The role of loop extrusion in enhancer-mediated gene activation DOI Creative Commons
Magdalena A. Karpińska,

Aukje Marieke Oudelaar

Current Opinion in Genetics & Development, Journal Year: 2023, Volume and Issue: 79, P. 102022 - 102022

Published: Feb. 25, 2023

Gene expression patterns in complex multicellular organisms are regulated by enhancers, which communicate with their target gene promoters three-dimensional (3D) chromatin structures. Despite advances our understanding of the mechanisms that organize mammalian genomes into compartments and topologically associating domains (TADs), it is not well understood how specific interactions between enhancers controlled this 3D context. In review, we give an overview recent evidence shows a process loop extrusion plays important role regulation enhancer-promoter communication discuss insights molecular mechanism contributes to enhancer-mediated activation.

Language: Английский

Genome folding through loop extrusion by SMC complexes DOI
Iain F. Davidson, Jan‐Michael Peters

Nature Reviews Molecular Cell Biology, Journal Year: 2021, Volume and Issue: 22(7), P. 445 - 464

Published: March 25, 2021

Language: Английский

Citations

407

Enhancer–promoter interactions and transcription are largely maintained upon acute loss of CTCF, cohesin, WAPL or YY1 DOI Creative Commons
Tsung-Han S. Hsieh, Claudia Cattoglio, Elena Slobodyanyuk

et al.

Nature Genetics, Journal Year: 2022, Volume and Issue: 54(12), P. 1919 - 1932

Published: Dec. 1, 2022

It remains unclear why acute depletion of CTCF (CCCTC-binding factor) and cohesin only marginally affects expression most genes despite substantially perturbing three-dimensional (3D) genome folding at the level domains structural loops. To address this conundrum, we used high-resolution Micro-C nascent transcript profiling in mouse embryonic stem cells. We find that enhancer-promoter (E-P) interactions are largely insensitive to (3-h) CTCF, or WAPL. YY1 has been proposed as a regulator E-P loops, but also had minimal effects on transcription 3D folding. Strikingly, live-cell, single-molecule imaging revealed reduced factor (TF) binding chromatin. Thus, although cohesin, WAPL is not required for short-term maintenance gene expression, our results suggest may facilitate TFs search bind their targets more efficiently.

Language: Английский

Citations

251

Promoter-proximal CTCF binding promotes distal enhancer-dependent gene activation DOI
Naoki Kubo, Haruhiko Ishii, Xiong Xiong

et al.

Nature Structural & Molecular Biology, Journal Year: 2021, Volume and Issue: 28(2), P. 152 - 161

Published: Jan. 4, 2021

Language: Английский

Citations

240

Region Capture Micro-C reveals coalescence of enhancers and promoters into nested microcompartments DOI
Viraat Y. Goel, Miles K. Huseyin, Anders S. Hansen

et al.

Nature Genetics, Journal Year: 2023, Volume and Issue: 55(6), P. 1048 - 1056

Published: May 8, 2023

Language: Английский

Citations

136

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

Niels J. Rinzema,

Konstantinos Sofiadis,

Sjoerd J. D. Tjalsma

et al.

Nature Structural & Molecular Biology, Journal Year: 2022, Volume and Issue: 29(6), P. 563 - 574

Published: June 1, 2022

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

Language: Английский

Citations

120

BET inhibition disrupts transcription but retains enhancer-promoter contact DOI Creative Commons
Nicholas T. Crump,

Erica Ballabio,

Laura Godfrey

et al.

Nature Communications, Journal Year: 2021, Volume and Issue: 12(1)

Published: Jan. 11, 2021

Abstract Enhancers are DNA sequences that enable complex temporal and tissue-specific regulation of genes in higher eukaryotes. Although it is not entirely clear how enhancer-promoter interactions can increase gene expression, this proximity has been observed multiple systems at loci thought to be essential for the maintenance expression. Bromodomain Extra-Terminal domain (BET) Mediator proteins have shown capable forming phase condensates super-enhancer function. Here, we show targeting cells with inhibitors BET or pharmacological degradation protein Bromodomain-containing 4 (BRD4) a strong impact on transcription but very little interactions. Dissolving reduces BRD4 binding enhancers also strongly affect transcription, without disrupting These results suggest activation separable events. Our findings further indicate dependent high levels Mediator, likely maintained by set factors including additional activator complexes and, some sites, CTCF cohesin.

Language: Английский

Citations

108

Analysis of sub-kilobase chromatin topology reveals nano-scale regulatory interactions with variable dependence on cohesin and CTCF DOI Creative Commons
Abrar Aljahani, Hua Peng, Magdalena A. Karpińska

et al.

Nature Communications, Journal Year: 2022, Volume and Issue: 13(1)

Published: April 19, 2022

Abstract Enhancers and promoters predominantly interact within large-scale topologically associating domains (TADs), which are formed by loop extrusion mediated cohesin CTCF. However, it is unclear whether complex chromatin structures exist at sub-kilobase-scale to what extent fine-scale regulatory interactions depend on extrusion. To address these questions, we present an MNase-based chromosome conformation capture (3C) approach, has enabled us generate the most detailed local interaction data date (20 bp resolution) precisely investigate effects of CTCF depletion architecture. Our reveal that cis -regulatory elements have distinct internal nano-scale structures, insulation dependent CTCF, but independent cohesin. In contrast, find causes a subtle reduction in longer-range enhancer-promoter can cause rewiring contacts. Together, our show not essential for interactions, contributes their robustness specificity precise regulation gene expression.

Language: Английский

Citations

95

Cohesin-dependence of neuronal gene expression relates to chromatin loop length DOI Creative Commons
Lesly Calderón, Felix D. Weiss, Jonathan A. Beagan

et al.

eLife, Journal Year: 2022, Volume and Issue: 11

Published: April 26, 2022

Cohesin and CTCF are major drivers of 3D genome organization, but their role in neurons is still emerging. Here, we show a prominent for cohesin the expression genes that facilitate neuronal maturation homeostasis. Unexpectedly, observed two classes activity-regulated with distinct reliance on mouse primary cortical neurons. Immediate early (IEGs) remained fully inducible by KCl BDNF, short-range enhancer-promoter contacts at IEGs

Language: Английский

Citations

87

The role of chromatin loop extrusion in antibody diversification DOI
Yu Zhang, Xuefei Zhang, Hai-Qiang Dai

et al.

Nature reviews. Immunology, Journal Year: 2022, Volume and Issue: 22(9), P. 550 - 566

Published: Feb. 15, 2022

Language: Английский

Citations

83

3D enhancer-promoter interactions and multi-connected hubs: Organizational principles and functional roles DOI Creative Commons

Christopher M Uyehara,

Effie Apostolou

Cell Reports, Journal Year: 2023, Volume and Issue: 42(4), P. 112068 - 112068

Published: April 1, 2023

The spatiotemporal control of gene expression is dependent on the activity cis-acting regulatory sequences, called enhancers, which regulate target genes over variable genomic distances and, often, by skipping intermediate promoters, suggesting mechanisms that enhancer-promoter communication. Recent genomics and imaging technologies have revealed highly complex interaction networks, whereas advanced functional studies started interrogating forces behind physical communication among multiple enhancers promoters. In this review, we first summarize our current understanding factors involved in communication, with a particular focus recent papers new layers complexities to old questions. second part subset connected "hubs" discuss their potential functions signal integration regulation, as well putative might determine dynamics assembly.

Language: Английский

Citations

82