Multivalent histone engagement by the linked tandem Tudor and PHD domains of UHRF1 is required for the epigenetic inheritance of DNA methylation

Genes Dev. 2013 Jun 1;27(11):1288-98. doi: 10.1101/gad.220467.113.

Abstract

Histone post-translational modifications regulate chromatin structure and function largely through interactions with effector proteins that often contain multiple histone-binding domains. While significant progress has been made characterizing individual effector domains, the role of paired domains and how they function in a combinatorial fashion within chromatin are poorly defined. Here we show that the linked tandem Tudor and plant homeodomain (PHD) of UHRF1 (ubiquitin-like PHD and RING finger domain-containing protein 1) operates as a functional unit in cells, providing a defined combinatorial readout of a heterochromatin signature within a single histone H3 tail that is essential for UHRF1-directed epigenetic inheritance of DNA methylation. These findings provide critical support for the "histone code" hypothesis, demonstrating that multivalent histone engagement plays a key role in driving a fundamental downstream biological event in chromatin.

Keywords: DNA methylation; DNMT1; UHRF1; epigenetic inheritance; histone code; multivalency.

Publication types

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

MeSH terms

  • CCAAT-Enhancer-Binding Proteins / chemistry*
  • CCAAT-Enhancer-Binding Proteins / metabolism*
  • DNA Methylation / genetics*
  • Epigenesis, Genetic*
  • Heterochromatin / genetics
  • Heterochromatin / metabolism
  • Histones / metabolism*
  • Homeodomain Proteins / chemistry*
  • Homeodomain Proteins / metabolism
  • Humans
  • Models, Molecular
  • Protein Structure, Tertiary
  • Ubiquitin-Protein Ligases

Substances

  • CCAAT-Enhancer-Binding Proteins
  • Heterochromatin
  • Histones
  • Homeodomain Proteins
  • UHRF1 protein, human
  • Ubiquitin-Protein Ligases