Structural insights into trans-histone regulation of H3K4 methylation by unique histone H4 binding of MLL3/4

Yanli Liu, Su Qin, Tsai-Yu Chen, Ming Lei, Shilpa S. Dhar, Jolene Caifeng Ho, Aiping Dong, Peter Loppnau, Yanjun Li, Min Gyu Lee () and Jinrong Min ()
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Yanli Liu: University of Toronto
Su Qin: University of Toronto
Tsai-Yu Chen: The University of Texas MD Anderson Cancer Center
Ming Lei: University of Toronto
Shilpa S. Dhar: The University of Texas MD Anderson Cancer Center
Jolene Caifeng Ho: University of Toronto
Aiping Dong: University of Toronto
Peter Loppnau: University of Toronto
Yanjun Li: University of Toronto
Min Gyu Lee: The University of Texas MD Anderson Cancer Center
Jinrong Min: University of Toronto

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

Abstract: Abstract MLL3 and MLL4 are two closely related members of the SET1/MLL family of histone H3K4 methyltransferases and are responsible for monomethylating histone H3K4 on enhancers, which are essential in regulating cell-type-specific gene expression. Mutations of MLL3 or MLL4 have been reported in different types of cancer. Recently, the PHD domains of MLL3/4 have been reported to recruit the MLL3/4 complexes to their target genes by binding to histone H4 during the NT2/D1 stem cell differentiation. Here we show that an extended PHD domain (ePHD6) involving the sixth PHD domain and its preceding zinc finger in MLL3 and MLL4 specifically recognizes an H4H18-containing histone H4 fragment and that modifications of residues surrounding H4H18 modulate H4 binding to MLL3/4. Our in vitro methyltransferase assays and cellular experiments further reveal that the interaction between ePHD6 of MLL3/4 and histone H4 is required for their nucleosomal methylation activity and MLL4-mediated neuronal differentiation of NT2/D1 cells.

Date: 2019
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DOI: 10.1038/s41467-018-07906-3

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