Mechanism for DPY30 and ASH2L intrinsically disordered regions to modulate the MLL/SET1 activity on chromatin

Young-Tae Lee; Alex Ayoub; Sang-Ho Park; Liang Sha; Jing Xu; Fengbiao Mao; Wei Zheng; Yang Zhang; Uhn-Soo Cho; Yali Dou

doi:10.1038/s41467-021-23268-9

Mechanism for DPY30 and ASH2L intrinsically disordered regions to modulate the MLL/SET1 activity on chromatin

Nat Commun. 2021 May 19;12(1):2953. doi: 10.1038/s41467-021-23268-9.

Authors

Young-Tae Lee^{1

2}, Alex Ayoub¹, Sang-Ho Park³, Liang Sha⁴, Jing Xu¹, Fengbiao Mao¹, Wei Zheng⁵, Yang Zhang^{3

5}, Uhn-Soo Cho³, Yali Dou^{6

7}

Affiliations

¹ Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
² Accent Therapeutics, 65 Hayden Avenue, Lexington, MA, USA.
³ Department of Biological Chemistry, University of Michigan, Ann Arbor, MI, USA.
⁴ Department of Medicine, Department of Biochemistry and Molecular Medicine, University of Southern California, Los Angeles, CA, USA.
⁵ Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA.
⁶ Department of Pathology, University of Michigan, Ann Arbor, MI, USA. yalidou@usc.edu.
⁷ Department of Medicine, Department of Biochemistry and Molecular Medicine, University of Southern California, Los Angeles, CA, USA. yalidou@usc.edu.

Abstract

Recent cryo-EM structures show the highly dynamic nature of the MLL1-NCP (nucleosome core particle) interaction. Functional implication and regulation of such dynamics remain unclear. Here we show that DPY30 and the intrinsically disordered regions (IDRs) of ASH2L work together in restricting the rotational dynamics of the MLL1 complex on the NCP. We show that DPY30 binding to ASH2L leads to stabilization and integration of ASH2L IDRs into the MLL1 complex and establishes new ASH2L-NCP contacts. The significance of ASH2L-DPY30 interactions is demonstrated by requirement of both ASH2L IDRs and DPY30 for dramatic increase of processivity and activity of the MLL1 complex. This DPY30 and ASH2L-IDR dependent regulation is NCP-specific and applies to all members of the MLL/SET1 family of enzymes. We further show that DPY30 is causal for de novo establishment of H3K4me3 in ESCs. Our study provides a paradigm of how H3K4me3 is regulated on chromatin and how H3K4me3 heterogeneity can be modulated by ASH2L IDR interacting proteins.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Line
Chromatin / metabolism
Cryoelectron Microscopy
DNA-Binding Proteins / chemistry*
DNA-Binding Proteins / genetics
DNA-Binding Proteins / metabolism*
Histone-Lysine N-Methyltransferase / metabolism*
Histones / metabolism
Human Embryonic Stem Cells / metabolism
Humans
In Vitro Techniques
Intrinsically Disordered Proteins / chemistry
Intrinsically Disordered Proteins / metabolism
Magnetic Resonance Spectroscopy
Mice
Models, Molecular
Mouse Embryonic Stem Cells / metabolism
Myeloid-Lymphoid Leukemia Protein / metabolism*
Nuclear Proteins / chemistry*
Nuclear Proteins / genetics
Nuclear Proteins / metabolism*
Nucleosomes / metabolism
Nucleosomes / ultrastructure
Protein Conformation
Protein Interaction Domains and Motifs
Scattering, Small Angle
Transcription Factors / chemistry*
Transcription Factors / genetics
Transcription Factors / metabolism*
X-Ray Diffraction

Substances

ASH2L protein, human
Chromatin
DNA-Binding Proteins
DPY30 protein, human
Histones
Intrinsically Disordered Proteins
KMT2A protein, human
Nuclear Proteins
Nucleosomes
Transcription Factors
Myeloid-Lymphoid Leukemia Protein
Histone-Lysine N-Methyltransferase
Setd1A protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding