Recent evidence that TADs and chromatin loops are dynamic structures

Anders S Hansen,Claudia Cattoglio,Xavier Darzacq,Robert Tjian

doi:10.1080/19491034.2017.1389365

Abstract

ABSTRACTMammalian genomes are folded into spatial domains, which regulate gene expression by modulating enhancer-promoter contacts. Here, we review recent studies on the structure and function of Topologically Associating Domains (TADs) and chromatin loops. We discuss how loop extrusion models can explain TAD formation and evidence that TADs are formed by the ring-shaped protein complex, cohesin, and that TAD boundaries are established by the DNA-binding protein, CTCF. We discuss our recent genomic, biochemical and single-molecule imaging studies on CTCF and cohesin, which suggest that TADs and chromatin loops are dynamic structures. We highlight complementary polymer simulation studies and Hi-C studies employing acute depletion of CTCF and cohesin, which also support such a dynamic model. We discuss the limitations of each approach and conclude that in aggregate the available evidence argues against stable loops and supports a model where TADs are dynamic structures that continually form and break throughout the cell cycle.

Highlights

Since the dynamics of the Loop Maintenance Complex (LMC) should reflect the dynamics of Topological Associating Domains (TADs) and chromatin loops, we studied the chromatin binding dynamics of CCCTCbinding factor (CTCF) and cohesin
We have attempted to synthesize recent evidence from single-molecule imaging, polymer simulation and HiC approaches to suggest that most TADs and chromatin loops are very likely highly dynamic structures with a mean lifetime of a few minutes to tens of minutes in most actively dividing mammalian cells
Each approach has its own advantages and limitations, we argue that in aggregate all the available evidence points to CTCF/cohesin-dependent TADs and chromatin loops being dynamic and not stable structures

Summary

Introduction

Mammalian genomes are folded at multiple scales and each scale highlights an important interplay between structure and function[1,2] (Fig. 1). This readily suggested a model wherein CTCF binds its cognate sites and recruits cohesin, which folds the in-between chromatin into a loop structure. In this model TADs emerge at the population level when averaged over the many distinct extrusion complexes at different positions in single cells (Fig. 2F) This highly dynamic view is consistent with the relatively modest »2-fold insulation observed between loci in adjacent. Loop domains were largely re-established 1 hour after auxin removal.[13] Taken together, these studies[13,14] suggest that the mechanisms by which TADs and loops are formed and broken down are both quite fast, which argues against stable TADs and favors dynamic TADs. We have proposed above that our imaging studies,[7] recent polymer simulation studies[8] and recent Hi-C studies employing acute cohesin degradation[13,14] all point to TADs being dynamic. Informative, it is difficult to reliably estimate hard numbers from such approaches

Conclusion and outlook

Findings

Funding Details