Architecture of the human regulatory network derived from ENCODE data

Nature. 2012 Sep 6;489(7414):91-100. doi: 10.1038/nature11245.


Transcription factors bind in a combinatorial fashion to specify the on-and-off states of genes; the ensemble of these binding events forms a regulatory network, constituting the wiring diagram for a cell. To examine the principles of the human transcriptional regulatory network, we determined the genomic binding information of 119 transcription-related factors in over 450 distinct experiments. We found the combinatorial, co-association of transcription factors to be highly context specific: distinct combinations of factors bind at specific genomic locations. In particular, there are significant differences in the binding proximal and distal to genes. We organized all the transcription factor binding into a hierarchy and integrated it with other genomic information (for example, microRNA regulation), forming a dense meta-network. Factors at different levels have different properties; for instance, top-level transcription factors more strongly influence expression and middle-level ones co-regulate targets to mitigate information-flow bottlenecks. Moreover, these co-regulations give rise to many enriched network motifs (for example, noise-buffering feed-forward loops). Finally, more connected network components are under stronger selection and exhibit a greater degree of allele-specific activity (that is, differential binding to the two parental alleles). The regulatory information obtained in this study will be crucial for interpreting personal genome sequences and understanding basic principles of human biology and disease.

Publication types

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

MeSH terms

  • Alleles
  • Cell Line
  • DNA / genetics*
  • Encyclopedias as Topic*
  • GATA1 Transcription Factor / metabolism
  • Gene Expression Profiling
  • Gene Regulatory Networks / genetics*
  • Genome, Human / genetics*
  • Genomics
  • Humans
  • K562 Cells
  • Molecular Sequence Annotation*
  • Organ Specificity
  • Phosphorylation / genetics
  • Polymorphism, Single Nucleotide / genetics
  • Protein Interaction Maps
  • RNA, Untranslated / genetics
  • RNA, Untranslated / metabolism
  • Regulatory Sequences, Nucleic Acid / genetics*
  • Selection, Genetic / genetics
  • Transcription Factors / metabolism*
  • Transcription Initiation Site


  • GATA1 Transcription Factor
  • RNA, Untranslated
  • Transcription Factors
  • DNA