Whitlock Jordan H, Wilk Elizabeth J, Howton Timothy C, Clark Amanda D, Lasseigne Brittany N
Department of Cell, Developmental and Integrative Biology, Heersink School of Medicine The University of Alabama at Birmingham, Birmingham, AL, U.S.A.
bioRxiv. 2023 Oct 14:2023.08.08.551337. doi: 10.1101/2023.08.08.551337.
The SET binding protein 1 () gene encodes a transcription factor (TF) involved in various cellular processes. Distinct variants have been linked to three different diseases. Germline variants cause the ultra-rare pediatric Schinzel Giedion Syndrome (SGS) and haploinsufficiency disorder (-HD), characterized by severe multisystemic abnormalities with neurodegeneration or a less severe brain phenotype accompanied by hypotonia and strabismus, respectively. Somatic variants in are associated with hematological malignancies and cancer development in other tissues in adults.
To better understand the tissue-specific mechanisms involving , we analyzed publicly available RNA-sequencing data from the Genotype-Tissue Expression (GTEx) project. We found and its known target genes were widely expressed across 31 adult human tissues. K-means clustering identified three distinct expression patterns of SETBP1 targets across tissues. Functional enrichment analysis (FEA) of each cluster revealed gene sets related to transcription regulation, DNA binding, and mitochondrial function. TF activity analysis of SETBP1 and its target TFs revealed tissue-specific TF activity, underscoring the role of tissue context-driven regulation and suggesting its impact in SETBP1-associated disease. In addition to uncovering tissue-specific molecular signatures of expression and TF activity, we provide a Shiny web application to facilitate exploring TF activity across human tissues for 758 TFs.
This study provides insight into the landscape of expression and TF activity across 31 non-diseased human tissues and reveals tissue-specific expression and activity of and its targets. In conjunction with the web application we constructed, our framework enables researchers to generate hypotheses related to the role tissue backgrounds play with respect to gene expression and TF activity in different disease contexts.
SET结合蛋白1（SETBP1）基因编码一种参与多种细胞过程的转录因子（TF）。不同的SETBP1变体与三种不同的疾病相关联。种系变体导致极为罕见的儿童辛兹尔·吉迪恩综合征（SGS）和SETBP1单倍体不足障碍（SETBP1-HD），其特征分别为伴有神经退行性变的严重多系统异常或伴有肌张力减退和斜视的较轻脑表型。SETBP1的体细胞变体与成人血液系统恶性肿瘤及其他组织中的癌症发生有关。
为了更好地理解涉及SETBP1的组织特异性机制，我们分析了来自基因型-组织表达（GTEx）项目的公开可用RNA测序数据。我们发现SETBP1及其已知靶基因在31种成人人体组织中广泛表达。K均值聚类确定了SETBP1靶标在各组织中的三种不同表达模式。对每个聚类的功能富集分析（FEA）揭示了与转录调控、DNA结合和线粒体功能相关的基因集。对SETBP1及其靶转录因子的转录因子活性分析揭示了组织特异性转录因子活性，强调了组织背景驱动调控的作用，并提示其在SETBP1相关疾病中的影响。除了揭示SETBP1表达和转录因子活性的组织特异性分子特征外，我们还提供了一个Shiny网络应用程序，以方便探索758种转录因子在人体组织中的转录因子活性。
本研究深入了解了SETBP1在31种非疾病人体组织中的表达格局和转录因子活性，揭示了SETBP1及其靶标的组织特异性表达和活性。结合我们构建的网络应用程序，我们的框架使研究人员能够生成与组织背景在不同疾病背景下对基因表达和转录因子活性所起作用相关的假设。
