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

C2H2 zinc finger proteins greatly expand the human regulatory lexicon.

Author information

1
Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario, Canada.
2
Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
3
1] Center for Autoimmune Genomics and Etiology (CAGE) and Divisions of Biomedical Informatics and Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA. [2] Canadian Institutes for Advanced Research, Toronto, Ontario, Canada.
4
1] Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario, Canada. [2] Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada. [3] Department of Computer Science, University of Toronto, Toronto, Ontario, Canada.
5
1] Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario, Canada. [2] Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
6
1] Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario, Canada. [2] Canadian Institutes for Advanced Research, Toronto, Ontario, Canada. [3] Department of Computer Science, University of Toronto, Toronto, Ontario, Canada. [4] Department of Electrical and Computer Engineering, University of Toronto, Toronto, Ontario, Canada.
7
1] Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario, Canada. [2] Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada. [3] Canadian Institutes for Advanced Research, Toronto, Ontario, Canada.

Abstract

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.

PMID:
25690854
DOI:
10.1038/nbt.3128
[Indexed for MEDLINE]

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