Format

Send to

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

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

Author information

1
Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO, 80045, USA.
2
Laboratory of Endocrinology and Receptor Biology, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD, 20892, USA.
3
Center for Epigenetics, Van Andel Research Institute, Grand Rapids, MI, 49503, USA.
4
Department of Biochemistry & Biophysics, The University of North Carolina School of Medicine, Chapel Hill, NC, 27599, USA.
5
Laboratory of Biochemistry and Molecular Biology, The Rockefeller University, New York, NY, 10065, USA.
6
Department of Pathology, University of Michigan, Ann Arbor, MI, 48109, USA.
7
Laboratory of Endocrinology and Receptor Biology, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD, 20892, USA. kai.ge@nih.gov.
8
Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO, 80045, USA. tatiana.kutateladze@ucdenver.edu.

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.

PMID:
31127101
PMCID:
PMC6534582
DOI:
10.1038/s41467-019-10324-8
[Indexed for MEDLINE]
Free PMC Article

Publication type, MeSH terms, Substances, Grant support

Publication type

MeSH terms

Substances

Grant support

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center