Cell Reports (2012-11-01)

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

DOI
https://doi.org/10.1016/j.celrep.2012.09.022
Journal volume & issue
Vol. 2, no. 5
pp. 1207 – 1219

Abstract

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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.