Molecular simulations of DNA loop extrusion explain and predict - PowerPoint PPT Presentation

Molecular simulations of DNA loop extrusion explain and predict human genome architecture Adrian Sanborn Stanford University; The Center for Genome Architecture at Baylor College of Medicine, Rice University

FUNDAMENTAL PUZZLE: SAME GENOME à DIFFERENT FUNCTIONS

THE GENOME IS FULL OF “SPOOKY ACTION AT A DISTANCE”

THE HUMAN GENOME IS LONG 3 BILLION LETTERS 2 METERS …CGTTTACGAAAATCGCAAAACTTTCGATACCCATAGGCTACTGATCATACGACCGTTTACGAAAATCGAAACCTTTCCGATCTAGGCTAC… Nucleus Cell 6 μm

100 Mb 10 Mb 1 Mb 100 Kb 10 Kb 1 Kb 100 bp 10 bp

HOW DOES THE GENOME FOLD? 1. Experimental Technology 2. Biology 3. Physics

PART I:   EXPERIMENTAL TECHNOLOGY

MICROSCOPY & FLUORESCENT IN SITU HYBRIDIZATION   FISH

HI-C MEASURES SPATIAL PROXIMITY OF THE FOLDED GENOME Lieberman-Aiden, van Berkum et al. Science 2009

CONTACT MAPPING Exploring structure via proximity

SIMPSONS   CONTACT MAP # of Pictures Together

HI-C MEASURES SPATIAL PROXIMITY OF THE FOLDED GENOME Lieberman-Aiden, van Berkum et al. Science 2009

Hi-C   GENERATES GENOME- WIDE CONTACT MAPS

Hi-C   GENERATES GENOME- Chromosome WIDE CONTACT MAPS

Genome Hi-C   GENERATES GENOME- WIDE CONTACT MAPS

Hi-C   GENERATES GENOME- WIDE CONTACT MAPS

Chromosome 8 Hi-C   GENERATES GENOME- WIDE CONTACT MAPS 0 700 Reads/250 kb 2

Hi-C   GENERATES GENOME- WIDE CONTACT MAPS 0 700 Reads/250 kb 2

A Hi-C   GENERATES GENOME- A WIDE CONTACT MAPS 0 700 Reads/250 kb 2

A B Hi-C   GENERATES GENOME- A WIDE CONTACT MAPS B 0 700 Reads/250 kb 2

NEW CONTACT MAPS ARE AT KILOBASE RESOLUTION 30 million contacts

NEW CONTACT MAPS ARE AT KILOBASE RESOLUTION 30 million contacts 5 billion contacts Rao & Huntley, et al., Cell 2014

PART II:   BIOLOGY Mary Ellen Scherl

LOOPS IN CHROMATIN = PEAKS IN A CONTACT MAP A+2 ε B-2 ε A+ ε B- ε A B B+2 ε A-2 ε A- ε B+ ε

THE GENOME HAS ~10,000 LOOPS. Rao & Huntley, et al., Cell 2014

LOOPS ARE OFTEN CONSERVED ACROSS CELL TYPE…

LOOPS ARE OFTEN CONSERVED ACROSS CELL TYPE… Rao & Huntley, et al., Cell 2014

…AND SPECIES.

…AND SPECIES. Rao & Huntley, et al., Cell 2014

LOOPS TURN GENES ON AND OFF .

LOOPS TURN GENES ON AND OFF . Rao & Huntley, et al., Cell 2014

LOOPS TURN GENES ON AND OFF .

LOOPS TURN GENES ON AND OFF . Rao & Huntley, et al., Cell 2014

LOOPS DEMARCATE CONTACT DOMAINS… Rao & Huntley, et al., Cell 2014

…WHICH PARTITION THE GENOME

…WHICH PARTITION THE GENOME Rao & Huntley, et al., Cell 2014

HOW DO LOOPS AND DOMAINS FORM?

PART III:   PHYSICS

CONTACT PROBABILITY AS A FUNCTION OF GENOMIC DISTANCE

FOLDED DNA IS NOT AT EQUILIBRIUM Erez Lieberman-Aiden, Nynke van Berkum et al. Science 2009

Sanborn & Rao, et al., PNAS, 2015

CONTACT PROBABILITY EXPONENT WITHIN DOMAINS IS -0.75 Sanborn & Rao, et al., PNAS, 2015

INTERNAL VERSUS EXTERNAL FORCES Sanborn & Rao, et al., PNAS, 2015

INTERNAL FORCES à LINEAR COLLAPSE Sanborn & Rao, et al., PNAS, 2015

TENSION GLOBULE RECAPITULATES OBSERVED CONTACT PROBABILITY Hi-C Tension globule Sanborn & Rao, et al., PNAS, 2015

INTERNAL FORCES ARE COMPUTATIONALLY INTENSIVE

INTERNAL FORCES ARE COMPUTATIONALLY INTENSIVE Polymer backbone Lennard-Jones forces Simulate Langevin dynamics using LAMMPS package

INTERNAL FORCES ARE COMPUTATIONALLY INTENSIVE • Simulations up to 50,000 beads (50 megabases) • Forces must be calculated between all pairs of beads • Hundreds of replicate structures must be simulated • GPU parallelization à ~10x speed-up

LOOPS AND DOMAINS FORM WITHIN TENSION GLOBULES

LOOPS ARE ANCHORED AT CONVERGENT CTCF SITES

LOOPS ARE ANCHORED AT CONVERGENT CTCF SITES Rao & Huntley, et al., Cell 2014

LOOP FORMATION BY DIFFUSION Sanborn & Rao, et al., PNAS, 2015

DIFFUSION DOES NOT EXPLAIN CONVERGENT RULE Sanborn & Rao, et al., PNAS, 2015

DIFFUSION DOES NOT EXPLAIN WHY LOOPS TEND NOT TO OVERLAP Sanborn & Rao, et al., PNAS, 2015

DIFFUSION DOES NOT EXPLAIN LACK OF FOCAL CONTACTS BETWEEN CHROMOSOMES Sanborn & Rao, et al., PNAS, 2015

DIFFUSION LEADS TO ENTANGLEMENT Sanborn & Rao, et al., PNAS, 2015

LOOPS AND DOMAINS FORM VIA EXTRUSION Najeeb Tarazi, Adrian Sanborn

LOOPS AND DOMAINS FORM VIA EXTRUSION Sanborn, Rao et al., PNAS 2015

EXTRUSION EXPLAINS MANY KEY OBSERVATIONS Sanborn, Rao et al., PNAS 2015

EXTRUSION EXPLAINS MANY KEY OBSERVATIONS Loops at convergent CTCF sites Sanborn, Rao et al., PNAS 2015

EXTRUSION EXPLAINS MANY KEY OBSERVATIONS Loops at convergent CTCF sites Loops don’t overlap Sanborn, Rao et al., PNAS 2015

EXTRUSION EXPLAINS MANY KEY OBSERVATIONS Loops at convergent CTCF sites Loops don’t overlap Loops are intrachromosomal Sanborn, Rao et al., PNAS 2015

EQUATIONS FOR SIMULATING EXTRUSION Polymer backbone Lennard-Jones forces Loop bonds

A DAY IN THE LIFE OF AN EXTRUSION COMPLEX Najeeb Tarazi, Adrian Sanborn

LOOP EXTRUSION FORMS   SPATIALLY SEGREGATED DOMAINS Najeeb Tarazi, Adrian Sanborn

Molecular simulations of DNA loop extrusion explain and predict - PowerPoint PPT Presentation

Molecular simulations of DNA loop extrusion explain and predict human genome architecture Adrian Sanborn Stanford University; The Center for Genome Architecture at Baylor College of Medicine, Rice University FUNDAMENTAL PUZZLE: SAME GENOME

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