TY - JOUR
T1 - Interplay between CTCF boundaries and a super enhancer controls cohesin extrusion trajectories and gene expression
AU - Vos, Erica S M
AU - Valdes-Quezada, Christian
AU - Huang, Yike
AU - Allahyar, Amin
AU - Verstegen, Marjon J A M
AU - Felder, Anna-Karina
AU - van der Vegt, Floor
AU - Uijttewaal, Esther C H
AU - Krijger, Peter H L
AU - de Laat, Wouter
N1 - Copyright © 2021 Elsevier Inc. All rights reserved.
PY - 2021/8/5
Y1 - 2021/8/5
N2 - To understand how chromatin domains coordinate gene expression, we dissected select genetic elements organizing topology and transcription around the Prdm14 super enhancer in mouse embryonic stem cells. Taking advantage of allelic polymorphisms, we developed methods to sensitively analyze changes in chromatin topology, gene expression, and protein recruitment. We show that enhancer insulation does not rely strictly on loop formation between its flanking boundaries, that the enhancer activates the Slco5a1 gene beyond its prominent domain boundary, and that it recruits cohesin for loop extrusion. Upon boundary inversion, we find that oppositely oriented CTCF terminates extrusion trajectories but does not stall cohesin, while deleted or mutated CTCF sites allow cohesin to extend its trajectory. Enhancer-mediated gene activation occurs independent of paused loop extrusion near the gene promoter. We expand upon the loop extrusion model to propose that cohesin loading and extrusion trajectories originating at an enhancer contribute to gene activation.
AB - To understand how chromatin domains coordinate gene expression, we dissected select genetic elements organizing topology and transcription around the Prdm14 super enhancer in mouse embryonic stem cells. Taking advantage of allelic polymorphisms, we developed methods to sensitively analyze changes in chromatin topology, gene expression, and protein recruitment. We show that enhancer insulation does not rely strictly on loop formation between its flanking boundaries, that the enhancer activates the Slco5a1 gene beyond its prominent domain boundary, and that it recruits cohesin for loop extrusion. Upon boundary inversion, we find that oppositely oriented CTCF terminates extrusion trajectories but does not stall cohesin, while deleted or mutated CTCF sites allow cohesin to extend its trajectory. Enhancer-mediated gene activation occurs independent of paused loop extrusion near the gene promoter. We expand upon the loop extrusion model to propose that cohesin loading and extrusion trajectories originating at an enhancer contribute to gene activation.
KW - Animals
KW - CCCTC-Binding Factor/genetics
KW - Cell Cycle Proteins/genetics
KW - Chromatin/genetics
KW - Chromosomal Proteins, Non-Histone/genetics
KW - DNA-Binding Proteins/genetics
KW - Enhancer Elements, Genetic
KW - Gene Expression
KW - Mice
KW - Mouse Embryonic Stem Cells
KW - Nuclear Receptor Coactivator 2/genetics
KW - Promoter Regions, Genetic
KW - RNA-Binding Proteins/genetics
KW - Transcription Factors/genetics
U2 - 10.1016/j.molcel.2021.06.008
DO - 10.1016/j.molcel.2021.06.008
M3 - Article
C2 - 34197738
SN - 1097-2765
VL - 81
SP - 3082-3095.e6
JO - Molecular Cell
JF - Molecular Cell
IS - 15
ER -