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

• Published in: Nature communications Vol. 10; no. 1; pp. 2314 - 11
• Main Authors: Zhang, Yi, Jang, Younghoon, Lee, Ji-Eun, Ahn, JaeWoo, Xu, Longxia, Holden, Michael R, Cornett, Evan M, Krajewski, Krzysztof, Klein, Brianna J, Wang, Shu-Ping, Dou, Yali, Roeder, Robert G, Strahl, Brian D, Rothbart, Scott B, Shi, Xiaobing, Ge, Kai, Kutateladze, Tatiana G
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 24.05.2019; Nature Publishing Group UK; Nature Portfolio
• Subjects: Acetylation; Acetyllysine; Acetyltransferase; Animals; Binding Sites; Catalysis; Chromatin; Chromatin - metabolism; Developmental disabilities; DNA-Binding Proteins - chemistry; DNA-Binding Proteins - genetics; DNA-Binding Proteins - isolation & purification; DNA-Binding Proteins - metabolism; Feature recognition; Gene Knockout Techniques; Gene regulation; HEK293 Cells; Histone Acetyltransferases - genetics; Histone Acetyltransferases - metabolism; Histone methyltransferase; Histone-Lysine N-Methyltransferase - chemistry; Histone-Lysine N-Methyltransferase - metabolism; Histones; Histones - chemistry; Histones - metabolism; Humans; Mice, Transgenic; Models, Molecular; Mutagenesis, Site-Directed; NMR; Nuclear magnetic resonance; Nuclear Magnetic Resonance, Biomolecular; Occupancy; PHD Zinc Fingers - physiology; Protein Processing, Post-Translational - physiology; Recombinant Proteins - chemistry; Recombinant Proteins - genetics; Recombinant Proteins - isolation & purification; Recombinant Proteins - metabolism; Selective binding; Transcription
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-10324-8

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.