Enhancer release and retargeting activates disease-susceptibility genes

Soohwan Oh, Jiaofang Shao, Joydeep Mitra, Feng Xiong, Matteo D’Antonio, 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

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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).

Original languageEnglish (US)
Pages (from-to)735-740
Number of pages6
JournalNature
Volume595
Issue number7869
DOIs
StatePublished - Jul 29 2021

ASJC Scopus subject areas

  • General

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