Multiparameter functional diversity of human C2H2 zinc finger proteins

  1. Timothy R. Hughes1,2
  1. 1Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario M5S 3E1, Canada;
  2. 2Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada;
  3. 3Department of Biosciences and Nutrition, Karolinska Institutet, SE 141 83, Sweden
  1. Corresponding authors: t.hughes{at}utoronto.ca; jack.greenblatt{at}utoronto.ca
  • 5 Present address: McGill University and Genome Quebec Innovation Centre, Department of Human Genetics, McGill University, Montreal, QC H3A 0G1, Canada

Abstract

C2H2 zinc finger proteins represent the largest and most enigmatic class of human transcription factors. Their C2H2-ZF arrays are highly variable, indicating that most will have unique DNA binding motifs. However, most of the binding motifs have not been directly determined. In addition, little is known about whether or how these proteins regulate transcription. Most of the ∼700 human C2H2-ZF proteins also contain at least one KRAB, SCAN, BTB, or SET domain, suggesting that they may have common interacting partners and/or effector functions. Here, we report a multifaceted functional analysis of 131 human C2H2-ZF proteins, encompassing DNA binding sites, interacting proteins, and transcriptional response to genetic perturbation. We confirm the expected diversity in DNA binding motifs and genomic binding sites, and provide motif models for 78 previously uncharacterized C2H2-ZF proteins, most of which are unique. Surprisingly, the diversity in protein–protein interactions is nearly as high as diversity in DNA binding motifs: Most C2H2-ZF proteins interact with a unique spectrum of co-activators and co-repressors. Thus, multiparameter diversification likely underlies the evolutionary success of this large class of human proteins.

Footnotes

  • 4 Co-first authors

  • [Supplemental material is available for this article.]

  • Article published online before print. Article, supplemental material, and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.209643.116.

  • Freely available online through the Genome Research Open Access option.

  • Received May 10, 2016.
  • Accepted October 24, 2016.

This article, published in Genome Research, is available under a Creative Commons License (Attribution 4.0 International), as described at http://creativecommons.org/licenses/by/4.0/.

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