Batool Fatima, Shireen Huma, Malik Muhammad Faizan, Abrar Muhammad, Abbasi Amir Ali
National Center for Bioinformatics, Program of Comparative and Evolutionary Genomics, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad 45320, Pakistan.
Biol Open. 2025 Feb 15;14(2). doi: 10.1242/bio.061751. Epub 2025 Feb 19.
Tissue-specific gene regulation in mammals involves the coordinated binding of multiple transcription factors (TFs). Using the forebrain as a model, we investigated the syntax of TF occupancy to determine tissue-specific enhancer regions. We analyzed forebrain-exclusive enhancers from the VISTA Enhancer Browser and a curated set of 23 TFs relevant to forebrain development and disease. Our findings revealed multiple distinct patterns of combinatorial TF binding, with the HES5-FOXP2-GATA3 triad being the most frequent in forebrain-specific enhancers. This syntactic structure was detected in 2614 enhancers from a genome-wide catalog of 25,000 predicted human forebrain enhancers. Notably, this catalog represents a computationally predicted dataset, distinct from the in vivo validated set of enhancers obtained from the VISTA Enhancer Browser. The shortlisted 2614 enhancers were further analyzed using genome-wide epigenetic data and evaluated for evolutionary conservation and disease relevance. Our findings highlight the value of these 2614 enhancers in forebrain-specific gene regulation and provide a framework for discovering tissue-specific enhancers, enhancing the understanding of enhancer function.
哺乳动物中的组织特异性基因调控涉及多种转录因子(TFs)的协同结合。我们以前脑为模型,研究了TF占据的句法结构,以确定组织特异性增强子区域。我们分析了来自VISTA增强子浏览器的前脑特异性增强子以及一组精心挑选的与前脑发育和疾病相关的23种TF。我们的研究结果揭示了多种不同的组合TF结合模式,其中HES5-FOXP2-GATA3三联体在前脑特异性增强子中最为常见。在25000个预测的人类前脑增强子的全基因组目录中的2614个增强子中检测到了这种句法结构。值得注意的是,该目录代表了一个通过计算预测的数据集,与从VISTA增强子浏览器获得的体内验证的增强子集不同。使用全基因组表观遗传数据对入围的2614个增强子进行了进一步分析,并评估了其进化保守性和疾病相关性。我们的研究结果突出了这2614个增强子在前脑特异性基因调控中的价值,并为发现组织特异性增强子提供了一个框架,增强了对增强子功能的理解。