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Cell Rep. 2016 May 31;15(9):2038-49. doi: 10.1016/j.celrep.2016.04.085. Epub 2016 May 19.

Formation of Chromosomal Domains by Loop Extrusion.

Author information

1
Graduate Program in Biophysics, Harvard University, Cambridge, MA 01238, USA; Institute for Medical Engineering and Science, Massachusetts Institute of Technology (MIT), Cambridge, MA 02139, USA.
2
Department of Physics, Massachusetts Institute of Technology (MIT), Cambridge, MA 02139, USA.
3
Program for Research in Mathematics, Engineering and Science for High School Students (PRIMES) and Undergraduate Research Opportunities Program (UROP), MIT, Cambridge, MA 02139, USA.
4
PhD Program in Computational and Systems Biology, MIT, Cambridge, MA 02139, USA.
5
Graduate Program in Biophysics, Harvard University, Cambridge, MA 01238, USA; Institute for Medical Engineering and Science, Massachusetts Institute of Technology (MIT), Cambridge, MA 02139, USA; Department of Physics, Massachusetts Institute of Technology (MIT), Cambridge, MA 02139, USA. Electronic address: leonid@mit.edu.

Abstract

Topologically associating domains (TADs) are fundamental structural and functional building blocks of human interphase chromosomes, yet the mechanisms of TAD formation remain unclear. 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 produces TADs and finer-scale features of Hi-C data. Each TAD emerges from multiple loops dynamically formed through extrusion, contrary to typical illustrations of single static loops. Loop extrusion both 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 the depletion of CTCF versus cohesin. Finally, loop extrusion has potentially far-ranging consequences for processes such as enhancer-promoter interactions, orientation-specific chromosomal looping, and compaction of mitotic chromosomes.

PMID:
27210764
PMCID:
PMC4889513
DOI:
10.1016/j.celrep.2016.04.085
[Indexed for MEDLINE]
Free PMC Article

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