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

Yi Zhang, Younghoon Jang, Ji-Eun Lee, JaeWoo Ahn, Longxia Xu, Michael R. Holden, Evan M. Cornett, Krzysztof Krajewski, Brianna J. Klein, Shu-Ping Wang, Yali Dou, Robert G. Roeder, Brian D. Strahl, Scott B. Rothbart, Xiaobing Shi, Kai Ge () and Tatiana G. Kutateladze ()
Additional contact information
Yi Zhang: University of Colorado School of Medicine
Younghoon Jang: National Institute of Diabetes and Digestive and Kidney Diseases, NIH
Ji-Eun Lee: National Institute of Diabetes and Digestive and Kidney Diseases, NIH
JaeWoo Ahn: University of Colorado School of Medicine
Longxia Xu: Van Andel Research Institute
Michael R. Holden: University of Colorado School of Medicine
Evan M. Cornett: Van Andel Research Institute
Krzysztof Krajewski: The University of North Carolina School of Medicine
Brianna J. Klein: University of Colorado School of Medicine
Shu-Ping Wang: The Rockefeller University
Yali Dou: University of Michigan
Robert G. Roeder: The Rockefeller University
Brian D. Strahl: The University of North Carolina School of Medicine
Scott B. Rothbart: Van Andel Research Institute
Xiaobing Shi: Van Andel Research Institute
Kai Ge: National Institute of Diabetes and Digestive and Kidney Diseases, NIH
Tatiana G. Kutateladze: University of Colorado School of Medicine

Nature Communications, 2019, vol. 10, issue 1, 1-11

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-10324-8

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