McWilliams School of Biomedical Informatics, University of Texas Health Science Center at Houston, Houston, TX, USA.
BMC Genomics. 2024 Apr 17;25(1):377. doi: 10.1186/s12864-024-10317-y.
Deciphering gene regulation is essential for understanding the underlying mechanisms of healthy and disease states. While the regulatory networks formed by transcription factors (TFs) and their target genes has been mostly studied with relation to cis effects such as in TF binding sites, we focused on trans effects of TFs on the expression of their transcribed genes and their potential mechanisms.
We provide a comprehensive tissue-specific atlas, spanning 49 tissues of TF variations affecting gene expression through computational models considering two potential mechanisms, including combinatorial regulation by the expression of the TFs, and by genetic variants within the TF. We demonstrate that similarity between tissues based on our discovered genes corresponds to other types of tissue similarity. The genes affected by complex TF regulation, and their modelled TFs, were highly enriched for pharmacogenomic functions, while the TFs themselves were also enriched in several cancer and metabolic pathways. Additionally, genes that appear in multiple clusters are enriched for regulation of immune system while tissue clusters include cluster-specific genes that are enriched for biological functions and diseases previously associated with the tissues forming the cluster. Finally, our atlas exposes multilevel regulation across multiple tissues, where TFs regulate other TFs through the two tested mechanisms.
Our tissue-specific atlas provides hierarchical tissue-specific trans genetic regulations that can be further studied for association with human phenotypes.
解析基因调控对于理解健康和疾病状态的潜在机制至关重要。虽然转录因子 (TFs) 及其靶基因形成的调控网络主要是通过顺式效应（如 TF 结合位点）进行研究的，但我们专注于 TF 对其转录基因表达的反式效应及其潜在机制。
我们提供了一个全面的组织特异性图谱，涵盖了 49 种组织中通过考虑两种潜在机制（包括 TF 表达的组合调控和 TF 内遗传变异的调控）影响基因表达的 TF 变化。我们证明，基于我们发现的基因的组织之间的相似性与其他类型的组织相似性相对应。受复杂 TF 调控影响的基因及其建模的 TF 在药物基因组学功能方面高度富集，而 TF 本身也在几个癌症和代谢途径中富集。此外，出现在多个簇中的基因在免疫系统的调节中富集，而组织簇包含簇特异性基因，这些基因在与形成簇的组织相关的生物学功能和疾病方面富集。最后，我们的图谱揭示了多个组织中的多层次调控，其中 TF 通过两种测试机制调节其他 TF。
我们的组织特异性图谱提供了分层的组织特异性反式遗传调控，可进一步研究与人类表型的关联。
