Graduate Programs in Molecular Biosciences, Rutgers The State University of New Jersey, 604 Allison Rd., Piscataway, NJ 08854, USA.
Department of Biochemistry and Molecular Biology, Rutgers The State University of New Jersey, 604 Allison Road, Piscataway, NJ 08854, USA.
Int J Mol Sci. 2024 Sep 11;25(18):9840. doi: 10.3390/ijms25189840.
Gene expression is orchestrated by a complex array of gene regulatory elements that govern transcription in a cell-type-specific manner. Though previously studied, the ability to utilize regulatory elements to identify disrupting variants remains largely elusive. To identify important factors within these regions, we generated enhancer-promoter interaction (EPI) networks and investigated the presence of disease-associated variants that fall within these regions. Our study analyzed six neuronal cell types across neural differentiation, allowing us to examine closely related cell types and across differentiation stages. Our results expand upon previous findings of cell-type specificity of enhancer, promoter, and transcription factor binding sites. Notably, we find that regulatory regions within EPI networks can identify the enrichment of variants associated with neuropsychiatric disorders within specific cell types and network sub-structures. This enrichment within sub-structures can allow for a better understanding of potential mechanisms by which variants may disrupt transcription. Together, our findings suggest that EPIs can be leveraged to better understand cell-type-specific regulatory architecture and used as a selection method for disease-associated variants to be tested in future functional assays. Combined with these future functional characterization assays, EPIs can be used to better identify and characterize regulatory variants' effects on such networks and model their mechanisms of gene regulation disruption across different disorders. Such findings can be applied in practical settings, such as diagnostic tools and drug development.
基因表达是由一系列复杂的基因调控元件来调控的，这些元件以细胞类型特异性的方式控制转录。尽管之前已经进行了研究，但利用调控元件来识别干扰变体的能力仍然很大程度上难以捉摸。为了确定这些区域内的重要因素，我们生成了增强子-启动子相互作用（EPI）网络，并研究了落在这些区域内的与疾病相关的变异体。我们的研究分析了神经分化过程中的六种神经元细胞类型，使我们能够仔细研究密切相关的细胞类型和分化阶段。我们的研究结果扩展了先前关于增强子、启动子和转录因子结合位点的细胞类型特异性的发现。值得注意的是，我们发现 EPI 网络中的调控区域可以识别与神经精神障碍相关的变体在特定细胞类型和网络子结构中的富集。这种在子结构中的富集可以更好地理解变体可能破坏转录的潜在机制。总之，我们的研究结果表明，EPI 可以被利用来更好地理解细胞类型特异性的调控结构，并作为一种选择方法来测试与疾病相关的变体，以便在未来的功能测定中进行测试。结合这些未来的功能特征测定，EPI 可以用于更好地识别和描述这些网络中调控变体对基因调控的干扰效应，并对不同疾病中的基因调控破坏机制进行建模。这些发现可以应用于实际应用中，如诊断工具和药物开发。
