美国加州大学圣地亚哥分校Michael G. Rosenfeld和美国德克萨斯大学健康科学中心Wenbo Li课题组合作取得最新进展。他们发现增强子的释放和重新定向激活了疾病易感基因。2021年5月26日出版的《自然》杂志发表了这项成果。
他们报告说，优选启动子的功能丧失可以释放其伴侣增强子，使其环化并激活附近的替代启动子（或替代启动子）。他们将此靶标转换过程称为“增强子释放和重新定向”。遗传缺失、基序扰动或突变以及dCas9介导的CTCF系链揭示，增强子的启动子选择可以通过CTCF在启动子上的结合，以黏附素依赖性方式来确定-与内部的“增强子扫描”模型一致联系结构域。
与启动子相关的CTCF显示出比在染色质结构域边界更低的亲和力，并且通常在同源增强子上缺乏优选的基序取向或伴侣CTCF，暗示了与边界CTCF不同的性质。对癌症突变，GTEx项目的数据和全基因组关联研究的风险基因座的分析，以及针对性的CRISPR干扰筛选，揭示了增强子的释放和重新靶向代表了被忽视的机制，该机制是疾病易感性基因激活的基础，如图所示。帕金森氏病的风险位点（NUCKS1-RAB7L1）和与癌症相关的三个基因座（CLPTM1L-TERT，ZCCHC7-PAX5和PVT1-MYC）。
据介绍，增强子及其靶启动子之间的功能结合可确保精确的基因转录。了解增强子选择启动子的基础对健康和疾病具有重要意义。
附：英文原文
Title: Enhancer release and retargeting activates disease-susceptibility genes
Author: Soohwan Oh, Jiaofang Shao, Joydeep Mitra, Feng Xiong, Matteo DAntonio, Ruoyu Wang, Ivan Garcia-Bassets, Qi Ma, Xiaoyu Zhu, Joo-Hyung Lee, Sreejith J. Nair, Feng Yang, Kenneth Ohgi, Kelly A. Frazer, Zhengdong D. Zhang, Wenbo Li, Michael G. Rosenfeld
Issue&Volume: 2021-05-26
Abstract: The functional engagement between an enhancer and its target promoter ensures precise gene transcription1. Understanding the basis of promoter choice by enhancers has important implications for health and disease. Here we report that functional loss of a preferred promoter can release its partner enhancer to loop to and activate an alternative promoter (or alternative promoters) in the neighbourhood. We refer to this target-switching process as ‘enhancer release and retargeting’. Genetic deletion, motif perturbation or mutation, and dCas9-mediated CTCF tethering reveal that promoter choice by an enhancer can be determined by the binding of CTCF at promoters, in a cohesin-dependent manner—consistent with a model of ‘enhancer scanning’ inside the contact domain. Promoter-associated CTCF shows a lower affinity than that at chromatin domain boundaries and often lacks a preferred motif orientation or a partnering CTCF at the cognate enhancer, suggesting properties distinct from boundary CTCF. Analyses of cancer mutations, data from the GTEx project and risk loci from genome-wide association studies, together with a focused CRISPR interference screen, reveal that enhancer release and retargeting represents an overlooked mechanism that underlies the activation of disease-susceptibility genes, as exemplified by a risk locus for Parkinson’s disease (NUCKS1–RAB7L1) and three loci associated with cancer (CLPTM1L–TERT, ZCCHC7–PAX5 and PVT1–MYC).
DOI: 10.1038/s41586-021-03577-1
Source: https://www.nature.com/articles/s41586-021-03577-1
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
