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

Authors :
Zhang Y
Jang Y
Lee JE
Ahn J
Xu L
Holden MR
Cornett EM
Krajewski K
Klein BJ
Wang SP
Dou Y
Roeder RG
Strahl BD
Rothbart SB
Shi X
Ge K
Kutateladze TG
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.

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