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Predictive polymer modeling reveals coupled fluctuations in chromosome conformation and transcription.

ABSTRACT: A new level of chromosome organization, topologically associating domains (TADs), was recently uncovered by chromosome conformation capture (3C) techniques. To explore TAD structure and function, we developed a polymer model that can extract the full repertoire of chromatin conformations within TADs from population-based 3C data. This model predicts actual physical distances and to what extent chromosomal contacts vary between cells. It also identifies interactions within single TADs that stabilize boundaries between TADs and allows us to identify and genetically validate key structural elements within TADs. Combining the model's predictions with high-resolution DNA FISH and quantitative RNA FISH for TADs within the X-inactivation center (Xic), we dissect the relationship between transcription and spatial proximity to cis-regulatory elements. We demonstrate that contacts between potential regulatory elements occur in the context of fluctuating structures rather than stable loops and propose that such fluctuations may contribute to asymmetric expression in the Xic during X inactivation.

SUBMITTER: Giorgetti L

PROVIDER: S-EPMC4427251 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

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Predictive polymer modeling reveals coupled fluctuations in chromosome conformation and transcription.

Giorgetti Luca L Galupa Rafael R Nora Elphège P EP Piolot Tristan T Lam France F Dekker Job J Tiana Guido G Heard Edith E

Cell 20140501 4

A new level of chromosome organization, topologically associating domains (TADs), was recently uncovered by chromosome conformation capture (3C) techniques. To explore TAD structure and function, we developed a polymer model that can extract the full repertoire of chromatin conformations within TADs from population-based 3C data. This model predicts actual physical distances and to what extent chromosomal contacts vary between cells. It also identifies interactions within single TADs that stabil ...[more]

PMID: 24813616

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Project description:Chromosome conformation capture experiments result in pairwise proximity measurements between chromosome locations in a genome, and they have been used to construct three-dimensional models of genomic regions, chromosomes, and entire genomes. These models can be used to understand long-range gene regulation, chromosome rearrangements, and the relationships between sequence and spatial location. However, it is unclear whether these pairwise distance constraints provide sufficient information to embed chromatin in three dimensions. A priori, it is possible that an infinite number of embeddings are consistent with the measurements due to a lack of constraints between some regions. It is therefore necessary to separate regions of the chromatin structure that are sufficiently constrained from regions with measurements that do not provide enough information to reconstruct the embedding.We present a new method based on graph rigidity to assess the suitability of experiments for constructing plausible three-dimensional models of chromatin structure. Underlying this analysis is a new, efficient, and accurate algorithm for finding sufficiently constrained (rigid) collections of constraints in three dimensions, a problem for which there is no known efficient algorithm. Applying the method to four recent chromosome conformation experiments, we find that, for even stringently filtered constraints, a large rigid component spans most of the measured region. Filtering highlights higher-confidence regions, and we find that the organization of these regions depends crucially on short-range interactions.Without performing an embedding or creating a frequency-to-distance mapping, our proposed approach establishes which substructures are supported by a sufficient framework of interactions. It also establishes that interactions from recent highly filtered genome-wide chromosome conformation experiments provide an adequate set of constraints for embedding. Pre-processing experimentally observed interactions with this method before relating chromatin structure to biological phenomena will ensure that hypothesized correlations are not driven by the arbitrary choice of a particular unconstrained embedding. The software for identifying rigid components is GPL-Licensed and available for download at http://cbcb.umd.edu/kingsford-group/starfish.

Dataset Information

Predictive polymer modeling reveals coupled fluctuations in chromosome conformation and transcription.

Publications

Predictive polymer modeling reveals coupled fluctuations in chromosome conformation and transcription.

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