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Nucleic Acids Res. 2014 Feb;42(3):1524-40. doi: 10.1093/nar/gkt998. Epub 2013 Oct 29.

Hox in motion: tracking HoxA cluster conformation during differentiation.

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  • 1Department of Biochemistry and Goodman Cancer Research Center, McGill University, Montréal, Québec, H3G 1Y6, Canada and School of Computer Science and McGill Centre for Bioinformatics, McGill University, Montréal, Québec, H3A 0E9, Canada.


Three-dimensional genome organization is an important higher order transcription regulation mechanism that can be studied with the chromosome conformation capture techniques. Here, we combined chromatin organization analysis by chromosome conformation capture-carbon copy, computational modeling and epigenomics to achieve the first integrated view, through time, of a connection between chromatin state and its architecture. We used this approach to examine the chromatin dynamics of the HoxA cluster in a human myeloid leukemia cell line at various stages of differentiation. We found that cellular differentiation involves a transient activation of the 5'-end HoxA genes coinciding with a loss of contacts throughout the cluster, and by specific silencing at the 3'-end with H3K27 methylation. The 3D modeling of the data revealed an extensive reorganization of the cluster between the two previously reported topologically associated domains in differentiated cells. Our results support a model whereby silencing by polycomb group proteins and reconfiguration of CTCF interactions at a topologically associated domain boundary participate in changing the HoxA cluster topology, which compartmentalizes the genes following differentiation.

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