in interphase from loop extrusion emergent chromosome organization krishna suraj · 2016-05-24 ·...
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Emergent chromosome organization in interphase from loop extrusion
Krishna Suraj
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Overview
Part 1: Background
Part 2: Components of a polymer model
2.1: One-dimensional LEF dynamics
2.2: Three-dimensional molecular dynamics
Part 3: Future directions
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How are loops and domains formed?2009 2012 2015
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De Novo Polymer Modelling
Image credits: Fudenberg, 2016
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De Novo Polymer Modelling
Image credits: Fudenberg, 2016
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Interphase extrusion polymer model
1-D LEF Dynamics
● Behavior of LEFs on the chromatin fiber provides model-specific forces for 3-D simulations
Fudenberg & Imakev et al., 2015
3-D Molecular Dynamics
● Physical forces between DNA monomers (repulsion, springs) dictate structure plus model-specific constraints
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SMCs as loop-extruding proteins
Alipour, Elnaz, and John F. Marko. "Self-organization of domain structures by DNA-loop-extruding enzymes." Nucleic acids research 40.22 (2012): 11202-11212.
Goloborodko et al, 2016
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Dynamics of LEFs
Goloborodko 2015 & Fudenberg & Imakev, 2015
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Spontaneous LEF dissociation
0.1
0.01
Dissociation probability
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LEF equilibration
More LEF dynamics
100 evenly spaced LEFS
100 randomly placed LEFS
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3-D molecular dynamics basics
● Numerical integration: calculating velocity and position of particles from one (very small) timestep to another
● Keep track of directional forces● Stochastic forces - small, random forces in any direction (implicit solvent)
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Forces that affect polymers
1. Harmonic bonds
2. Steric repulsion
3. Bending energy
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Molecular dynamics simulations
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Boundary Elements
● Translocation-interfering molecules/proteins
● Can be directional
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Future directions
-Complications to the interphase model:
-Would RNA transcription or DNA replication interfere with SMCs on the chromatin fiber?
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Thinking biologically about interphase events...
www.mun.ca
en.wikipedia.org
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Interference during transcription or replication
RNA polymerase/helicase/DNA polymerase
Biological processes during interphase could interfere with SMCs - possibly causing them to dissociate
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Acknowledgements
● Special thanks to my mentor, Dr. Geoffrey Fudenberg● Professor Leonid Mirny and the rest of the Mirny Lab● My parents and family● MIT PRIMES program