Building regulatory landscapes reveals that an enhancer can recruit cohesin to create contact domains, engage CTCF sites and activate distant genes

TY - JOUR

T1 - Building regulatory landscapes reveals that an enhancer can recruit cohesin to create contact domains, engage CTCF sites and activate distant genes

AU - Rinzema, Niels J

AU - Sofiadis, Konstantinos

AU - Tjalsma, Sjoerd J D

AU - Verstegen, Marjon J A M

AU - Oz, Yuva

AU - Valdes-Quezada, Christian

AU - Felder, Anna-Karina

AU - Filipovska, Teodora

AU - van der Elst, Stefan

AU - de Andrade Dos Ramos, Zaria

AU - Han, Ruiqi

AU - Krijger, Peter H L

AU - de Laat, Wouter

N1 - © 2022. The Author(s).

PY - 2022/6

Y1 - 2022/6

N2 - Developmental gene expression is often controlled by distal regulatory DNA elements called enhancers. Distant enhancer action is restricted to structural chromosomal domains that are flanked by CTCF-associated boundaries and formed through cohesin chromatin loop extrusion. To better understand how enhancers, genes and CTCF boundaries together form structural domains and control expression, we used a bottom-up approach, building series of active regulatory landscapes in inactive chromatin. We demonstrate here that gene transcription levels and activity over time reduce with increased enhancer distance. The enhancer recruits cohesin to stimulate domain formation and engage flanking CTCF sites in loop formation. It requires cohesin exclusively for the activation of distant genes, not of proximal genes, with nearby CTCF boundaries supporting efficient long-range enhancer action. Our work supports a dual activity model for enhancers: its classic role of stimulating transcription initiation and elongation from target gene promoters and a role of recruiting cohesin for the creation of chromosomal domains, the engagement of CTCF sites in chromatin looping and the activation of distal target genes.

AB - Developmental gene expression is often controlled by distal regulatory DNA elements called enhancers. Distant enhancer action is restricted to structural chromosomal domains that are flanked by CTCF-associated boundaries and formed through cohesin chromatin loop extrusion. To better understand how enhancers, genes and CTCF boundaries together form structural domains and control expression, we used a bottom-up approach, building series of active regulatory landscapes in inactive chromatin. We demonstrate here that gene transcription levels and activity over time reduce with increased enhancer distance. The enhancer recruits cohesin to stimulate domain formation and engage flanking CTCF sites in loop formation. It requires cohesin exclusively for the activation of distant genes, not of proximal genes, with nearby CTCF boundaries supporting efficient long-range enhancer action. Our work supports a dual activity model for enhancers: its classic role of stimulating transcription initiation and elongation from target gene promoters and a role of recruiting cohesin for the creation of chromosomal domains, the engagement of CTCF sites in chromatin looping and the activation of distal target genes.

KW - Binding Sites

KW - CCCTC-Binding Factor/genetics

KW - Cell Cycle Proteins/genetics

KW - Chromatin/genetics

KW - Chromosomal Proteins, Non-Histone/genetics

KW - Enhancer Elements, Genetic/genetics

U2 - 10.1038/s41594-022-00787-7

DO - 10.1038/s41594-022-00787-7

M3 - Article

C2 - 35710842

SN - 1545-9993

VL - 29

SP - 563

EP - 574

JO - Nature Structural & Molecular Biology

JF - Nature Structural & Molecular Biology

IS - 6

ER -