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不同辅因子的依赖性定义出人类增强子的不同类型
2022-06-03 23:10
来源：小柯机器人

奥地利维也纳大学Alexander Stark小组发现，不同辅因子的依赖性定义出人类增强子的不同类型。该项研究成果于2022年6月1日在线发表在《自然》杂志上。

研究人员按照辅因子的依赖性对人类增强子进行了分类，并表明这些类别提供了一个框架，可用于了解增强子的序列和染色质多样性及其在不同基因调控程序中的作用。在8个辅因子快速降解之后，研究人员在HCT116细胞中使用STARR-seq对沿着整个人类基因组的增强子活动进行了量化。这项分析确定了不同类型的增强子，它们具有不同的辅因子需求、序列和染色质特性。一些增强子对核心中介体亚单位MED14或溴结构域蛋白BRD4的耗尽不敏感，并调节不同的转录程序。
 
特别是，典型的中介体对P53反应性增强子似乎是不需要的，而MED14耗尽的细胞诱导了内源性P53靶基因。同样，BRD4对于带有CCAAT盒和TATA盒的基因（包括组蛋白基因和LTR12逆转录基因）的转录或热休克基因的诱导也不需要。这种通过辅因子依赖性对增强子的分类揭示了可以绕过广泛利用的辅因子的不同增强子类型，这说明了激活转录的替代方式是如何分离基因表达程序的，并为理解增强子功能和调节特异性提供了一个概念框架。
 
据介绍，所有多细胞生物都依赖于由基因组增强子调节的不同基因转录，增强子通过被转录因子招募的辅因子发挥作用。新的证据表明，并非所有的增强子都需要所有的辅因子，然而这些观察是否反映了更普遍的原则或不同类型的增强子仍然是未知的。
 
附：英文原文
 
Title: Differential cofactor dependencies define distinct types of human enhancers

Author: Neumayr, Christoph, Haberle, Vanja, Serebreni, Leonid, Karner, Katharina, Hendy, Oliver, Boija, Ann, Henninger, Jonathan E., Li, Charles H., Stejskal, Karel, Lin, Gen, Bergauer, Katharina, Pagani, Michaela, Rath, Martina, Mechtler, Karl, Arnold, Cosmas D., Stark, Alexander

Issue&Volume: 2022-06-01

Abstract: All multicellular organisms rely on differential gene transcription regulated by genomic enhancers, which function through cofactors that are recruited by transcription factors1,2. Emerging evidence suggests that not all cofactors are required at all enhancers3,4,5, yet whether these observations reflect more general principles or distinct types of enhancers remained unknown. Here we categorized human enhancers by their cofactor dependencies and show that these categories provide a framework to understand the sequence and chromatin diversity of enhancers and their roles in different gene-regulatory programmes. We quantified enhancer activities along the entire human genome using STARR-seq6 in HCT116 cells, following the rapid degradation of eight cofactors. This analysis identified different types of enhancers with distinct cofactor requirements, sequences and chromatin properties. Some enhancers were insensitive to the depletion of the core Mediator subunit MED14 or the bromodomain protein BRD4 and regulated distinct transcriptional programmes. In particular, canonical Mediator7 seemed dispensable for P53-responsive enhancers, and MED14-depleted cells induced endogenous P53 target genes. Similarly, BRD4 was not required for the transcription of genes that bear CCAAT boxes and a TATA box (including histone genes and LTR12 retrotransposons) or for the induction of heat-shock genes. This categorization of enhancers through cofactor dependencies reveals distinct enhancer types that can bypass broadly utilized cofactors, which illustrates how alternative ways to activate transcription separate gene expression programmes and provide a conceptual framework to understand enhancer function and regulatory specificity.

DOI: 10.1038/s41586-022-04779-x

Source: https://www.nature.com/articles/s41586-022-04779-x

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html


本期文章：《自然》：Online/在线发表

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