title: Large-scale functional organization of long-range chromatin interaction networks.
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.
authors.affiliation: Genome Institute of Singapore, 60 Biopolis Street, Singapore 138672. sandhuks@iisermohali.ac.in
authors.forename: Kuljeet Singh
authors.initials: KS
authors.lastname: Sandhu
authors.forename: Guoliang
authors.initials: G
authors.lastname: Li
authors.forename: Huay Mei
authors.initials: HM
authors.lastname: Poh
authors.forename: Yu Ling Kelly
authors.initials: YL
authors.lastname: Quek
authors.forename: Yee Yen
authors.initials: YY
authors.lastname: Sia
authors.forename: Su Qin
authors.initials: SQ
authors.lastname: Peh
authors.forename: Fabianus Hendriyan
authors.initials: FH
authors.lastname: Mulawadi
authors.forename: Joanne
authors.initials: J
authors.lastname: Lim
authors.forename: Mile
authors.initials: M
authors.lastname: Sikic
authors.forename: Francesca
authors.initials: F
authors.lastname: Menghi
authors.forename: Anbupalam
authors.initials: A
authors.lastname: Thalamuthu
authors.forename: Wing Kin
authors.initials: WK
authors.lastname: Sung
authors.forename: Xiaoan
authors.initials: X
authors.lastname: Ruan
authors.forename: Melissa Jane
authors.initials: MJ
authors.lastname: Fullwood
authors.forename: Edison
authors.initials: E
authors.lastname: Liu
authors.forename: Peter
authors.initials: P
authors.lastname: Csermely
authors.forename: Yijun
authors.initials: Y
authors.lastname: Ruan
mesh_terms: D000818:Animals; D005075:Biological Evolution; D002843:Chromatin / Q000378:metabolism*; D053263:Gene Regulatory Networks; D016678:Genome; D015894:Genome, Human; D055106:Genome-Wide Association Study; D006801:Humans; D020014:K562 Cells; D061986:MCF-7 Cells; D051379:Mice; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D012319:RNA Polymerase II / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D002843:Chromatin; D012319:RNA Polymerase II