Genome in 3D: models of chromosome folding
Monday, October 16, 2017 - 4:15pm
101 Icahn
Quantitative & Computational Biology

Abstract: DNA of the human genome is 2m long and is folded into chromosomes that fit in 10-micron cellular nucleus. How are these long polymers of DNA folded and organized in 3D inside the nucleus? How can proteins that are much smaller than chromosomes drive chromosome compaction, segregation or control functional interactions at much larger scales?

Recently developed experimental technique (Hi-C) provides comprehensive information about frequencies of spatial interactions between genomic loci. Inferring principles of 3D organization of chromosomes from these data is a challenging biophysical problem, rooted in statistical physics of polymers.

Our works suggest that chromosomes are organized by an active, energy-consuming, process. We proposed that active process of “loop extrusion” can be a universal mechanism responsible for formation of domains in interphase [1], and chromosome compaction and segregation in metaphase [2].  I will review recent experimental studies [3-6] that provide strong support to loop extrusion as a universal mechanism of chromosome folding.

1. Fudenberg G, Imakaev M, Lu C, Goloborodko A, Abdennur N, Mirny LA.

Formation of Chromosomal Domains by Loop Extrusion.

Cell Rep. 2016 May 31;15(9):2038-49

2. Goloborodko A, Imakaev MV, Marko JF, Mirny L.

Compaction and segregation of sister chromatids via active loop extrusion.

Elife. 2016 May 18;5.

3. Nora EP, Goloborodko A, Valton A-L , Gibcus J , Uebersohn A, Abdennur N , Dekker J , Mirny LA , Bruneau BG

Targeted degradation of CTCF decouples local insulation of chromosome domains from higher-order genomic compartmentalization

Cell May 18, 169:5 (2017)

4. Schwarzer W, Abdennur N, Goloborodko A, Pekowska A , Fudenberg G , Loe-Mie Y, Fonseca NA , Huber W , Haering C, Mirny LA, Spitz F Two independent modes of chromosome organization are revealed by cohesin removal

Nature Sept (2017)

5. Flyamer IM, Gassler J, Imakaev M, et al., Single-nucleus Hi-C reveals unique chromatin reorganization at oocyte-to-zygote transition,

Nature, 544(7648) (2017)

6. Gibcus J, Samejima K, Goloborodko A, et al., Mitotic chromosomes fold by condensin-dependent helical winding of chromatin loop arrays

Leonid Mirny

Mirny lab combines quantitative, typically physics-rooted, approaches with analysis of genomics data to address fundamental problems in biology, most recently we focused on two problems: (1) higher-order chromatin structure; (2) evolution of cancer during neoplastic progression. Our work on chromosomes aims to characterize 3D architecture of the genome and processes that lead to its organization and reorganization in the cell cycle and development. Prof. Mirny is actively involved in activities of the 4D Nucleome Consortium, were he co-directs (jointly with Prof. Job Dekker) Center for Structure and Physics of the Genome, is involved in the work of Data Coordination and Integration Center, and Publication Policy working group.  Work of the Mirny lab on cancer aims at understanding the role of multiple “passenger” genetic events, such as individual mutations and chromosomal alterations, in cancer progression. Mirny lab has a history of successful collaborations with several experimental labs.