Large-scale functional organization of long-range chromatin interaction networks

Cell Rep. 2012 Nov 29;2(5):1207-19. doi: 10.1016/j.celrep.2012.09.022. Epub 2012 Oct 25.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biological Evolution
  • Chromatin / metabolism*
  • Gene Regulatory Networks
  • Genome
  • Genome, Human
  • Genome-Wide Association Study
  • Humans
  • K562 Cells
  • MCF-7 Cells
  • Mice
  • Polymorphism, Single Nucleotide
  • Promoter Regions, Genetic
  • RNA Polymerase II / metabolism
  • Transcription, Genetic

Substances

  • Chromatin
  • RNA Polymerase II