TY - JOUR
T1 - Enhancer release and retargeting activates disease-susceptibility genes
AU - Oh, Soohwan
AU - Shao, Jiaofang
AU - Mitra, Joydeep
AU - Xiong, Feng
AU - D’Antonio, Matteo
AU - Wang, Ruoyu
AU - Garcia-Bassets, Ivan
AU - Ma, Qi
AU - Zhu, Xiaoyu
AU - Lee, Joo Hyung
AU - Nair, Sreejith J.
AU - Yang, Feng
AU - Ohgi, Kenneth
AU - Frazer, Kelly A.
AU - Zhang, Zhengdong D.
AU - Li, Wenbo
AU - Rosenfeld, Michael G.
N1 - Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2021/7/29
Y1 - 2021/7/29
N2 - 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).
AB - 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).
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U2 - 10.1038/s41586-021-03577-1
DO - 10.1038/s41586-021-03577-1
M3 - Article
C2 - 34040254
AN - SCOPUS:85106461581
SN - 0028-0836
VL - 595
SP - 735
EP - 740
JO - Nature
JF - Nature
IS - 7869
ER -