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

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.
Mesh Terms:
Cell Line, Tumor, DNA-Binding Proteins, Enhancer Elements, Genetic, HEK293 Cells, Histones, Humans, Methylation, Nucleosomes, PHD Zinc Fingers, Protein Binding, Protein Processing, Post-Translational
Nat Commun
Date: Dec. 03, 2018
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