Spt5介導的增強子轉錄直接偶聯增強子激活與啟動子相互作用

Spt5介導的增強子轉錄直接偶聯增強子激活與啟動子相互作用

作者：

小柯機器人

發布時間：2020/4/13 12:41:01

近日，奧地利分子病理研究所Rushad Pavri課題組發現，Spt5介導的增強子轉錄直接偶聯增強子激活與啟動子相互作用。相關論文於2020年4月6日在線發表在《自然—遺傳學》雜誌上。

活躍的增強子經常被轉錄，但是增強子轉錄的調節作用仍然存在爭議。通過敲低激活小鼠B細胞中RNA聚合酶II的暫停和延伸因子Spt5，研究人員發現大約50％的增強子-基因對顯示出共同調控的轉錄，這與增強子轉錄的潛在功能一致。

 

具體而言，Spt5敲低導致免疫球蛋白重鏈基因座（Igh）失去了增強子-啟動子的物理相互作用和基因表達，從而阻礙了抗體類別轉換的重組。該缺陷與增強子轉錄的喪失緊密相關，但不影響組蛋白H3第27位賴氨酸的乙醯化、染色質可及性以及增強子上中介體和cohesin 的佔位。

 

令人驚訝的是，Spt5敲低細胞中CRISPRa介導的增強子轉錄的回補恢復了Igh基因的表達。這些工作表明，Spt5介導的增強子轉錄是活躍增強子及其靶啟動子之間的物理和功能相互作用的基礎。

 

附：英文原文

Title: Spt5-mediated enhancer transcription directly couples enhancer activation with physical promoter interaction

Author: Johanna Fitz, Tobias Neumann, Monika Steininger, Eva-Maria Wiedemann, Adriana Cantoran Garcia, Alexander Athanasiadis, Ursula E. Schoeberl, Rushad Pavri

Issue&Volume: 2020-04-06

Abstract: Active enhancers are frequently transcribed, yet the regulatory role of enhancer transcription remains debated. Here, we depleted the RNA polymerase II pausing and elongation factor Spt5 in activated mouse B cells and found that approximately 50% of enhancer–gene pairs showed co-regulated transcription, consistent with a potential functional requirement for enhancer transcription. In particular, Spt5 depletion led to loss of super-enhancer–promoter physical interaction and gene expression at the immunoglobulin heavy-chain locus (Igh), abrogating antibody class switch recombination. This defect correlated strictly with loss of enhancer transcription but did not affect acetylation of histone H3 at lysine 27, chromatin accessibility and occupancy of Mediator and cohesin at the enhancer. Strikingly, CRISPRa-mediated rescue of enhancer transcription in Spt5-depleted cells restored Igh gene expression. Our work suggests that Spt5-mediated enhancer transcription underlies the physical and functional interaction between a subset of active enhancers and their target promoters.

DOI: 10.1038/s41588-020-0605-6

Source: https://www.nature.com/articles/s41588-020-0605-6