Cryo-EM structure of the human MLL1 core complex bound to the nucleosome

AbstractMixed lineage leukemia (MLL) family histone methyltransferases are enzymes that deposit histone H3 Lys4 (K4) mono-/di-/tri-methylation and regulate gene expression in mammals. Despite extensive structural and biochemical studies, the molecular mechanisms whereby the MLL complexes recognize histone H3K4 within nucleosome core particles (NCPs) remain unclear. Here we report the single-particle cryo-electron microscopy (cryo-EM) structure of the NCP-bound human MLL1 core complex. We show that the MLL1 core complex anchors to the NCP via the conserved RbBP5 and ASH2L, which interact extensively with nucleosomal DNA and the surface close to the N-terminal tail of histone H4. Concurrent interactions of RbBP5 and ASH2L with the NCP uniquely align the catalytic MLL1SET domain at the nucleosome dyad, thereby facilitating symmetrical access to both H3K4 substrates within the NCP. Our study sheds light on how the MLL1 complex engages chromatin and how chromatin binding promotes MLL1 tri-methylation activity.

Download Full-text

Cryo-EM structure of the human Mixed Lineage Leukemia-1 complex bound to the nucleosome

10.1101/737478 ◽

2019 ◽

Author(s):

Sang Ho Park ◽

Alex Ayoub ◽

Young Tae Lee ◽

Jing Xu ◽

Hanseong Kim ◽

...

Keyword(s):

Mixed Lineage Leukemia ◽

Chromatin Binding ◽

Histone H4 ◽

Core Complex ◽

Regulate Gene Expression ◽

Histone Methyltransferases ◽

Nucleosome Core ◽

Nucleosomal Dna ◽

Histone H3k4 ◽

Methylation Activity

SUMMARYMixed Lineage Leukemia (MLL) family histone methyltransferases are the key enzymes that deposit histone H3 Lys4 (K4) mono-/di-/tri-methylation and regulate gene expression in mammals. Despite extensive structural and biochemical studies, the molecular mechanism by which the MLL complexes recognize histone H3K4 within the nucleosome core particle (NCP) remains unclear. Here, we report the single-particle cryo-electron microscopy (cryo-EM) structure of the human MLL1 core complex bound to the NCP. The MLL1 core complex anchors on the NCP through RbBP5 and ASH2L, which interacts extensively with nucleosomal DNA as well as the surface close to histone H4 N-terminal tail. Concurrent interactions of RbBP5 and ASH2L with the NCP uniquely align the catalytic MLL1SET domain at the nucleosome dyad, allowing symmetrical access to both H3K4 substrates within the NCP. Our study sheds light on how the MLL1 complex engages chromatin and how chromatin binding promotes MLL1 tri-methylation activity.

Download Full-text

Predicting near-UV electronic circular dichroism in nucleosomal DNA by means of DFT response theory

Physical Chemistry Chemical Physics ◽

10.1039/c5cp02481a ◽

2015 ◽

Vol 17 (34) ◽

pp. 21866-21879 ◽

Cited By ~ 10

Author(s):

Patrick Norman ◽

Joseph Parello ◽

Prasad L. Polavarapu ◽

Mathieu Linares

Keyword(s):

Circular Dichroism ◽

Density Functional ◽

Time Dependent ◽

Functional Theory ◽

Electronic Circular Dichroism ◽

Nucleosome Core ◽

Nucleosome Core Particles ◽

Nucleosomal Dna ◽

Circular Dichroïsm ◽

Dependent Density

It is demonstrated that time-dependent density functional theory (DFT) calculations can accurately predict changes in near-UV electronic circular dichroism (ECD) spectra of DNA as the structure is altered from the linear (free) B-DNA form to the supercoiled N-DNA form found in nucleosome core particles.

Download Full-text

Histone dynamics mediate DNA unwrapping and sliding in nucleosomes

Nature Communications ◽

10.1038/s41467-021-22636-9 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Grigoriy A. Armeev ◽

Anastasiia S. Kniazeva ◽

Galina A. Komarova ◽

Mikhail P. Kirpichnikov ◽

Alexey K. Shaytan

Keyword(s):

Building Blocks ◽

Dna Dynamics ◽

Conformational Variability ◽

Nucleosome Core ◽

Nucleosome Dynamics ◽

Nucleosome Core Particles ◽

Nucleosomal Dna ◽

Dna Base ◽

Dna Unwrapping ◽

Dynamics Simulations

AbstractNucleosomes are elementary building blocks of chromatin in eukaryotes. They tightly wrap ∼147 DNA base pairs around an octamer of histone proteins. How nucleosome structural dynamics affect genome functioning is not completely clear. Here we report all-atom molecular dynamics simulations of nucleosome core particles at a timescale of 15 microseconds. At this timescale, functional modes of nucleosome dynamics such as spontaneous nucleosomal DNA breathing, unwrapping, twisting, and sliding were observed. We identified atomistic mechanisms of these processes by analyzing the accompanying structural rearrangements of the histone octamer and histone-DNA contacts. Octamer dynamics and plasticity were found to enable DNA unwrapping and sliding. Through multi-scale modeling, we showed that nucleosomal DNA dynamics contribute to significant conformational variability of the chromatin fiber at the supranucleosomal level. Our study further supports mechanistic coupling between fine details of histone dynamics and chromatin functioning, provides a framework for understanding the effects of various chromatin modifications.

Download Full-text

Studies of histidine phosphorylation by a nuclear protein histidine kinase show that histidine-75 in histone H4 is masked in nucleosome core particles and in chromatin

Archives of Biochemistry and Biophysics ◽

10.1016/0003-9861(89)90321-4 ◽

1989 ◽

Vol 268 (2) ◽

pp. 546-550 ◽

Cited By ~ 16

Author(s):

Ying-Fei Wei ◽

James E. Morgan ◽

Harry R. Matthews

Keyword(s):

Histidine Kinase ◽

Nuclear Protein ◽

Histone H4 ◽

Nucleosome Core ◽

Nucleosome Core Particles ◽

Histidine Phosphorylation ◽

Core Particles

Download Full-text

The effect of linker DNA on the structure and interaction of nucleosome core particles

Soft Matter ◽

10.1039/c8sm00998h ◽

2018 ◽

Vol 14 (45) ◽

pp. 9096-9106 ◽

Cited By ~ 1

Author(s):

Yen-Chih Huang ◽

Chun-Jen Su ◽

Nikolay Korolev ◽

Nikolay V. Berezhnoy ◽

Sai Wang ◽

...

Keyword(s):

Small Angle ◽

Core Particle ◽

Nucleosome Core Particle ◽

X Ray ◽

Nucleosome Core ◽

Nucleosome Core Particles ◽

X Ray Scattering ◽

Nucleosomal Dna ◽

The Impact

Small angle X-ray scattering reveals linker DNA-induced partial unwrapping of nucleosomal DNA on the nucleosome core particle (NCP) and the impact on NCP interaction demonstrating the crucial role of linker DNA.

Download Full-text

Multivalent interactions drive nucleosome binding and efficient chromatin deacetylation by SIRT6

Nature Communications ◽

10.1038/s41467-020-19018-y ◽

2020 ◽

Vol 11 (1) ◽

Author(s):

Wallace H. Liu ◽

Jie Zheng ◽

Jessica L. Feldman ◽

Mark A. Klein ◽

Vyacheslav I. Kuznetsov ◽

...

Keyword(s):

Histone Deacetylases ◽

Nucleosome Core ◽

Intrinsically Disordered ◽

Nucleosome Core Particles ◽

Nucleosomal Dna ◽

C Terminus ◽

Intrinsic Capacity ◽

Multivalent Interactions ◽

H3 Acetylation ◽

Nucleosome Binding

Abstract The protein deacetylase SIRT6 maintains cellular homeostasis through multiple pathways that include the deacetylation of histone H3 and repression of transcription. Prior work suggests that SIRT6 is associated with chromatin and can substantially reduce global levels of H3 acetylation, but how SIRT6 is able to accomplish this feat is unknown. Here, we describe an exquisitely tight interaction between SIRT6 and nucleosome core particles, in which a 2:1 enzyme:nucleosome complex assembles via asymmetric binding with distinct affinities. While both SIRT6 molecules associate with the acidic patch on the nucleosome, we find that the intrinsically disordered SIRT6 C-terminus promotes binding at the higher affinity site through recognition of nucleosomal DNA. Together, multivalent interactions couple productive binding to efficient deacetylation of histones on endogenous chromatin. Unique among histone deacetylases, SIRT6 possesses the intrinsic capacity to tightly interact with nucleosomes for efficient activity.

Download Full-text

How do histone modifications contribute to transgenerational epigenetic inheritance in C. elegans?

Biochemical Society Transactions ◽

10.1042/bst20190944 ◽

2020 ◽

Vol 48 (3) ◽

pp. 1019-1034 ◽

Cited By ~ 1

Author(s):

Rachel M. Woodhouse ◽

Alyson Ashe

Keyword(s):

Histone Modifications ◽

Molecular Mechanisms ◽

Epigenetic Inheritance ◽

Nematode Caenorhabditis Elegans ◽

Histone Methyltransferases ◽

Transgenerational Epigenetic Inheritance ◽

C Elegans ◽

Recent Developments ◽

Gene Regulatory

Gene regulatory information can be inherited between generations in a phenomenon termed transgenerational epigenetic inheritance (TEI). While examples of TEI in many animals accumulate, the nematode Caenorhabditis elegans has proven particularly useful in investigating the underlying molecular mechanisms of this phenomenon. In C. elegans and other animals, the modification of histone proteins has emerged as a potential carrier and effector of transgenerational epigenetic information. In this review, we explore the contribution of histone modifications to TEI in C. elegans. We describe the role of repressive histone marks, histone methyltransferases, and associated chromatin factors in heritable gene silencing, and discuss recent developments and unanswered questions in how these factors integrate with other known TEI mechanisms. We also review the transgenerational effects of the manipulation of histone modifications on germline health and longevity.

Download Full-text

The Development of Inhibitors Targeting the Mixed Lineage Leukemia 1 (MLL1)-WD Repeat Domain 5 Protein (WDR5) Protein- Protein Interaction

Current Medicinal Chemistry ◽

10.2174/0929867326666190528080514 ◽

2020 ◽

Vol 27 (33) ◽

pp. 5530-5542

Author(s):

Xiaoqing Ye ◽

Gang Chen ◽

Jia Jin ◽

Binzhong Zhang ◽

Yinda Wang ◽

...

Keyword(s):

Gene Expression ◽

Protein Interaction ◽

Fusion Proteins ◽

Recent Progress ◽

Mixed Lineage Leukemia ◽

Core Complex ◽

Histone Methyltransferases ◽

Protein Protein Interaction ◽

Histone 3 ◽

Repeat Domain

Mixed Lineage Leukemia 1 (MLL1), an important member of Histone Methyltransferases (HMT) family, is capable of catalyzing mono-, di-, and trimethylation of Histone 3 lysine 4 (H3K4). The optimal catalytic activity of MLL1 requires the formation of a core complex consisting of MLL1, WDR5, RbBP5, and ASH2L. The Protein-Protein Interaction (PPI) between WDR5 and MLL1 plays an important role in abnormal gene expression during tumorigenesis, and disturbing this interaction may have a potential for the treatment of leukemia harboring MLL1 fusion proteins. In this review, we will summarize recent progress in the development of inhibitors targeting MLL1- WDR5 interaction.

Download Full-text