Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA.
Department of Genetics, Stanford University, Stanford, CA, USA.
Nucleic Acids Res. 2021 Dec 2;49(21):12196-12210. doi: 10.1093/nar/gkab1105.
The term 'super enhancers' (SE) has been widely used to describe stretches of closely localized enhancers that are occupied collectively by large numbers of transcription factors (TFs) and co-factors, and control the transcription of highly-expressed genes. Through integrated analysis of >600 DNase-seq, ChIP-seq, GRO-seq, STARR-seq, RNA-seq, Hi-C and ChIA-PET data in five human cancer cell lines, we identified a new class of autonomous SEs (aSEs) that are excluded from classic SE calls by the widely used Rank Ordering of Super-Enhancers (ROSE) method. TF footprint analysis revealed that compared to classic SEs and regular enhancers, aSEs are tightly bound by a dense array of master lineage TFs, which serve as anchors to recruit additional TFs and co-factors in trans. In addition, aSEs are preferentially enriched for Cohesins, which likely involve in stabilizing long-distance interactions between aSEs and their distal target genes. Finally, we showed that aSEs can be reliably predicted using a single DNase-seq data or combined with Mediator and/or P300 ChIP-seq. Overall, our study demonstrates that aSEs represent a unique class of functionally important enhancer elements that distally regulate the transcription of highly expressed genes.
“超级增强子”（SE）一词被广泛用于描述紧密定位的增强子区域，这些区域被大量转录因子（TFs）和共因子共同占据，并控制高表达基因的转录。通过对 5 个人类癌细胞系中的>600 个 DNase-seq、ChIP-seq、GRO-seq、STARR-seq、RNA-seq、Hi-C 和 ChIA-PET 数据进行综合分析，我们鉴定了一类新的自主超级增强子（aSEs），这些超级增强子通过广泛使用的超级增强子排序（ROSE）方法被排除在经典超级增强子的定义之外。TF 足迹分析显示，与经典超级增强子和常规增强子相比，aSEs 被一系列密集的主谱系 TF 紧密结合，这些 TF 作为锚点，在转录水平上募集额外的 TF 和共因子。此外，aSEs 优先富集黏连蛋白，这可能涉及到稳定 aSEs 与其远端靶基因之间的长距离相互作用。最后，我们表明，aSEs 可以使用单个 DNase-seq 数据或与 Mediator 和/或 P300 ChIP-seq 相结合来可靠地预测。总之，我们的研究表明，aSEs 代表了一类独特的、具有重要功能的增强子元件，它们远距离调控高表达基因的转录。
