissues using 8,279 whole-genome expression profiles from the Genotype-Tissue Expression (GTEx) project. We find sex-biased regulatory network structures in each tissue. Even though most transcription factors (TFs) are not differentially expressed between males and females, many have sex-biased regulatory targeting patterns. In each tissue, genes that are differentially targeted by TFs between the sexes are enriched for tissue-related functions and diseases. In brain tissue, for example, genes associated with Parkinson's disease and Alzheimer's disease are targeted by different sets of TFs in each sex. Our systems-based analysis identifies a repertoire of TFs that play important roles in sex-specific architecture of gene regulatory networks, and it underlines sex-specific regulatory processes in both health and disease.
性别差异在许多疾病中表现明显，可能导致特定性别的治疗反应。为了了解性别差异的分子基础，我们通过使用来自 Genotype-Tissue Expression (GTEx) 项目的 8,279 个全基因组表达谱，在 29 个人体健康组织中构建了特定样本的基因调控网络，评估了性别偏向的基因调控。我们发现每个组织中都存在性别偏向的调控网络结构。尽管大多数转录因子 (TFs) 在男性和女性之间没有差异表达，但许多 TFs 具有性别偏向的调控靶向模式。在每种组织中，TFs 在性别之间差异靶向的基因富集了与组织相关的功能和疾病。例如，在脑组织中，与帕金森病和阿尔茨海默病相关的基因受到不同 TF 集的靶向作用。我们的系统分析确定了一组 TF，它们在性别特异性基因调控网络的结构中发挥着重要作用，并强调了健康和疾病中性别特异性调控过程。
