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Nat Commun. 2019 Jan 3;10(1):36. doi: 10.1038/s41467-018-07906-3.

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

Author information

1
Structural Genomics Consortium, University of Toronto, 101 College Street, Toronto, Ontario, M5G 1L7, Canada.
2
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas, 77030, USA.
3
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas, 77030, USA. mglee@mdanderson.org.
4
Structural Genomics Consortium, University of Toronto, 101 College Street, Toronto, Ontario, M5G 1L7, Canada. jr.min@utoronto.ca.
5
Department of Physiology, University of Toronto, Toronto, Ontario, M5S 1A8, Canada. jr.min@utoronto.ca.

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.

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