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; Jinrong Min

doi:10.1038/s41467-018-07906-3

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, Jinrong Min

Molecular & Cellular Oncology

Research output: Contribution to journal › Article › peer-review

29 Scopus citations

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 (ePHD ₆ ) 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 ePHD ₆ of MLL3/4 and histone H4 is required for their nucleosomal methylation activity and MLL4-mediated neuronal differentiation of NT2/D1 cells.

Original language	English (US)
Article number	36
Journal	Nature communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-07906-3
State	Published - Dec 1 2019

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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

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 (ePHD 6 ) 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 ePHD 6 of MLL3/4 and histone H4 is required for their nucleosomal methylation activity and MLL4-mediated neuronal differentiation of NT2/D1 cells.",

author = "Yanli Liu and Su Qin and Chen, {Tsai Yu} and Ming Lei and Dhar, {Shilpa S.} and Ho, {Jolene Caifeng} and Aiping Dong and Peter Loppnau and Yanjun Li and Lee, {Min Gyu} and Jinrong Min",

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doi = "10.1038/s41467-018-07906-3",

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AU - Liu, Yanli

AU - Qin, Su

AU - Chen, Tsai Yu

AU - Lei, Ming

AU - Dhar, Shilpa S.

AU - Ho, Jolene Caifeng

AU - Dong, Aiping

AU - Loppnau, Peter

AU - Li, Yanjun

AU - Lee, Min Gyu

AU - Min, Jinrong

PY - 2019/12/1

Y1 - 2019/12/1

N2 - 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 (ePHD 6 ) 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 ePHD 6 of MLL3/4 and histone H4 is required for their nucleosomal methylation activity and MLL4-mediated neuronal differentiation of NT2/D1 cells.

AB - 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 (ePHD 6 ) 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 ePHD 6 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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Structural insights into trans-histone regulation of H3K4 methylation by unique histone H4 binding of MLL3/4

Abstract

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MD Anderson CCSG core facilities

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