ZZEF1 is a Histone Reader and Transcriptional Coregulator of Krüppel-Like Factors

J Mol Biol. 2021 Jan 22;433(2):166722. doi: 10.1016/j.jmb.2020.11.021. Epub 2020 Nov 21.

Abstract

The ZZ-type zinc finger and EF-hand domain protein 1 (ZZEF1) is a multidomain-containing protein. Mutations of ZZEF1 has been implicated in several kinds of human diseases such as diabetes and cancers. However, the function of the ZZEF protein remains largely unknown. Here we show that ZZEF1 functions as a histone H3 reader. The second ZZ domain of ZZEF1 (ZZEF1ZZ2) binds to the N-terminus of histone H3 and is capable of accommodating common epigenetic marks on the H3 tail. The N-terminal amino acids, especially Ala1, of H3 and an acidic cavity of ZZEF1ZZ2 are critical for the ZZ-H3 interaction. RNA-seq analysis in human lung cancer cell line H1299 reveals that downregulated genes upon ZZEF1 depletion are specifically enriched in genes regulated by Krüppel-like factors. Indeed, ZZEF1 physically interacts with KLF9 and KLF6, and regulates a common set of target genes of these transcription factors. Together, our findings suggest a model in which ZZEF1 binds to histone H3 tail and promotes KLF9/6-mediated gene regulation.

Keywords: H3; KLF9; Krüppel-like factors; ZZ domain; ZZEF1.

Publication types

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

MeSH terms

  • Amino Acid Motifs
  • Amino Acid Sequence
  • Binding Sites
  • Cell Line, Tumor
  • Gene Expression Regulation
  • Histones / chemistry*
  • Histones / metabolism
  • Humans
  • Kruppel-Like Transcription Factors / chemistry*
  • Kruppel-Like Transcription Factors / metabolism*
  • Models, Biological
  • Protein Binding
  • Protein Interaction Domains and Motifs
  • Transcription Factors / chemistry
  • Transcription Factors / metabolism
  • Zinc Fingers*

Substances

  • Histones
  • Kruppel-Like Transcription Factors
  • Transcription Factors