C2H2 zinc finger proteins greatly expand the human regulatory lexicon

Nat Biotechnol. 2015 May;33(5):555-62. doi: 10.1038/nbt.3128. Epub 2015 Feb 18.


Cys2-His2 zinc finger (C2H2-ZF) proteins represent the largest class of putative human transcription factors. However, for most C2H2-ZF proteins it is unknown whether they even bind DNA or, if they do, to which sequences. Here, by combining data from a modified bacterial one-hybrid system with protein-binding microarray and chromatin immunoprecipitation analyses, we show that natural C2H2-ZFs encoded in the human genome bind DNA both in vitro and in vivo, and we infer the DNA recognition code using DNA-binding data for thousands of natural C2H2-ZF domains. In vivo binding data are generally consistent with our recognition code and indicate that C2H2-ZF proteins recognize more motifs than all other human transcription factors combined. We provide direct evidence that most KRAB-containing C2H2-ZF proteins bind specific endogenous retroelements (EREs), ranging from currently active to ancient families. The majority of C2H2-ZF proteins, including KRAB proteins, also show widespread binding to regulatory regions, indicating that the human genome contains an extensive and largely unstudied adaptive C2H2-ZF regulatory network that targets a diverse range of genes and pathways.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Chromatin / metabolism
  • DNA-Binding Proteins / genetics
  • Gene Expression Regulation
  • Genome, Human*
  • Humans
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Protein Binding
  • Regulatory Sequences, Nucleic Acid
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism*
  • Retroelements / genetics*


  • BCL11A protein, human
  • Carrier Proteins
  • Chromatin
  • DNA-Binding Proteins
  • Nuclear Proteins
  • Repressor Proteins
  • Retroelements
  • ZNF350 protein, human

Associated data

  • GEO/GSE52523