Cryo-EM structures of PRC2 simultaneously engaged with two functionally distinct nucleosomes

Poepsel, Simon; Kasinath, Vignesh; Nogales, Eva

doi:10.1038/s41594-018-0023-y

Title: Cryo-EM structures of PRC2 simultaneously engaged with two functionally distinct nucleosomes

Abstract

Epigenetic regulation is mediated by protein complexes that couple recognition of chromatin marks to activity or recruitment of chromatin-modifying enzymes. Polycomb repressive complex 2 (PRC2), a gene silencer that methylates lysine 27 of histone H3, is stimulated upon recognition of its own catalytic product and has been shown to be more active on dinucleosomes than H3 tails or single nucleosomes. These properties probably facilitate local H3K27me2/3 spreading, causing heterochromatin formation and gene repression. Here, cryo-EM reconstructions of human PRC2 bound to bifunctional dinucleosomes show how a single PRC2, via interactions with nucleosomal DNA, positions the H3 tails of the activating and substrate nucleosome to interact with the EED subunit and the SET domain of EZH2, respectively. We show how the geometry of the PRC2–DNA interactions allows PRC2 to accommodate varying lengths of the linker DNA between nucleosomes. Furthermore, our structures illustrate how an epigenetic regulator engages with a complex chromatin substrate.

Authors:

^[1]; Kasinath, Vignesh ^[1];

^[2]

Univ. of California, Berkeley, CA (United States). California Inst. for Quantitative Biology (QB3); Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Molecular Biophysics and Integrative Bio-Imaging Div.
Univ. of California, Berkeley, CA (United States). California Inst. for Quantitative Biology (QB3), Howard Hughes Medical Inst., and Dept. of Molecular and Cell Biology; Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Molecular Biophysics and Integrative Bio-Imaging Div.

Publication Date:: Mon Jan 29 00:00:00 EST 2018

Research Org.:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States). National Energy Research Scientific Computing Center (NERSC)

Sponsoring Org.:: USDOE Office of Science (SC)

OSTI Identifier:: 1490278

Grant/Contract Number:: AC02-05CH11231

Resource Type:: Accepted Manuscript

Journal Name:: Nature Structural & Molecular Biology

Additional Journal Information:: Journal Volume: 25; Journal Issue: 2; Journal ID: ISSN 1545-9993

Publisher:: Nature Publishing Group

Country of Publication:: United States

Language:: English

Subject:: 59 BASIC BIOLOGICAL SCIENCES

Citation Formats


                    Poepsel, Simon, Kasinath, Vignesh, and Nogales, Eva. Cryo-EM structures of PRC2 simultaneously engaged with two functionally distinct nucleosomes.  United States: N. p., 2018. 
Web.  doi:10.1038/s41594-018-0023-y.

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                    Poepsel, Simon, Kasinath, Vignesh, & Nogales, Eva. Cryo-EM structures of PRC2 simultaneously engaged with two functionally distinct nucleosomes.  United States.  https://doi.org/10.1038/s41594-018-0023-y

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                    Poepsel, Simon, Kasinath, Vignesh, and Nogales, Eva. Mon .  
"Cryo-EM structures of PRC2 simultaneously engaged with two functionally distinct nucleosomes".  United States.  https://doi.org/10.1038/s41594-018-0023-y.  https://www.osti.gov/servlets/purl/1490278.

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@article{osti_1490278,

  title        = {Cryo-EM structures of PRC2 simultaneously engaged with two functionally distinct nucleosomes},

  author       = {Poepsel, Simon and Kasinath, Vignesh and Nogales, Eva},

  abstractNote = {Epigenetic regulation is mediated by protein complexes that couple recognition of chromatin marks to activity or recruitment of chromatin-modifying enzymes. Polycomb repressive complex 2 (PRC2), a gene silencer that methylates lysine 27 of histone H3, is stimulated upon recognition of its own catalytic product and has been shown to be more active on dinucleosomes than H3 tails or single nucleosomes. These properties probably facilitate local H3K27me2/3 spreading, causing heterochromatin formation and gene repression. Here, cryo-EM reconstructions of human PRC2 bound to bifunctional dinucleosomes show how a single PRC2, via interactions with nucleosomal DNA, positions the H3 tails of the activating and substrate nucleosome to interact with the EED subunit and the SET domain of EZH2, respectively. We show how the geometry of the PRC2–DNA interactions allows PRC2 to accommodate varying lengths of the linker DNA between nucleosomes. Furthermore, our structures illustrate how an epigenetic regulator engages with a complex chromatin substrate.},

  doi          = {10.1038/s41594-018-0023-y},

  journal      = {Nature Structural & Molecular Biology},

  number       = 2,

  volume       = 25,

  place        = {United States},

  year         = {Mon Jan 29 00:00:00 EST 2018},

  month        = {Mon Jan 29 00:00:00 EST 2018}

}

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RNA exploits an exposed regulatory site to inhibit the enzymatic activity of PRC2
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Zhang, Qi; McKenzie, Nicholas J.; Warneford-Thomson, Robert
Nature Structural & Molecular Biology, Vol. 26, Issue 3
DOI: 10.1038/s41594-019-0197-y

G-tract RNA removes Polycomb repressive complex 2 from genes
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Beltran, Manuel; Tavares, Manuel; Justin, Neil
Nature Structural & Molecular Biology, Vol. 26, Issue 10
DOI: 10.1038/s41594-019-0293-z

The EZH2 SANT1 domain is a histone reader providing sensitivity to the modification state of the H4 tail
journal, January 2019

Weaver, Tyler M.; Liu, Jiachen; Connelly, Katelyn E.
Scientific Reports, Vol. 9, Issue 1
DOI: 10.1038/s41598-018-37699-w

Chromatin fiber structural motifs as regulatory hubs of genome function?
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Moraru, Manuela; Schalch, Thomas
Essays in Biochemistry, Vol. 63, Issue 1
DOI: 10.1042/ebc20180065

Mechanistic insights into histone deposition and nucleosome assembly by the chromatin assembly factor-1
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Sauer, Paul V.; Gu, Yajie; Liu, Wallace H.
Nucleic Acids Research, Vol. 46, Issue 19
DOI: 10.1093/nar/gky823

PRC2 is high maintenance
journal, May 2019

Yu, Jia-Ray; Lee, Chul-Hwan; Oksuz, Ozgur
Genes & Development, Vol. 33, Issue 15-16
DOI: 10.1101/gad.325050.119

Regulation of histone methylation by automethylation of PRC2
journal, September 2019

Wang, Xueyin; Long, Yicheng; Paucek, Richard D.
Genes & Development, Vol. 33, Issue 19-20
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An inter‐dimer allosteric switch controls NMDA receptor activity
journal, November 2018

Esmenjaud, Jean‐Baptiste; Stroebel, David; Chan, Kelvin
The EMBO Journal, Vol. 38, Issue 2
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Polycomb Assemblies Multitask to Regulate Transcription
journal, June 2019

Vidal, Miguel
Epigenomes, Vol. 3, Issue 2
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The EZH2 SANT1 Domain is a Histone Reader Providing Sensitivity to the Modification State of the H4 Tail
journal, February 2018

Weaver, Tyler M.; Liu, Jiachen; Connelly, Katelyn E.
Biophysical Journal, Vol. 114, Issue 3
DOI: 10.1016/j.bpj.2017.11.2463

The cryo-EM resolution revolution and transcription complexes
journal, October 2018

Hanske, Jonas; Sadian, Yashar; Müller, Christoph W.
Current Opinion in Structural Biology, Vol. 52
DOI: 10.1016/j.sbi.2018.07.002

Theoretical analysis of Polycomb-Trithorax systems predicts that poised chromatin is bistable and not bivalent
journal, May 2019

Sneppen, Kim; Ringrose, Leonie
Nature Communications, Vol. 10, Issue 1
DOI: 10.1038/s41467-019-10130-2

Cryo-EM structure of the human MLL1 core complex bound to the nucleosome
journal, December 2019

Park, Sang Ho; Ayoub, Alex; Lee, Young-Tae
Nature Communications, Vol. 10, Issue 1
DOI: 10.1038/s41467-019-13550-2

G-tracts give PRC2 the boot
journal, October 2019

Wrighton, Katharine H.
Nature Reviews Molecular Cell Biology, Vol. 20, Issue 11
DOI: 10.1038/s41580-019-0184-5

Chromatin fiber structural motifs as regulatory hubs of genome function?
journal, April 2019

Moraru, Manuela; Schalch, Thomas
Essays in Biochemistry, Vol. 63, Issue 1
DOI: 10.1042/ebc20180065

The in situ structures of mono-, di-, and trinucleosomes in human heterochromatin
journal, October 2018

Cai, Shujun; Böck, Désirée; Pilhofer, Martin
Molecular Biology of the Cell, Vol. 29, Issue 20
DOI: 10.1091/mbc.e18-05-0331

Mechanistic insights into histone deposition and nucleosome assembly by the chromatin assembly factor-1
journal, September 2018

Sauer, Paul V.; Gu, Yajie; Liu, Wallace H.
Nucleic Acids Research, Vol. 46, Issue 19
DOI: 10.1093/nar/gky823

Lysine Acetyltransferase Inhibitors From Natural Sources
journal, August 2020

Fiorentino, Francesco; Mai, Antonello; Rotili, Dante
Frontiers in Pharmacology, Vol. 11
DOI: 10.3389/fphar.2020.01243

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The function of EED within polycomb repressive complex 2 (PRC2) is mediated by a complex network of protein–protein interactions. Allosteric activation of PRC2 by binding of methylated proteins to the embryonic ectoderm development (EED) aromatic cage is essential for full catalytic activity, but details of this regulation are not fully understood. EED’s recognition of the product of PRC2 activity, histone H3 lysine 27 trimethylation (H3K27me3), stimulates PRC2 methyltransferase activity at adjacent nucleosomes leading to H3K27me3 propagation and, ultimately, gene repression. By coupling combinatorial chemistry and structure-based design, we optimized a low-affinity methylated jumonji, AT-rich interactive domain 2 (Jarid2) peptide tomore »« less
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Title: Cryo-EM structures of PRC2 simultaneously engaged with two functionally distinct nucleosomes

Abstract

Citation Formats

Characterization of nucleosome core particles containing histone proteins made in bacteria 1 1Edited by A. Klug journal, September 1997

Accelerated cryo-EM structure determination with parallelisation using GPUs in RELION-2 journal, November 2016

Nucleosome-binding activities within JARID2 and EZH1 regulate the function of PRC2 on chromatin journal, December 2013

Structures of human PRC2 with its cofactors AEBP2 and JARID2 journal, January 2018

iMODFIT: Efficient and robust flexible fitting based on vibrational analysis in internal coordinates journal, November 2013

Accurate determination of local defocus and specimen tilt in electron microscopy journal, June 2003

DoG Picker and TiltPicker: Software tools to facilitate particle selection in single particle electron microscopy journal, May 2009

Prevention of overfitting in cryo-EM structure determination journal, July 2012

Appion: An integrated, database-driven pipeline to facilitate EM image processing journal, April 2009

Automated molecular microscopy: The new Leginon system journal, July 2005

Jarid2 and PRC2, partners in regulating gene expression journal, February 2010

Molecular architecture of human polycomb repressive complex 2 journal, October 2012

Asymmetrically Modified Nucleosomes journal, September 2012

Mechanism of chromatin remodelling revealed by the Snf2-nucleosome structure journal, April 2017

Functional Demarcation of Active and Silent Chromatin Domains in Human HOX Loci by Noncoding RNAs journal, June 2007

Histone Methylation by PRC2 Is Inhibited by Active Chromatin Marks journal, May 2011

Role of Histone H3 Lysine 27 Methylation in Polycomb-Group Silencing journal, September 2002

The structural basis of modified nucleosome recognition by 53BP1 journal, July 2016

MotionCor2: anisotropic correction of beam-induced motion for improved cryo-electron microscopy journal, February 2017

3D-DART: a DNA structure modelling server journal, May 2009

Bsoft: Image processing and molecular modeling for electron microscopy journal, January 2007

Role of the polycomb protein EED in the propagation of repressive histone marks journal, September 2009

The SANT domain: a unique histone-tail-binding module? journal, February 2004

Gctf: Real-time CTF determination and correction journal, January 2016

Structural basis of histone H3K27 trimethylation by an active polycomb repressive complex 2 journal, October 2015

New DNA sequence rules for high affinity binding to histone octamer and sequence-directed nucleosome positioning journal, February 1998

Crystal Structures of Nucleosome Core Particles Containing the ‘601’ Strong Positioning Sequence journal, October 2010

Histone target selection within chromatin: an exemplary case of teamwork journal, May 2014

A model for transmission of the H3K27me3 epigenetic mark journal, October 2008

Understanding the language of Lys36 methylation at histone H3 journal, January 2012

Optimal Determination of Particle Orientation, Absolute Hand, and Contrast Loss in Single-particle Electron Cryomicroscopy journal, October 2003

A Bayesian View on Cryo-EM Structure Determination journal, January 2012

Visualizing density maps with UCSF Chimera journal, January 2007

Dense Chromatin Activates Polycomb Repressive Complex 2 to Regulate H3 Lysine 27 Methylation journal, August 2012

The Site-Specific Installation of Methyl-Lysine Analogs into Recombinant Histones journal, March 2007

Topology representing network enables highly accurate classification of protein images taken by cryo electron-microscope without masking journal, September 2003

Polycomb Proteins Targeted by a Short Repeat RNA to the Mouse X Chromosome journal, October 2008

DNA binding by PHF1 prolongs PRC2 residence time on chromatin and thereby promotes H3K27 methylation journal, October 2017

AEBP2 as a potential targeting protein for Polycomb Repression Complex PRC2 journal, March 2009

Phf19 links methylated Lys36 of histone H3 to regulation of Polycomb activity journal, October 2012

Chemically ubiquitylated histone H2B stimulates hDot1L-mediated intranucleosomal methylation journal, April 2008

Substrate Preferences of the EZH2 Histone Methyltransferase Complex journal, January 2006

Molecular analysis of PRC2 recruitment to DNA in chromatin and its inhibition by RNA journal, October 2017

Post-translational modifications of tau protein: Implications for Alzheimer's disease journal, March 2011

Structural basis of oncogenic histone H3K27M inhibition of human polycomb repressive complex 2 journal, April 2016

SPIDER image processing for single-particle reconstruction of biological macromolecules from electron micrographs journal, October 2008

ChromEMT: Visualizing 3D chromatin structure and compaction in interphase and mitotic cells journal, July 2017

Sampling the conformational space of the catalytic subunit of human γ-secretase journal, December 2015

PARP1 exhibits enhanced association and catalytic efficiency with γH2A.X-nucleosome journal, December 2019

Red light-induced structure changes in phytochrome A from Pisum sativum journal, February 2021

Below 3 Å structure of apoferritin using a multipurpose TEM with a side entry cryoholder journal, April 2021

Structures of human PRC2 with its cofactors AEBP2 and JARID2 text, January 2018

A Bayesian view on cryo-EM structure determination conference, May 2012

Substrate Preferences of the EZH2 Histone Methyltransferase Complex text, January 2006

Chemically ubiquitylated histone H2B stimulates hDot1L-mediated intranucleosomal methylation text, January 2008

New DNA sequence rules for high affinity binding to histone octamer and sequence-directed nucleosome positioning journal, February 1998

The Site-Specific Installation of Methyl-Lysine Analogs into Recombinant Histones journal, March 2007

HOTAIR Lifts Noncoding RNAs to New Levels journal, June 2007

Optimal Determination of Particle Orientation, Absolute Hand, and Contrast Loss in Single-particle Electron Cryomicroscopy journal, October 2003

Automated molecular microscopy: The new Leginon system journal, July 2005

Bsoft: Image processing and molecular modeling for electron microscopy journal, January 2007

Appion: An integrated, database-driven pipeline to facilitate EM image processing journal, April 2009

DoG Picker and TiltPicker: Software tools to facilitate particle selection in single particle electron microscopy journal, May 2009

iMODFIT: Efficient and robust flexible fitting based on vibrational analysis in internal coordinates journal, November 2013

Histone Methylation by PRC2 Is Inhibited by Active Chromatin Marks journal, May 2011

Post-translational modifications of tau protein: Implications for Alzheimer's disease journal, March 2011

Chemically ubiquitylated histone H2B stimulates hDot1L-mediated intranucleosomal methylation journal, April 2008

Role of the polycomb protein EED in the propagation of repressive histone marks journal, September 2009

The structural basis of modified nucleosome recognition by 53BP1 journal, July 2016

Mechanism of chromatin remodelling revealed by the Snf2-nucleosome structure journal, April 2017

Prevention of overfitting in cryo-EM structure determination journal, July 2012

SPIDER image processing for single-particle reconstruction of biological macromolecules from electron micrographs journal, October 2008

The SANT domain: a unique histone-tail-binding module? journal, February 2004

Understanding the language of Lys36 methylation at histone H3 journal, January 2012

Phf19 links methylated Lys36 of histone H3 to regulation of Polycomb activity journal, October 2012

Molecular analysis of PRC2 recruitment to DNA in chromatin and its inhibition by RNA journal, October 2017

H3K36 Methylation Antagonizes PRC2-mediated H3K27 Methylation journal, January 2011

Characterization of nucleosome core particles containing histone proteins made in bacteria 1 1Edited by A. Klug
journal, September 1997

Accelerated cryo-EM structure determination with parallelisation using GPUs in RELION-2
journal, November 2016

Nucleosome-binding activities within JARID2 and EZH1 regulate the function of PRC2 on chromatin
journal, December 2013

Structures of human PRC2 with its cofactors AEBP2 and JARID2
journal, January 2018

iMODFIT: Efficient and robust flexible fitting based on vibrational analysis in internal coordinates
journal, November 2013

Accurate determination of local defocus and specimen tilt in electron microscopy
journal, June 2003

DoG Picker and TiltPicker: Software tools to facilitate particle selection in single particle electron microscopy
journal, May 2009

Prevention of overfitting in cryo-EM structure determination
journal, July 2012

Appion: An integrated, database-driven pipeline to facilitate EM image processing
journal, April 2009

Automated molecular microscopy: The new Leginon system
journal, July 2005

Jarid2 and PRC2, partners in regulating gene expression
journal, February 2010

Molecular architecture of human polycomb repressive complex 2
journal, October 2012

Asymmetrically Modified Nucleosomes
journal, September 2012

Mechanism of chromatin remodelling revealed by the Snf2-nucleosome structure
journal, April 2017

Functional Demarcation of Active and Silent Chromatin Domains in Human HOX Loci by Noncoding RNAs
journal, June 2007

Histone Methylation by PRC2 Is Inhibited by Active Chromatin Marks
journal, May 2011

Role of Histone H3 Lysine 27 Methylation in Polycomb-Group Silencing
journal, September 2002

The structural basis of modified nucleosome recognition by 53BP1
journal, July 2016

MotionCor2: anisotropic correction of beam-induced motion for improved cryo-electron microscopy
journal, February 2017

3D-DART: a DNA structure modelling server
journal, May 2009

Bsoft: Image processing and molecular modeling for electron microscopy
journal, January 2007

Role of the polycomb protein EED in the propagation of repressive histone marks
journal, September 2009

The SANT domain: a unique histone-tail-binding module?
journal, February 2004

Gctf: Real-time CTF determination and correction
journal, January 2016

Structural basis of histone H3K27 trimethylation by an active polycomb repressive complex 2
journal, October 2015

New DNA sequence rules for high affinity binding to histone octamer and sequence-directed nucleosome positioning
journal, February 1998

Crystal Structures of Nucleosome Core Particles Containing the ‘601’ Strong Positioning Sequence
journal, October 2010

Histone target selection within chromatin: an exemplary case of teamwork
journal, May 2014

A model for transmission of the H3K27me3 epigenetic mark
journal, October 2008

Understanding the language of Lys36 methylation at histone H3
journal, January 2012

Optimal Determination of Particle Orientation, Absolute Hand, and Contrast Loss in Single-particle Electron Cryomicroscopy
journal, October 2003

A Bayesian View on Cryo-EM Structure Determination
journal, January 2012

Visualizing density maps with UCSF Chimera
journal, January 2007

Dense Chromatin Activates Polycomb Repressive Complex 2 to Regulate H3 Lysine 27 Methylation
journal, August 2012

The Site-Specific Installation of Methyl-Lysine Analogs into Recombinant Histones
journal, March 2007

Topology representing network enables highly accurate classification of protein images taken by cryo electron-microscope without masking
journal, September 2003

Polycomb Proteins Targeted by a Short Repeat RNA to the Mouse X Chromosome
journal, October 2008

DNA binding by PHF1 prolongs PRC2 residence time on chromatin and thereby promotes H3K27 methylation
journal, October 2017

AEBP2 as a potential targeting protein for Polycomb Repression Complex PRC2
journal, March 2009

Phf19 links methylated Lys36 of histone H3 to regulation of Polycomb activity
journal, October 2012

Chemically ubiquitylated histone H2B stimulates hDot1L-mediated intranucleosomal methylation
journal, April 2008

Substrate Preferences of the EZH2 Histone Methyltransferase Complex
journal, January 2006

Molecular analysis of PRC2 recruitment to DNA in chromatin and its inhibition by RNA
journal, October 2017

Post-translational modifications of tau protein: Implications for Alzheimer's disease
journal, March 2011

Structural basis of oncogenic histone H3K27M inhibition of human polycomb repressive complex 2
journal, April 2016

SPIDER image processing for single-particle reconstruction of biological macromolecules from electron micrographs
journal, October 2008

ChromEMT: Visualizing 3D chromatin structure and compaction in interphase and mitotic cells
journal, July 2017

Sampling the conformational space of the catalytic subunit of human γ-secretase
journal, December 2015

PARP1 exhibits enhanced association and catalytic efficiency with γH2A.X-nucleosome
journal, December 2019

Red light-induced structure changes in phytochrome A from Pisum sativum
journal, February 2021

Below 3 Å structure of apoferritin using a multipurpose TEM with a side entry cryoholder
journal, April 2021

Structures of human PRC2 with its cofactors AEBP2 and JARID2
text, January 2018

A Bayesian view on cryo-EM structure determination
conference, May 2012

Substrate Preferences of the EZH2 Histone Methyltransferase Complex
text, January 2006

Chemically ubiquitylated histone H2B stimulates hDot1L-mediated intranucleosomal methylation
text, January 2008

New DNA sequence rules for high affinity binding to histone octamer and sequence-directed nucleosome positioning
journal, February 1998

The Site-Specific Installation of Methyl-Lysine Analogs into Recombinant Histones
journal, March 2007

HOTAIR Lifts Noncoding RNAs to New Levels
journal, June 2007

Optimal Determination of Particle Orientation, Absolute Hand, and Contrast Loss in Single-particle Electron Cryomicroscopy
journal, October 2003

Automated molecular microscopy: The new Leginon system
journal, July 2005

Bsoft: Image processing and molecular modeling for electron microscopy
journal, January 2007

Appion: An integrated, database-driven pipeline to facilitate EM image processing
journal, April 2009

DoG Picker and TiltPicker: Software tools to facilitate particle selection in single particle electron microscopy
journal, May 2009

iMODFIT: Efficient and robust flexible fitting based on vibrational analysis in internal coordinates
journal, November 2013

Histone Methylation by PRC2 Is Inhibited by Active Chromatin Marks
journal, May 2011

Post-translational modifications of tau protein: Implications for Alzheimer's disease
journal, March 2011

Chemically ubiquitylated histone H2B stimulates hDot1L-mediated intranucleosomal methylation
journal, April 2008

Role of the polycomb protein EED in the propagation of repressive histone marks
journal, September 2009

The structural basis of modified nucleosome recognition by 53BP1
journal, July 2016

Mechanism of chromatin remodelling revealed by the Snf2-nucleosome structure
journal, April 2017

Prevention of overfitting in cryo-EM structure determination
journal, July 2012

SPIDER image processing for single-particle reconstruction of biological macromolecules from electron micrographs
journal, October 2008

The SANT domain: a unique histone-tail-binding module?
journal, February 2004

Understanding the language of Lys36 methylation at histone H3
journal, January 2012

Phf19 links methylated Lys36 of histone H3 to regulation of Polycomb activity
journal, October 2012

Molecular analysis of PRC2 recruitment to DNA in chromatin and its inhibition by RNA
journal, October 2017

H3K36 Methylation Antagonizes PRC2-mediated H3K27 Methylation
journal, January 2011

AEBP2 as a potential targeting protein for Polycomb Repression Complex PRC2
journal, March 2009

3D-DART: a DNA structure modelling server
journal, May 2009

Nucleosome-binding activities within JARID2 and EZH1 regulate the function of PRC2 on chromatin
journal, December 2013