美国康奈尔大学Haiyuan Yu和John T. Lis课题组发现转录赋予增强子元件结构、功能和逻辑。这一研究成果于2020年9月21日发表在《自然-遗传学》上。

使用大量平行报告基因分析对两个主要增强子模型进行功能比较，研究人员发现基因远距离转录起始位点是活性增强子有效的预测因子，其分辨率高于组蛋白修饰。研究表明，活性增强子元件是由活性转录起始位点决定的，并证明验证这些边界足以揭示增强子的功能，并确认核心启动子序列对增强子活性是必需的。

通过分析相邻的增强子，研究人员发现它们的联合活性通常是由增强子簇中更强元件驱动的。最后，研究人员使用CRISPR–Cas9对远端增强子簇进行功能分析验证了这些结果。总之，高分辨率增强子边界的定义可以将复杂的调控位点解卷积为模块单元。

据介绍，远端增强子在发育和疾病发生过程中起着关键作用，但其仍然是人类最不了解的调节元件之一。

附：英文原文

Title: Transcription imparts architecture, function and logic to enhancer units

Author: Nathaniel D. Tippens, Jin Liang, Alden King-Yung Leung, Shayne D. Wierbowski, Abdullah Ozer, James G. Booth, John T. Lis, Haiyuan Yu

Issue&Volume: 2020-09-21

Abstract: Distal enhancers play pivotal roles in development and disease yet remain one of the least understood regulatory elements. We used massively parallel reporter assays to perform functional comparisons of two leading enhancer models and find that gene-distal transcription start sites are robust predictors of active enhancers with higher resolution than histone modifications. We show that active enhancer units are precisely delineated by active transcription start sites, validate that these boundaries are sufficient for capturing enhancer function, and confirm that core promoter sequences are necessary for this activity. We assay adjacent enhancers and find that their joint activity is often driven by the stronger unit within the cluster. Finally, we validate these results through functional dissection of a distal enhancer cluster using CRISPR–Cas9 deletions. In summary, definition of high-resolution enhancer boundaries enables deconvolution of complex regulatory loci into modular units.

DOI: 10.1038/s41588-020-0686-2

Source: https://www.nature.com/articles/s41588-020-0686-2