ASH2L regulates ubiquitylation signaling to MLL: Trans-Regulation of H3 K4 methylation in higher eukaryotes

Lipeng Wu; Shirley Y. Lee; Bo Zhou; Uyen T.T. Nguyen; Tom W. Muir; Song Tan; Yali Dou

doi:10.1016/j.molcel.2013.01.033

ASH2L regulates ubiquitylation signaling to MLL: Trans-Regulation of H3 K4 methylation in higher eukaryotes

Lipeng Wu, Shirley Y. Lee, Bo Zhou, Uyen T.T. Nguyen, Tom W. Muir, Song Tan, Yali Dou

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Abstract

Crosstalk between H2B ubiquitylation (H2Bub) and H3 K4 methylation plays important roles in coordinating functions of diverse cofactors during transcription activation. The underlying mechanism for this trans-tail signaling pathway is poorly defined in higher eukaryotes. Here, we show the following: (1) ASH2L in the MLL complex is essential for H2Bub-dependent H3 K4 methylation. Deleting or mutating K99 of the N-terminal winged helix (WH) motif in ASH2L abrogates H2Bub-dependent regulation. (2) Crosstalk can occur in trans and does not require ubiquitin to be on nucleosomes or histones to exert regulatory effects. (3) trans-regulation by ubiquitin promotes MLL activity for all three methylation states. (4) MLL3, an MLL homolog, does not respond to H2Bub, highlighting regulatory specificity for MLL family histone methyltransferases. Altogether, our results potentially expand the classic histone crosstalk to nonhistone proteins, which broadens the scope of chromatin regulation by ubiquitylation signaling.

Original language	English (US)
Pages (from-to)	1108-1120
Number of pages	13
Journal	Molecular cell
Volume	49
Issue number	6
DOIs	https://doi.org/10.1016/j.molcel.2013.01.033
State	Published - Mar 28 2013

All Science Journal Classification (ASJC) codes

Molecular Biology
Cell Biology

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10.1016/j.molcel.2013.01.033

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title = "ASH2L regulates ubiquitylation signaling to MLL: Trans-Regulation of H3 K4 methylation in higher eukaryotes",

abstract = "Crosstalk between H2B ubiquitylation (H2Bub) and H3 K4 methylation plays important roles in coordinating functions of diverse cofactors during transcription activation. The underlying mechanism for this trans-tail signaling pathway is poorly defined in higher eukaryotes. Here, we show the following: (1) ASH2L in the MLL complex is essential for H2Bub-dependent H3 K4 methylation. Deleting or mutating K99 of the N-terminal winged helix (WH) motif in ASH2L abrogates H2Bub-dependent regulation. (2) Crosstalk can occur in trans and does not require ubiquitin to be on nucleosomes or histones to exert regulatory effects. (3) trans-regulation by ubiquitin promotes MLL activity for all three methylation states. (4) MLL3, an MLL homolog, does not respond to H2Bub, highlighting regulatory specificity for MLL family histone methyltransferases. Altogether, our results potentially expand the classic histone crosstalk to nonhistone proteins, which broadens the scope of chromatin regulation by ubiquitylation signaling.",

author = "Lipeng Wu and Lee, {Shirley Y.} and Bo Zhou and Nguyen, {Uyen T.T.} and Muir, {Tom W.} and Song Tan and Yali Dou",

note = "Funding Information: This work is supported grants from the NIGMS (GM082856), American Cancer Society, SU2C, and Leukemia and Lymphoma Society Scholar to Y.D. We are grateful to Drs. Ming Lei and Yong Chen for the expression vectors for ASH2L, MLL, and MLL3 SET domains, as well as for general discussions of the project. ",

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AU - Zhou, Bo

AU - Nguyen, Uyen T.T.

AU - Muir, Tom W.

AU - Tan, Song

AU - Dou, Yali

N1 - Funding Information: This work is supported grants from the NIGMS (GM082856), American Cancer Society, SU2C, and Leukemia and Lymphoma Society Scholar to Y.D. We are grateful to Drs. Ming Lei and Yong Chen for the expression vectors for ASH2L, MLL, and MLL3 SET domains, as well as for general discussions of the project.

PY - 2013/3/28

Y1 - 2013/3/28

N2 - Crosstalk between H2B ubiquitylation (H2Bub) and H3 K4 methylation plays important roles in coordinating functions of diverse cofactors during transcription activation. The underlying mechanism for this trans-tail signaling pathway is poorly defined in higher eukaryotes. Here, we show the following: (1) ASH2L in the MLL complex is essential for H2Bub-dependent H3 K4 methylation. Deleting or mutating K99 of the N-terminal winged helix (WH) motif in ASH2L abrogates H2Bub-dependent regulation. (2) Crosstalk can occur in trans and does not require ubiquitin to be on nucleosomes or histones to exert regulatory effects. (3) trans-regulation by ubiquitin promotes MLL activity for all three methylation states. (4) MLL3, an MLL homolog, does not respond to H2Bub, highlighting regulatory specificity for MLL family histone methyltransferases. Altogether, our results potentially expand the classic histone crosstalk to nonhistone proteins, which broadens the scope of chromatin regulation by ubiquitylation signaling.

AB - Crosstalk between H2B ubiquitylation (H2Bub) and H3 K4 methylation plays important roles in coordinating functions of diverse cofactors during transcription activation. The underlying mechanism for this trans-tail signaling pathway is poorly defined in higher eukaryotes. Here, we show the following: (1) ASH2L in the MLL complex is essential for H2Bub-dependent H3 K4 methylation. Deleting or mutating K99 of the N-terminal winged helix (WH) motif in ASH2L abrogates H2Bub-dependent regulation. (2) Crosstalk can occur in trans and does not require ubiquitin to be on nucleosomes or histones to exert regulatory effects. (3) trans-regulation by ubiquitin promotes MLL activity for all three methylation states. (4) MLL3, an MLL homolog, does not respond to H2Bub, highlighting regulatory specificity for MLL family histone methyltransferases. Altogether, our results potentially expand the classic histone crosstalk to nonhistone proteins, which broadens the scope of chromatin regulation by ubiquitylation signaling.

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ASH2L regulates ubiquitylation signaling to MLL: Trans-Regulation of H3 K4 methylation in higher eukaryotes

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