Emerging Evidence of Chromosome Folding by Loop Extrusion

Abstract

Chromosome organization poses a remarkable physical problem with many biological consequences: how can molecular interactions between proteins at the nanometer scale organize micron-long chromatinized DNA molecules, insulating or facilitating interactions between specific genomic elements? The mechanism of active loop extrusion holds great promise for explaining interphase and mitotic chromosome folding, yet remains difficult to assay directly. We discuss predictions from our polymer models of loop extrusion with barrier elements, and review recent experimental studies that provide strong support for loop extrusion, focusing on perturbations to CTCF and cohesin assayed via Hi-C in interphase. Finally, we discuss a likely molecular mechanism of loop extrusion by SMC complexes.

A chromosome folding intermediate at the condensin-to-cohesin transition during telophase

“…For example, P(s) plots for interphase and mitosis are distinct ( Fig. 4a) and have been used to test models of chromosome folding 1,10,28,29,36 . We calculated P(s) for Hi-C data obtained from cells at different times after release from prometaphase arrest.…”

“…During interphase cohesin organizes chromosomes in loops, thought to be the result of a dynamic loop extrusion process 1 . Loop extrusion can occur all along chromosomes but is blocked at CTCF sites leading to detectable loops between convergent CTCF sites [2][3][4][5][6][7] and the formation of topologically associating domains (TADs [7][8][9].…”

How the Genome Folds: The Biophysics of Four-Dimensional Chromatin Organization

“…Loops show up as peaks, often located at TAD corners. The box shows chromatin regions undergoing cohesin-mediated loop extrusion (44). In this scenario, cohesin is loaded on DNA by Nipbl, and once loaded extrudes DNA until reaching a properly oriented CTCF boundary.…”

“…Molecular dynamics simulations of loop extrusion (106,45,86,121), although assuming some ad-hoc parameters (e.g. an average processivity of ∼200 kb, a 10% permeability of CTCF boundaries and uni-directional or bidirectional movements) are remarkably successful at explaining almost all the experimental evidence mentioned above, as well as the effect of several experimental perturbations summarized next (44).…”

DeepMILO: a deep learning approach to predict the impact of non-coding sequence variants on 3D chromatin structure

“…Moreover, multiple studies have shown that transcription factors (TFs) other than CTCF and cohesin may play an important role in loop formation [8,9]. Recent experiments [7] support the loop extrusion model [10,11], which suggests that structural maintenance of chromosome (SMC) proteins (e.g., cohesin or condensin) extrude chromatin until blocked by two CTCF proteins bound at convergent CTCF motif sites to form loops. Yet, it is not clear how and when CTCF proteins can prevent SMC proteins from extruding, and how SMC proteins can translocate along the chromatin at the rapid speeds observed in experiments [7,12,13].…”