Selective binding of the PHD6 finger of MLL4 to histone H4K16ac links MLL4 and MOF

Nat Commun. 2019 May 24;10(1):2314. doi: 10.1038/s41467-019-10324-8.

Abstract

Histone methyltransferase MLL4 is centrally involved in transcriptional regulation and is often mutated in human diseases, including cancer and developmental disorders. MLL4 contains a catalytic SET domain that mono-methylates histone H3K4 and seven PHD fingers of unclear function. Here, we identify the PHD6 finger of MLL4 (MLL4-PHD6) as a selective reader of the epigenetic modification H4K16ac. The solution NMR structure of MLL4-PHD6 in complex with a H4K16ac peptide along with binding and mutational analyses reveal unique mechanistic features underlying recognition of H4K16ac. Genomic studies show that one third of MLL4 chromatin binding sites overlap with H4K16ac-enriched regions in vivo and that MLL4 occupancy in a set of genomic targets depends on the acetyltransferase activity of MOF, a H4K16ac-specific acetyltransferase. The recognition of H4K16ac is conserved in the PHD7 finger of paralogous MLL3. Together, our findings reveal a previously uncharacterized acetyllysine reader and suggest that selective targeting of H4K16ac by MLL4 provides a direct functional link between MLL4, MOF and H4K16 acetylation.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Acetylation
  • Animals
  • Binding Sites
  • Chromatin / metabolism
  • DNA-Binding Proteins / chemistry
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / isolation & purification
  • DNA-Binding Proteins / metabolism*
  • Gene Knockout Techniques
  • HEK293 Cells
  • Histone Acetyltransferases / genetics
  • Histone Acetyltransferases / metabolism*
  • Histone-Lysine N-Methyltransferase / chemistry
  • Histone-Lysine N-Methyltransferase / metabolism*
  • Histones / chemistry
  • Histones / metabolism*
  • Humans
  • Mice, Transgenic
  • Models, Molecular
  • Mutagenesis, Site-Directed
  • Nuclear Magnetic Resonance, Biomolecular
  • PHD Zinc Fingers / physiology*
  • Protein Processing, Post-Translational / physiology
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / genetics
  • Recombinant Proteins / isolation & purification
  • Recombinant Proteins / metabolism

Substances

  • Chromatin
  • DNA-Binding Proteins
  • Histones
  • Recombinant Proteins
  • Histone-Lysine N-Methyltransferase
  • MLL4 protein, human
  • MLL4 protein, mouse
  • Histone Acetyltransferases
  • MOF protein, mouse