analysis of higher order chromatin structure
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Current Topics of Genomics and Epigenomics. Analysis of Higher Order Chromatin Structure. Outline . Motivation for analysis of higher order chromatin structure Methods for studying long range chromatin interactions Topological domains Functional implications of topological domains - PowerPoint PPT PresentationTRANSCRIPT
Analysis of Higher Order Chromatin Structure
Current Topics of Genomics and Epigenomics
Outline Motivation for analysis of higher order
chromatin structure Methods for studying long range
chromatin interactions Topological domains Functional implications of topological
domains Break for 5’ Paper discussion
Chromosome conformation capture carbon copy (5C)
Dostie et al., 2006
Chromosome conformation capture carbon copy (5C)
Dostie et al., 2006
Identification of long range chromatin interaction in the human cells by 5C
Sanyal et al. Nature 2012 (DOI:10.1038/nature11279)
Network of long range chromatin interaction at promoters
Sanyal et al. Nature 2012 (DOI:10.1038/nature11279)
Network of long range chromatin interaction at promoters 50% of TSSs display one or more long-
range interaction, with some interacting with as many as 20 distal fragments.
Expressed TSSs interact with slightly more fragments as compared to non-expressed TSSs
Out of all distal fragments interrogated, 10% interacted with one or more TSS, with some interacting with more than 10.
gene–element interactions are not exclusively one-to-one, and multiple genes and distal elements can assemble in larger clusters
Sanyal et al. Nature 2012 (DOI:10.1038/nature11279)
Hi-C for genome-wide analysis of higher order chromatin structure
Lieberman-Aiden et al., 2009
Hi-C for genome-wide analysis of higher order chromatin structure
Hi-C vs. FISH
Mouse ES cells (from 433 Million Reads) Dixon et al., Nature, 2012
The genome is composed of megabase sized topological domains
Hi-C data reveals strong local chromatin interaction domains
Dixon et al. Nature 2012
The genome is composed of megabase sized topological domains
Topological Domains in Mouse ES cells
N = 2200
Properties of the topological domains Topological domains are stable between different cell
types.
hESC
IMR90
Dixon et al. Nature 2012
Properties of the topological domains Topological domains are stable between different cell
types. Topological domains are conserved between species
Dixon et al. Nature 2012
Observations Hi-C analysis reveals that the mammalian genome
consists of mega-base sized topological domains (also known as TADs).
Topological domains are stable across cell types and largely preserved during evolution, suggesting that they are a basic property of the chromosome architecture.
Higher order structure of the topological domains
Lieberman-Aiden et al., 2009
Compartment A
Compartment B
Topological Domains vs. Compartment A & B
Replication Timing Data
3-D model of a chromosome
Structure model of the mouse Chr 2 is reconstructed using Bayesian inference approach
This chromosome appears to take a helical configuration
Topological domains in compartment A and B are located on different side of the chromosomal structure Red: compartment A domains Blue: compartment B domains
Hu et al., PLoS Comp Bio. 2013
3-D model of a chromosome
Heterochromatin and euchromatin are located on different faces of the chromosomal structure (Red: H3K9m3 enriched domains; Blue: H3K9me3 depleted domains)
Hu et al., PLoS Comp Bio. 2013
3-D model of a chromosome
Lamina B binding sites are clustered on one face of the chromosomal helical structure
Red: enriched for Lamina B binding sites
Blue: depleted for Lamina B binding
Hu et al., PLoS Comp Bio. 2013
3-D model of a chromosome
Transcriptionally active domains are located on one face of the chromosomal helical structure
Red: enriched for RNA polymerase II binding sites
Blue: depleted for RNA polymerase II binding sites
Hu et al., PLoS Comp Bio. 2013
Functional implications of topological domains Prediction: Partitioning of the genome
into topological domains would naturally restrict the enhancers to selective promoters
Shh and its distal enhancer are located in the same topological domain
Enhancer
How do topological domains form?
The topological domain boundaries coincide with heterochromatin domain boundaries
Dixon et al. Nature 2012
What protein factors bind to the topological domain boundaries?
Kim et al. PNAS 2011
Not all CTCF binding sites are at the boundaries
Topological domain boundaries are also enriched for housekeeping genes
Further Reading Reviews
Giacomo Cavalli & Tom Misteli, “Functional implications of genome topology”, Nat Struct Mol Biol, 2013 vol. 20 (3) pp. 290-9
Michael Bulger, Mark Groudine, “Functional and Mechanistic Diversity of Distal Transcription Enhancers”, Cell, 144 (2011) 327-339. doi:10.1016/j.cell.2011.01.024
T Cremer, C Cremer, “Chromosome territories, nuclear architecture and gene regulation in mammalian cells”, Nat Rev Genet, 2001 vol. 2 (4) pp. 292-301
Tom Misteli, “Beyond the sequence: cellular organization of genome function”, Cell, 2007 vol. 128 (4) pp. 787-800
Elzo de Wit, Wouter de Laat, “A decade of 3C technologies: insights into nuclear organization”, Genes & Development, 2012 vol. 26 (1) pp. 11-24
Sjoerd Holwerda, Wouter de Laat, “Chromatin loops, gene positioning, and gene expression”, Front. Gene., 2012 vol. 3 pp. 1-13
ChIA-PET (chromatin interaction analysis by paired-end tags)
Fullwood … Ruan, Nature 2009 vol. 462 (7269) pp. 58-64