Abstract
BackgroundLong-range interactions between regulatory DNA elements such as enhancers, insulators and promoters play an important role in regulating transcription. As chromatin contacts have been found throughout the human genome and in different cell types, spatial transcriptional control is now viewed as a general mechanism of gene expression regulation. Chromosome Conformation Capture Carbon Copy (5C) and its variant Hi-C are techniques used to measure the interaction frequency (IF) between specific regions of the genome. Our goal is to use the IF data generated by these experiments to computationally model and analyze three-dimensional chromatin organization.ResultsWe formulate a probabilistic model linking 5C/Hi-C data to physical distances and describe a Markov chain Monte Carlo (MCMC) approach called MCMC5C to generate a representative sample from the posterior distribution over structures from IF data. Structures produced from parallel MCMC runs on the same dataset demonstrate that our MCMC method mixes quickly and is able to sample from the posterior distribution of structures and find subclasses of structures. Structural properties (base looping, condensation, and local density) were defined and their distribution measured across the ensembles of structures generated. We applied these methods to a biological model of human myelomonocyte cellular differentiation and identified distinct chromatin conformation signatures (CCSs) corresponding to each of the cellular states. We also demonstrate the ability of our method to run on Hi-C data and produce a model of human chromosome 14 at 1Mb resolution that is consistent with previously observed structural properties as measured by 3D-FISH.ConclusionsWe believe that tools like MCMC5C are essential for the reliable analysis of data from the 3C-derived techniques such as 5C and Hi-C. By integrating complex, high-dimensional and noisy datasets into an easy to interpret ensemble of three-dimensional conformations, MCMC5C allows researchers to reliably interpret the result of their assay and contrast conformations under different conditions.Availabilityhttp://Dostielab.biochem.mcgill.ca
Highlights
Long-range interactions between regulatory DNA elements such as enhancers, insulators and promoters play an important role in regulating transcription
MCMC5C was able to sample structures from the posterior distribution defined by the interaction frequency data by recovering structures that closely match the gold standard from which the simulated interaction frequency dataset was generated.These results suggest that the sampling approach succeeds at finding the correct structure, at least under the assumption that the IF data is generated from the pairwise distances using our model
The role of high-level chromatin conformation in regulating gene expression is well accepted, only a few loci have been studied in detail [17,20,53,54,55]
Summary
Long-range interactions between regulatory DNA elements such as enhancers, insulators and promoters play an important role in regulating transcription. The paternal ICR is methylated and cannot be bound by CTCF, allowing the Igf gene and its enhancer sequence to interact through a long-range loop, thereby regulating expression to only the paternal allele [13,14,15,16]. Such long-range interactions have been found throughout metazoan genomes where far many of them appear to correlate well with the transcriptional state of target genes [6,17,18,19,20]. Mapping of physical contacts within (cis) and between (trans) chromosomes will be essential to fully understand gene regulation
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