Emerging Evidence for Loop Extrusion

Geoffrey Fudenberg*, Nezar Abdennur*, Maxim Imakaev, Anton Goloborodko, Leonid Mirny

Cold Spring Harbor Symposia on Quantitative Biology: Chromosome Segregation & Structure, Volume 82. doi:10.1101/sqb.2017.82.034710

bioRxiv (Feb, 2018) doi:10.1101/264648

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.

HiGlass Displays

Experimental phenotypes are consistent with predictions from loop extrusion simulations.

Top row: unperturbed experimental Hi-C maps, replotted from indicated studies. Middle Row: Hi-C maps for indicated perturbations. Left column: ​Schwarzer et al. used tissue-specific CRE-inducible gene deletion in mouse liver cells to deplete Nipbl (Schwarzer et al. 2017). Middle column: ​ Nora et al. used an auxin-inducible degron system to deplete CTCF in mESCs (Nora et al. 2017). Right column: ​Haarhuis et al. deleted Wapl in the Hap1 haploid human cell line, via CRISPR (Haarhuis et al. 2017).

TAD Anatomy

Interphase Hi-C data from mouse ES and neural progenitor cells (Bonev et al. 2017) illustrating contact patterns that collectively describe mammalian TADs: including contact enrichment/insulation, "flames" (a.k.a. lines or tracks), peaks and peak grids. Note that there exist similar features — associated with genome compartmentalization — also visible as squares along the diagonal of a Hi-C map, but differ in that they further extend into a checkered grid in cis and in trans. While these latter patterns overlap with and are very often conflated with TADs in the literature, they have been shown to arise from the action of a completely independent and competing biological mechanism from that which produces the features highlighted here.

More on the way!