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Selective binding of the PHD6 finger of MLL4 to histone H4K16ac links MLL4 and MOF.
- Source :
-
Nature communications [Nat Commun] 2019 May 24; Vol. 10 (1), pp. 2314. Date of Electronic Publication: 2019 May 24. - Publication Year :
- 2019
-
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.
- Subjects :
- Acetylation
Animals
Binding Sites
Chromatin metabolism
DNA-Binding Proteins chemistry
DNA-Binding Proteins genetics
DNA-Binding Proteins isolation & purification
Gene Knockout Techniques
HEK293 Cells
Histone Acetyltransferases genetics
Histone-Lysine N-Methyltransferase chemistry
Histones chemistry
Humans
Mice, Transgenic
Models, Molecular
Mutagenesis, Site-Directed
Nuclear Magnetic Resonance, Biomolecular
Protein Processing, Post-Translational physiology
Recombinant Proteins chemistry
Recombinant Proteins genetics
Recombinant Proteins isolation & purification
Recombinant Proteins metabolism
DNA-Binding Proteins metabolism
Histone Acetyltransferases metabolism
Histone-Lysine N-Methyltransferase metabolism
Histones metabolism
PHD Zinc Fingers physiology
Subjects
Details
- Language :
- English
- ISSN :
- 2041-1723
- Volume :
- 10
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Nature communications
- Publication Type :
- Academic Journal
- Accession number :
- 31127101
- Full Text :
- https://doi.org/10.1038/s41467-019-10324-8