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Exploring the three-dimensional organization of genomes: interpreting chromatin interaction data

Subjects

Key Points

  • Mining increasingly comprehensive chromatin interaction maps for chromosomal domains and complete genomes requires novel computational methods and modelling tools.

  • Looping interactions between specific genomic elements — for example, gene promoters and regulatory elements — can be identified from chromatin interaction data by detecting interaction frequencies that are significantly higher than empirically estimated background levels. Looping interactions appear to be very abundant: most promoters interact with several other genomic elements.

  • Statistical analysis of Hi-C data identifies multiple scales of domain organization: larger (1–10 Mb) chromosomal compartments and smaller (<1 Mb) topologically associating domains.

  • Restraint-based modelling provides experiment-based models of genomes and genomic domains. Such models can be used as a starting point for targeted structure–function analyses.

  • Polymer simulations provide insights into the global chromatin organization that are consistent with statistical features of the interaction data, suggesting physical principles of chromatin folding.

Abstract

How DNA is organized in three dimensions inside the cell nucleus and how this affects the ways in which cells access, read and interpret genetic information are among the longest standing questions in cell biology. Using newly developed molecular, genomic and computational approaches based on the chromosome conformation capture technology (such as 3C, 4C, 5C and Hi-C), the spatial organization of genomes is being explored at unprecedented resolution. Interpreting the increasingly large chromatin interaction data sets is now posing novel challenges. Here we describe several types of statistical and computational approaches that have recently been developed to analyse chromatin interaction data.

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Figure 1: Examples of 3C, 4C, 5C and Hi-C data sets.
Figure 2: Processes leading to close spatial proximity of loci.
Figure 3: Chromatin looping interactions and topologically associating domains.
Figure 4: Three-dimensional modelling of genomes and genomic domains.
Figure 5: Large-scale features of genome folding.

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Acknowledgements

We are grateful to all the members of our groups for many discussions about three-dimensional genomics. Supported by grants from the US National Institutes of Health (NIH), US National Human Genome Research Institute (HG003143 and HG003143-06S1) and a W.M. Keck Foundation distinguished young scholar in medical research grant to J.D.; financial support from the Spanish Ministerio de Ciencia e Innovación (BFU2010-19310/BMC), the Human Frontiers Science Program (RGP0044/2011) and the BLUEPRINT project (EU FP7 grant agreement 282510) to M.A.M.-R.; and a grant from the NIH National Cancer Institute (Physical Sciences–Oncology Center at Massachusetts Institutes of Technology Grant U54CA143874) to L.A.M.

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Glossary

Restraint-based modelling

A computational method to model the three-dimensional structure of an object represented by points and restraints between them.

Chromosome territories

Each territory is the domain of a nucleus occupied by a chromosome.

Polycomb bodies

Discrete nuclear foci containing Polycomb proteins and their silenced target genes. Polycomb bodies have been observed in Drosophila melanogaster and human cells by imaging and in situ hybridization.

Nuclear lamina

A scaffold of lamin proteins predominantly found in the nuclear periphery associated with the inner surface of the nuclear membrane.

Transcription factory

A nuclear compartments in which active transcription takes place; it has a high concentration of RNA polymerase II.

Constraints

Forces (or scoring functions) that restrict the movement of objects (or points) that they apply to. Often used synonymously with 'restraint'.

Locus control region

(LCR). A cis-acting element that organizes a gene cluster into an active chromatin domain and enhances transcription in a tissue-specific manner.

CTCF

A highly conserved zinc finger protein that influences chromatin organization and architecture and is implicated in diverse regulatory functions, including transcriptional activation, repression and insulation.

X-chromosome inactivation centre

A genetically defined locus of several megabases on the X chromosome of mammals that is required to initiate transcriptional repression along a single X chromosome in female cells.

Boundary elements

DNA elements that lie between two gene-controlling elements, such as a promoter and an enhancer, or between two large chromosomal domains, preventing their communication or interaction. The function of boundary elements is usually mediated by the binding of specific factors.

Restraints

Forces (or scoring functions) that maintain the objects (or points) to which they apply at their position of equilibrium.

Rabl configuration

A pattern of nuclear organization in which centromeres of all chromosomes are spatially clustered and their arms run in parallel. This organization has been proposed to be a passive consequence of chromosome segregation but can also be actively maintained by mechanisms that cluster centromeres.

Fractal globule

A dense, non-equilibrium polymer state, which emerges as a result of a polymer condensation. In this state, the polymer is unknotted and each region of the chain is locally compact, allowing easy opening and closing of chromosomal regions.

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Dekker, J., Marti-Renom, M. & Mirny, L. Exploring the three-dimensional organization of genomes: interpreting chromatin interaction data. Nat Rev Genet 14, 390–403 (2013). https://doi.org/10.1038/nrg3454

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