title: Formation of Chromosomal Domains by Loop Extrusion.
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.
authors.affiliation: 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.
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Fudenberg
authors.affiliation: Department of Physics, Massachusetts Institute of Technology (MIT), Cambridge, MA 02139, USA.
authors.forename: Maxim
authors.initials: M
authors.lastname: Imakaev
authors.affiliation: Program for Research in Mathematics, Engineering and Science for High School Students (PRIMES) and Undergraduate Research Opportunities Program (UROP), MIT, Cambridge, MA 02139, USA.
authors.forename: Carolyn
authors.initials: C
authors.lastname: Lu
authors.affiliation: Department of Physics, Massachusetts Institute of Technology (MIT), Cambridge, MA 02139, USA.
authors.forename: Anton
authors.initials: A
authors.lastname: Goloborodko
authors.affiliation: PhD Program in Computational and Systems Biology, MIT, Cambridge, MA 02139, USA.
authors.forename: Nezar
authors.initials: N
authors.lastname: Abdennur
authors.affiliation: 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.
authors.forename: Leonid A
authors.initials: LA
authors.lastname: Mirny
mesh_terms: D000076246:CCCTC-Binding Factor / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism; D002875:Chromosomes / Q000737:chemistry*; D038101:Insulator Elements / Q000235:genetics; D008958:Models, Molecular; D009690:Nucleic Acid Conformation; D017384:Sequence Deletion; D000097722:Cohesins
chemical_list: D000076246:CCCTC-Binding Factor; D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; D000097722:Cohesins