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Title: Large-Scale Functional Organization of Long-Range Chromatin Interaction Networks
Authors: 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.
Issue Date: 2012
Citation: 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. ScholarBank@NUS Repository.
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. It is becoming increasingly clear that genes are not autonomous transcriptional units; instead, they physically interact with one another to coordinate transcriptional regulation. Using a network approach, Ruan and colleagues unravel an evolutionarily constrained systems organization of transcription-associated chromatin in the human genome. Their observations provide a possible chromatin-level explanation for how disease-associated mutations evolve and how key cellular genes escape genetic and transcriptional errors. © 2012 The Authors.
Source Title: Cell Reports
ISSN: 22111247
DOI: 10.1016/j.celrep.2012.09.022
Appears in Collections:Staff Publications

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