Large-Scale Functional Organization of Long-Range Chromatin Interaction Networks

Kuljeet Singh Sandhu, Guoliang Li, Huay Mei Poh, Yu Ling Kelly Quek, Yee Yen Sia, Su Qin Peh, Fabianus Hendriyan Mulawadi, Joanne Lim, Mile Sikic, Francesca Menghi, Anbupalam Thalamuthu, Wing Kin Sung, Xiaoan Ruan, Melissa Jane Fullwood, Edison Liu, Peter Csermely, Yijun Ruan

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Abstract

Chromatin interactions play important roles in transcription regulation. To better understand the underlying evolutionary and functional constraints of these interactions, we implemented a systems approach to examine RNA polymerase-II-associated chromatin interactions in human cells. We found that 40% of the total genomic elements involved in chromatin interactions converged to a giant, scale-free-like, hierarchical network organized into chromatin communities. The communities were enriched in specific functions and were syntenic through evolution. Disease-associated SNPs from genome-wide association studies were enriched among the nodes with fewer interactions, implying their selection against deleterious interactions by limiting the total number of interactions, a model that we further reconciled using somatic and germline cancer mutation data. The hubs lacked disease-associated SNPs, constituted a nonrandomly interconnected core of key cellular functions, and exhibited lethality in mouse mutants, supporting an evolutionary selection that favored the nonrandom spatial clustering of the least-evolving key genomic domains against random genetic or transcriptional errors in the genome. Altogether, our analyses reveal a systems-level evolutionary framework that shapes functionally compartmentalized and error-tolerant transcriptional regulation of human genome in three dimensions.

Original languageEnglish
Pages (from-to)1207-1219
Number of pages13
JournalCell Reports
Volume2
Issue number5
DOIs
Publication statusPublished - Nov 29 2012

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Sandhu, K. S., Li, G., Poh, H. M., Quek, Y. L. K., Sia, Y. Y., Peh, S. Q., Mulawadi, F. H., Lim, J., Sikic, M., Menghi, F., Thalamuthu, A., Sung, W. K., Ruan, X., Fullwood, M. J., Liu, E., Csermely, P., & Ruan, Y. (2012). Large-Scale Functional Organization of Long-Range Chromatin Interaction Networks. Cell Reports, 2(5), 1207-1219. https://doi.org/10.1016/j.celrep.2012.09.022