Large-scale functional organization of long-range chromatin interaction networks.
Cell Rep 2012 Nov 29; 2(5):1207-19.
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.
Sandhu, Kuljeet Singh; Li, Guoliang; Poh, Huay Mei; Quek, Yu Ling Kelly; Sia, Yee Yen; Peh, Su Qin; Mulawadi, Fabianus Hendriyan; Lim, Joanne; Sikic, Mile; Menghi, Francesca; Thalamuthu, Anbupalam; Sung, Wing Kin; Ruan, Xiaoan; Fullwood, Melissa Jane; Liu, Edison T.; Csermely, Peter; and Ruan, Yijun, "Large-scale functional organization of long-range chromatin interaction networks." (2012). Faculty Research 2012. 212.