State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin Institutes of Health Science, Department of Geriatrics, Tianjin Medical University General Hospital, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.
Tianjin Geriatrics Institute, Tianjin Key Laboratory of Elderly Health, Tianjin Medical University General Hospital, Tianjin, China.
Nat Commun. 2024 Oct 9;15(1):8758. doi: 10.1038/s41467-024-53131-6.
Promoters play a crucial role in regulating gene transcription. However, our understanding of how genetic variants influence alternative promoter selection is still incomplete. In this study, we implement a framework to identify genetic variants that affect the relative usage of alternative promoters, known as promoter usage quantitative trait loci (puQTLs). By constructing an atlas of human puQTLs across 49 different tissues from 838 individuals, we have identified approximately 76,856 independent loci associated with promoter usage, encompassing 602,009 genetic variants. Our study demonstrates that puQTLs represent a distinct type of molecular quantitative trait loci, effectively uncovering regulatory targets and patterns. Furthermore, puQTLs are regulating in a tissue-specific manner and are enriched with binding sites of epigenetic marks and transcription factors, especially those involved in chromatin architecture formation. Notably, we have also found that puQTLs colocalize with complex traits or diseases and contribute to their heritability. Collectively, our findings underscore the significant role of puQTLs in elucidating the molecular mechanisms underlying tissue development and complex diseases.
启动子在调节基因转录中起着至关重要的作用。然而，我们对遗传变异如何影响替代启动子选择的理解仍不完整。在这项研究中，我们实施了一个框架来识别影响替代启动子相对使用的遗传变异，即启动子使用数量性状基因座（puQTLs）。通过构建来自 838 个人的 49 种不同组织的人类 puQTLs 图谱，我们已经确定了大约 76856 个与启动子使用相关的独立基因座，包含 602009 个遗传变异。我们的研究表明，puQTLs 代表了一种独特的分子数量性状基因座类型，有效地揭示了调控靶标和模式。此外，puQTLs 以组织特异性的方式进行调控，并且富含表观遗传标记和转录因子的结合位点，特别是那些涉及染色质结构形成的转录因子。值得注意的是，我们还发现 puQTLs 与复杂性状或疾病共定位，并对其遗传率有贡献。总的来说，我们的研究结果强调了 puQTLs 在阐明组织发育和复杂疾病的分子机制方面的重要作用。
