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3DGenomics
Marc A. Marti-Renom
Structural Genomics Group CNAG-CRG
3DGenomics Marc A. Marti-Renom Structural Genomics Group CNAG-CRG - - PowerPoint PPT Presentation
3DGenomics Marc A. Marti-Renom Structural Genomics Group CNAG-CRG - - PowerPoint PPT Presentation
3DGenomics Marc A. Marti-Renom Structural Genomics Group CNAG-CRG Structural Genomics Group http://www.marciuslab.org Integrative Modeling Platform http://www.integrativemodeling.org Experiments Computations Physics Evolution f()
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Structural Genomics Group
http://www.marciuslab.org
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f(·)
Experiments Computations Physics Evolution
Integrative Modeling Platform
http://www.integrativemodeling.org
From: Russel, D. et al. PLOS Biology 10, e1001244 (2012).
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Data Integration
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Data Integration
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Data Integration
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Complex genome organization
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μ 10 10 10 Resolution s Time 10 10 10 10 10 10 10 10 μm Volume 10 10 10 10 10 DNA length nt 10 10 10 10
Knowledge
IDM INM
Resolution Gap
Marti-Renom, M. A. & Mirny, L. A. PLoS Comput Biol 7, e1002125 (2011)
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Level I: Radial genome organization
Takizawa, T., Meaburn, K. J. & Misteli, T. The meaning of gene positioning. Cell 135, 9–13 (2008).
β β
Chromosome size Gene density Expression
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Level II: Euchromatin vs heterochromatin
Electron microscopy
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Level III: Lamina-genome interactions
Adapted from Molecular Cell 38, 603-613, 2010
to neural/glial The poising’’ ), in promoters here and architec-
- ver-
large step
nuclear membrane nuclear lamina internal chromatin
(mostly active)
lamina-associated domains
(repressed)
Genes mRNA
AC
“Unlocking” gene Stemcell genes Cell-cycle gene Neuronal gene
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Level IV: Higher-order organization
A compartments 20 Mb 2 Mb B compartments Interaction preference TADs Compartments
Dekker, J., Marti-Renom, M. A. & Mirny, L. A. Exploring the three-dimensional organization of genomes: interpreting chromatin interaction data. Nat Rev Genet 14, 390–403 (2013).
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Level V: Chromatin loops
Gene Gene enhancers Gene activity
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Level V: Loop-extrusion as a driving force
Fudenberg, G., Imakaev, M., Lu, C., Goloborodko, A., Abdennur, N., & Mirny, L. A. (2015). Formation of Chromosomal Domains by Loop Extrusion. bioRxiv.
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Level VI: Nucleosome
Chromosome Chromatin fibre Nucleosome
Adapted from Richard E. Ballermann, 2012
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Complex genome organization
Cavalli, G. & Misteli, T. Functional implications of genome topology. Nat Struct Mol Biol 20, 290–299 (2013).
DNA Chromatin domains Superdomains Chromosome territories Lamina Transcription hub Centromere cluster Nuclear pore Inactive Active Non- coding Nucleus Marina Corral
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Modeling Genomes
Marti-Renom, M. A. & Mirny, L. A. PLoS Comput Biol 7, e1002125 (2011)
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Experiments Computation
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Biomolecular structure determination 2D-NOESY data Chromosome structure determination 5C data
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Chromosome Conformation Capture
Chromatin-associated factors GeneBiotin dCTP fill in Endonuclease digestion
Protein ProteinSonication Immunoprecipitation Immunoprecipitation biotinilated linkers Contact library PCR with specifjc primers PCR with universal primers Multiplexed amplification Digestion with four base cutter Ligation Inverse PCR Sonicate Pull down PCR with specifjc primers Mmel digestion Pull down
B B B B B B B B B B B B B B B B B B B BDETECTION LIGATION CUTTING CROSSLINK COMPUTATIONAL ANALYSIS REVERSE CROSSLINKS
3C 5C 4C Hi-C ChIP-loop ChIA-PET Principle Contacts between All against all4,18 All contacts with a All against all10 Contacts between All contacts associated
Hakim, O., & Misteli, T. (2012). SnapShot: Chromosome Confirmation Capture. Cell, 148(5), 1068–1068.e2.
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Modeling 3D Genomes
Baù, D. & Marti-Renom, M. A. Methods 58, 300–306 (2012).
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