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Albany 2013: Book of Abstracts

category image Albany 2013
Conversation 18
June 11-15 2013
©Adenine Press (2012)

2D to 3D: Interaction Frequency Maps to Chromatin Higher-Order Folded Conformations

Chromatin is a fiber of histone proteins and DNA present in the nuclei of eukaryotic cells. The higher-order folding of chromatin into chromosomes, which affects various genomic processes ranging from transcription to recombination, has so far remained elusive. Recently, sophisticated experimental techniques, known as chromosome conformation capture, have been developed to measure the frequencies of interaction between different DNA segments within and across chromosomes (Dekker et al., 2002; Lieberman-Aiden et al., 2009). Such interaction frequencies (IFs) can in principle be used to deduce higher-order folding of the chromatin fiber, though this is a highly challenging computational problem. Here, we present novel computational approach to recover the ensemble of chromatin conformations consistent with a set of given IF measurements (Meluzzi & Arya, 2012). Our approach comprises three modules. A model builder builds a restrained bead-chain model of the examined chromosomal domain, capturing both the physical properties of the chromatin fiber and the looping interactions. An ensemble generator performs a dynamical simulation of the restrained bead-chain to determine its conformational ensemble and to compute the IFs between all chromatin segments. An adaptive refiner uses a learning algorithm to iteratively refine the strengths of the imposed restraints until a match between the computed and input IF map is achieved. Our approach thus offers multiple advantages over existing alternatives: use of physical models of chromatin; avoidance of preconceived relationships between IFs and spatial distances; prediction of ensembles rather than unique structures; and intrinsic validation of the computed ensemble based on IF. The above approach has been validated against multiple simulated test systems, and we are currently refining the approach against known experimental IF and spatial distance measurements. We expect the final, refined approach to become a valuable tool for researchers examining the higher order organization of chromatin.

This research has been supported by an American Cancer Society Instructional Research Grant 70-002 provided to G.A. through the Moores Cancer Center, University of California, San Diego.

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References

    J. Dekker, K. Rippe, M. Dekker & Kleckner. N. (2002). Capturing chromosome conformation. Science 295, 1306-1311.

    E. Lieberman-Aiden et al. (2009) Comprehensive mapping of long-range interactions reveals folding principles of the human genome. Science 326, 289-293.

    D. Meluzzi & Arya. G. (2012). Recovering ensembles of chromatin conformations from contact frequencies. Nucleic Acids Res. In press (doi:10.1093/nar/gks1029).

Dario Meluzzi
Gaurav Arya

Department of NanoEngineering
University of California, San Diego
La Jolla, CA 92093

Phone: (858) 822-5542
Fax: (858) 534-9553
garya@ucsd.edu