Formation of Chromosomal Domains by Loop Extrusion

By Geoffrey Fudenberg, Maxim Imakaev, Carolyn W. Lu, Anton Goloborodko, Nezar Abdennur, Leonid A. Mirny. bioRxiv, 2015

1,787 citations recorded by the source corpus.

Topologically Associating Domains (TADs) are fundamental structural and functional building blocks of human interphase chromosomes, yet mechanisms of TAD formation remain unknown. Here we propose that loop extrusion underlies TAD formation. In this process, cis-acting loop-extruding factors, likely cohesins, form progressively larger loops, but stall at TAD boundaries due to interactions with boundary proteins, including CTCF. Using polymer simulations, we show that this model can produce TADs as determined by our analyses of Hi-C data. Contrary to typical illustrations, each TAD consists of multiple dynamically formed loops, rather than a single static loop. Our model explains diverse experimental observations, including the preferential orientation of CTCF motifs, enrichments of architectural proteins at TAD boundaries, and boundary deletion experiments, and makes specific predictions for depletion of CTCF versus cohesin. The emerging picture is that TADs arise from actively forming, growing, and dissociating loops, presenting a framework for understanding interphase chromosomal organization.

View Paper: https://www.semanticscholar.org/paper/03c39e6c419ea8039d012f32d80d31f7ab4d5b47

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

1. J. Nuebler
2. B. Bintu
3. Rieke Kempfer
4. Alistair N. Boettiger
5. Leslie J. Mateo
6. A. Pombo
7. Jun-Han Su
8. Nicholas A. Sinnott-Armstrong

Citations in the corpus

• Single-nucleus Hi-C reveals unique chromatin reorganization at oocyte-to-zygote transition (2017, unknown): “The mechanism of TAD formation by loop extrusion and boundary insulation 21,22 provides a rationale for TAD stochasticity and frequent boundary violations.”
• Regulation of disease-associated gene expression in the 3D genome (2016, unknown): “On the basis of these findings, it has now been suggested that loop extrusion 95 underlies TAD formation 93,96 (reviewed in REF.”
• Topologically associating domains and chromatin loops depend on cohesin and are regulated by CTCF, WAPL, and PDS5 proteins (2017, unknown): “These observations imply that CTCF, unlike cohesin, is not required for long-range chromatin interactions per se, but has an important role in defining their precise position, consistent with the proposed role of CTCF as a boundary for loop extrusion (Sanborn et al, 2015; Fudenberg et al, 2016).”
• Super-resolution chromatin tracing reveals domains and cooperative interactions in single cells (2018, background): “The loop extrusion model (22, 40), in which cohesin complexes extrude DNA until stopped by a pair of CTCF motifs, has been proposed to explain the formation of TADs and sub-TADs at the population level (22, 25, 40, 41).”
• Ever-changing landscapes: transcriptional enhancers in development and evolution (2016, unknown): “…a chromosomal loop is randomly initiated then continuously fed through an extrusion complex containing a cohesin ring until convergent CTCF binding sites are encountered, at which point the loop structure is stabilized, likely via CTCF dimerization (Fudenberg et al., 2015; Sanborn et al., 2015).”
• Chromatin organization by an interplay of loop extrusion and compartmental segregation (2017, background): “CTCF-enriched boundaries of TADs are modeled by barriers that block extrusion of LEFs with probability 90% in WT (16).”