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Article ; Online: Getting under the skin of Polycomb-dependent gene regulation.

Blackledge, Neil P / Klose, Robert J

2021 Volume 35, Issue 5-6, Page(s) 301–303

Abstract: The Polycomb repressive system functions through chromatin to regulate gene expression and development. In this issue ... ...

Abstract	The Polycomb repressive system functions through chromatin to regulate gene expression and development. In this issue of
MeSH term(s)	Animals ; Epidermis/growth & development ; Gene Expression Regulation, Developmental/genetics ; Mice ; Polycomb-Group Proteins/metabolism ; Transcription Factors/genetics
Chemical Substances	Polycomb-Group Proteins ; Transcription Factors
Language	English
Publishing date	2021-02-27
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	806684-x
ISSN	1549-5477 ; 0890-9369
ISSN (online)	1549-5477
ISSN	0890-9369
DOI	10.1101/gad.348257.121
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Zs.MG 54: Show issues

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Article ; Online: The molecular principles of gene regulation by Polycomb repressive complexes.

Blackledge, Neil P / Klose, Robert J

Nature reviews. Molecular cell biology

2021 Volume 22, Issue 12, Page(s) 815–833

Abstract: Precise control of gene expression is fundamental to cell function and development. Although ultimately gene expression relies on DNA-binding transcription factors to guide the activity of the transcription machinery to genes, it has also become clear ... ...

Abstract	Precise control of gene expression is fundamental to cell function and development. Although ultimately gene expression relies on DNA-binding transcription factors to guide the activity of the transcription machinery to genes, it has also become clear that chromatin and histone post-translational modification have fundamental roles in gene regulation. Polycomb repressive complexes represent a paradigm of chromatin-based gene regulation in animals. The Polycomb repressive system comprises two central protein complexes, Polycomb repressive complex 1 (PRC1) and PRC2, which are essential for normal gene regulation and development. Our early understanding of Polycomb function relied on studies in simple model organisms, but more recently it has become apparent that this system has expanded and diverged in mammals. Detailed studies are now uncovering the molecular mechanisms that enable mammalian PRC1 and PRC2 to identify their target sites in the genome, communicate through feedback mechanisms to create Polycomb chromatin domains and control transcription to regulate gene expression. In this Review, we discuss and contextualize the emerging principles that define how this fascinating chromatin-based system regulates gene expression in mammals.
MeSH term(s)	Chromatin/chemistry ; Chromatin/metabolism ; Gene Expression Regulation/genetics ; Histones/metabolism ; Humans ; Methylation ; Polycomb Repressive Complex 1/chemistry ; Polycomb Repressive Complex 1/metabolism ; Polycomb Repressive Complex 2/chemistry ; Polycomb Repressive Complex 2/metabolism ; Protein Processing, Post-Translational ; Transcription, Genetic ; Ubiquitination
Chemical Substances	Chromatin ; Histones ; Polycomb Repressive Complex 2 (EC 2.1.1.43) ; Polycomb Repressive Complex 1 (EC 2.3.2.27)
Language	English
Publishing date	2021-08-16
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2031313-5
ISSN	1471-0080 ; 1471-0072
ISSN (online)	1471-0080
ISSN	1471-0072
DOI	10.1038/s41580-021-00398-y
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Article ; Online: A CpG island-encoded mechanism protects genes from premature transcription termination.

Hughes, Amy L / Szczurek, Aleksander T / Kelley, Jessica R / Lastuvkova, Anna / Turberfield, Anne H / Dimitrova, Emilia / Blackledge, Neil P / Klose, Robert J

Nature communications

2023 Volume 14, Issue 1, Page(s) 726

Abstract: Transcription must be tightly controlled to regulate gene expression and development. However, our understanding of the molecular mechanisms that influence transcription and how these are coordinated in cells to ensure normal gene expression remains ... ...

Abstract	Transcription must be tightly controlled to regulate gene expression and development. However, our understanding of the molecular mechanisms that influence transcription and how these are coordinated in cells to ensure normal gene expression remains rudimentary. Here, by dissecting the function of the SET1 chromatin-modifying complexes that bind to CpG island-associated gene promoters, we discover that they play a specific and essential role in enabling the expression of low to moderately transcribed genes. Counterintuitively, this effect can occur independently of SET1 complex histone-modifying activity and instead relies on an interaction with the RNA Polymerase II-binding protein WDR82. Unexpectedly, we discover that SET1 complexes enable gene expression by antagonising premature transcription termination by the ZC3H4/WDR82 complex at CpG island-associated genes. In contrast, at extragenic sites of transcription, which typically lack CpG islands and SET1 complex occupancy, we show that the activity of ZC3H4/WDR82 is unopposed. Therefore, we reveal a gene regulatory mechanism whereby CpG islands are bound by a protein complex that specifically protects genic transcripts from premature termination, effectively distinguishing genic from extragenic transcription and enabling normal gene expression.
MeSH term(s)	CpG Islands/genetics ; Transcription, Genetic ; Histones/metabolism ; Chromatin/genetics ; RNA Polymerase II/genetics ; RNA Polymerase II/metabolism ; DNA Methylation/genetics
Chemical Substances	Histones ; Chromatin ; RNA Polymerase II (EC 2.7.7.-)
Language	English
Publishing date	2023-02-09
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-023-36236-2
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Article: Epi-microRNA mediated metabolic reprogramming ensures affinity maturation.

Nakagawa, Rinako / Llorian, Miriam / Varsani-Brown, Sunita / Chakravarty, Probir / Camarillo, Jeannie M / Barry, David / George, Roger / Blackledge, Neil P / Duddy, Graham / Kelleher, Neil L / Klose, Rob J / Turner, Martin / Calado, Dinis Pedro

bioRxiv : the preprint server for biology

2023

Abstract: To increase antibody affinity against pathogens, positively selected GC-B cells initiate cell division in the light zone (LZ) of germinal centres (GCs). Among those, higher-affinity clones migrate to the dark zone (DZ) and vigorously proliferate by ... ...

Abstract	To increase antibody affinity against pathogens, positively selected GC-B cells initiate cell division in the light zone (LZ) of germinal centres (GCs). Among those, higher-affinity clones migrate to the dark zone (DZ) and vigorously proliferate by relying on oxidative phosphorylation (OXPHOS). However, it remains unknown how positively selected GC-B cells adapt their metabolism for cell division in the glycolysis-dominant, cell cycle arrest-inducing, hypoxic LZ microenvironment. Here, we show that microRNA (miR)-155 mediates metabolic reprogramming during positive selection to protect high-affinity clones. Transcriptome examination and mass spectrometry analysis revealed that miR-155 regulates H3K36me2 levels by directly repressing hypoxia-induced histone lysine demethylase, Kdm2a. This is indispensable for enhancing OXPHOS through optimizing the expression of vital nuclear mitochondrial genes under hypoxia. The miR-155-Kdm2a interaction is crucial to prevent excessive production of reactive oxygen species and apoptosis. Thus, miR-155-mediated epigenetic regulation promotes mitochondrial fitness in high-affinity clones, ensuring their expansion and consequently affinity maturation.
Language	English
Publishing date	2023-10-31
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.07.31.551250
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Article ; Online: A CpG island-encoded mechanism protects genes from premature transcription termination

Amy L. Hughes / Aleksander T. Szczurek / Jessica R. Kelley / Anna Lastuvkova / Anne H. Turberfield / Emilia Dimitrova / Neil P. Blackledge / Robert J. Klose

Nature Communications, Vol 14, Iss 1, Pp 1-

2023 Volume 19

Abstract: Here the authors discover that SET1 complexes function as transcription anti-termination factors that bind to CpG islands and protect low to moderately transcribed genes from the pervasive termination activity of the ZC3H4 complex. ...

Abstract	Here the authors discover that SET1 complexes function as transcription anti-termination factors that bind to CpG islands and protect low to moderately transcribed genes from the pervasive termination activity of the ZC3H4 complex.
Keywords	Science ; Q
Language	English
Publishing date	2023-02-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: BAP1 constrains pervasive H2AK119ub1 to control the transcriptional potential of the genome.

Fursova, Nadezda A / Turberfield, Anne H / Blackledge, Neil P / Findlater, Emma L / Lastuvkova, Anna / Huseyin, Miles K / Dobrinić, Paula / Klose, Robert J

Genes & development

2021 Volume 35, Issue 9-10, Page(s) 749–770

Abstract: Histone-modifying systems play fundamental roles in gene regulation and the development of multicellular organisms. Histone modifications that are enriched at gene regulatory elements have been heavily studied, but the function of modifications found ... ...

Abstract	Histone-modifying systems play fundamental roles in gene regulation and the development of multicellular organisms. Histone modifications that are enriched at gene regulatory elements have been heavily studied, but the function of modifications found more broadly throughout the genome remains poorly understood. This is exemplified by histone H2A monoubiquitylation (H2AK119ub1), which is enriched at Polycomb-repressed gene promoters but also covers the genome at lower levels. Here, using inducible genetic perturbations and quantitative genomics, we found that the BAP1 deubiquitylase plays an essential role in constraining H2AK119ub1 throughout the genome. Removal of BAP1 leads to pervasive genome-wide accumulation of H2AK119ub1, which causes widespread reductions in gene expression. We show that elevated H2AK119ub1 preferentially counteracts Ser5 phosphorylation on the C-terminal domain of RNA polymerase II at gene regulatory elements and causes reductions in transcription and transcription-associated histone modifications. Furthermore, failure to constrain pervasive H2AK119ub1 compromises Polycomb complex occupancy at a subset of Polycomb target genes, which leads to their derepression, providing a potential molecular rationale for why the BAP1 ortholog in
MeSH term(s)	Animals ; Cell Line ; Gene Expression Regulation/genetics ; Genome/genetics ; HEK293 Cells ; Histone Code/genetics ; Histones/genetics ; Histones/metabolism ; Humans ; Mice ; Mouse Embryonic Stem Cells ; Phosphorylation/genetics ; Polycomb-Group Proteins/genetics ; Polycomb-Group Proteins/metabolism ; Tumor Suppressor Proteins/genetics ; Tumor Suppressor Proteins/metabolism ; Ubiquitin Thiolesterase/genetics ; Ubiquitin Thiolesterase/metabolism
Chemical Substances	BAP1 protein, human ; BAP1 protein, mouse ; Histones ; Polycomb-Group Proteins ; Tumor Suppressor Proteins ; Ubiquitin Thiolesterase (EC 3.4.19.12)
Language	English
Publishing date	2021-04-22
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	806684-x
ISSN	1549-5477 ; 0890-9369
ISSN (online)	1549-5477
ISSN	0890-9369
DOI	10.1101/gad.347005.120
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Article ; Online: Polycomb repressive complex 1 shapes the nucleosome landscape but not accessibility at target genes.

King, Hamish W / Fursova, Nadezda A / Blackledge, Neil P / Klose, Robert J

Genome research

2018 Volume 28, Issue 10, Page(s) 1494–1507

Abstract: Polycomb group (PcG) proteins are transcriptional repressors that play important roles in regulating gene expression during animal development. In vitro experiments have shown that PcG protein complexes can compact chromatin to limit the activity of ... ...

Abstract	Polycomb group (PcG) proteins are transcriptional repressors that play important roles in regulating gene expression during animal development. In vitro experiments have shown that PcG protein complexes can compact chromatin to limit the activity of chromatin remodeling enzymes and access of the transcriptional machinery to DNA. In fitting with these ideas, gene promoters associated with PcG proteins have been reported to be less accessible than other gene promoters. However, it remains largely untested in vivo whether PcG proteins define chromatin accessibility or other chromatin features. To address this important question, we examine the chromatin accessibility and nucleosome landscape at PcG protein-bound promoters in mouse embryonic stem cells using the assay for transposase accessible chromatin (ATAC)-seq. Combined with genetic ablation strategies, we unexpectedly discover that although PcG protein-occupied gene promoters exhibit reduced accessibility, this does not rely on PcG proteins. Instead, the Polycomb repressive complex 1 (PRC1) appears to play a unique role in driving elevated nucleosome occupancy and decreased nucleosomal spacing in Polycomb chromatin domains. Our new genome-scale observations argue, in contrast to the prevailing view, that PcG proteins do not significantly affect chromatin accessibility and highlight an underappreciated complexity in the relationship between chromatin accessibility, the nucleosome landscape, and PcG-mediated transcriptional repression.
MeSH term(s)	Animals ; Cells, Cultured ; Gene Knockout Techniques ; Mice ; Mouse Embryonic Stem Cells ; Nucleosomes/genetics ; Nucleosomes/metabolism ; Polycomb Repressive Complex 1/metabolism ; Polycomb-Group Proteins/metabolism ; Promoter Regions, Genetic ; RNA Polymerase II/metabolism ; Sequence Analysis, RNA
Chemical Substances	Nucleosomes ; Polycomb-Group Proteins ; Polycomb Repressive Complex 1 (EC 2.3.2.27) ; RNA Polymerase II (EC 2.7.7.-)
Language	English
Publishing date	2018-08-28
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1284872-4
ISSN	1549-5469 ; 1088-9051 ; 1054-9803
ISSN (online)	1549-5469
ISSN	1088-9051 ; 1054-9803
DOI	10.1101/gr.237180.118
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Zs.A 3729: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MG 8: Show issues

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Article ; Online: Biochemical Identification of Nonmethylated DNA by BioCAP-Seq.

Long, Hannah K / Rose, Nathan R / Blackledge, Neil P / Klose, Robert J

Methods in molecular biology (Clifton, N.J.)

2018 Volume 1766, Page(s) 15–29

Abstract: CpG islands are regions of vertebrate genomes that often function as gene regulatory elements and are associated with most gene promoters. CpG island elements usually contain nonmethylated CpG dinucleotides, while the remainder of the genome is ... ...

Abstract	CpG islands are regions of vertebrate genomes that often function as gene regulatory elements and are associated with most gene promoters. CpG island elements usually contain nonmethylated CpG dinucleotides, while the remainder of the genome is pervasively methylated. We developed a biochemical approach called biotinylated CxxC affinity purification (BioCAP) to unbiasedly isolate regions of the genome that contain nonmethylated CpG dinucleotides. The resulting highly pure nonmethylated DNA is easily analyzed by quantitative PCR to interrogate specific loci or via massively parallel sequencing to yield genome-wide profiles.
MeSH term(s)	Animals ; Biotinylation ; CpG Islands/genetics ; DNA/chemistry ; DNA/genetics ; DNA/metabolism ; DNA Methylation ; F-Box Proteins/chemistry ; F-Box Proteins/genetics ; F-Box Proteins/metabolism ; Genetic Loci/genetics ; High-Throughput Nucleotide Sequencing ; Humans ; Jumonji Domain-Containing Histone Demethylases/chemistry ; Jumonji Domain-Containing Histone Demethylases/genetics ; Jumonji Domain-Containing Histone Demethylases/metabolism ; Mice ; Promoter Regions, Genetic/genetics ; Recombinant Proteins/chemistry ; Recombinant Proteins/genetics ; Recombinant Proteins/metabolism ; Sequence Analysis, DNA/methods
Chemical Substances	F-Box Proteins ; Recombinant Proteins ; DNA (9007-49-2) ; Jumonji Domain-Containing Histone Demethylases (EC 1.14.11.-) ; KDM2A protein, human (EC 1.14.11.27)
Language	English
Publishing date	2018-03-15
Publishing country	United States
Document type	Journal Article
ISSN	1940-6029
ISSN (online)	1940-6029
DOI	10.1007/978-1-4939-7768-0_2
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Targeting Polycomb systems to regulate gene expression: modifications to a complex story.

Blackledge, Neil P / Rose, Nathan R / Klose, Robert J

Nature reviews. Molecular cell biology

2015 Volume 16, Issue 11, Page(s) 643–649

Abstract: Polycomb group proteins are transcriptional repressors that are essential for normal gene regulation during development. Recent studies suggest that Polycomb repressive complexes (PRCs) recognize and are recruited to their genomic target sites through a ... ...

Abstract	Polycomb group proteins are transcriptional repressors that are essential for normal gene regulation during development. Recent studies suggest that Polycomb repressive complexes (PRCs) recognize and are recruited to their genomic target sites through a range of different mechanisms, which involve transcription factors, CpG island elements and non-coding RNAs. Together with the realization that the interplay between PRC1 and PRC2 is more intricate than was previously appreciated, this has increased our understanding of the vertebrate Polycomb system at the molecular level.
MeSH term(s)	Animals ; Cell Cycle Proteins/metabolism ; Chromatin/genetics ; CpG Islands/genetics ; DNA-Binding Proteins/metabolism ; Gene Expression Regulation/genetics ; Histones/metabolism ; Humans ; Mice ; Polycomb Repressive Complex 1/metabolism ; Polycomb Repressive Complex 2/metabolism ; RNA, Untranslated/genetics ; RNA-Binding Proteins/metabolism ; Transcription Factors/metabolism ; Transcription, Genetic/genetics
Chemical Substances	Cell Cycle Proteins ; Chromatin ; DNA-Binding Proteins ; Histones ; PRC1 protein, human ; RNA, Untranslated ; RNA-Binding Proteins ; Transcription Factors ; Polycomb Repressive Complex 2 (EC 2.1.1.43) ; Polycomb Repressive Complex 1 (EC 2.3.2.27)
Language	English
Publishing date	2015-11
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2031313-5
ISSN	1471-0080 ; 1471-0072
ISSN (online)	1471-0080
ISSN	1471-0072
DOI	10.1038/nrm4067
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Article ; Online: CpG island chromatin: a platform for gene regulation.

Blackledge, Neil P / Klose, Robert

Epigenetics

2011 Volume 6, Issue 2, Page(s) 147–152

Abstract: The majority of mammalian gene promoters are encompassed within regions of the genome called CpG islands that have an elevated level of non-methylated CpG dinucleotides. Despite over 20 years of study, the precise mechanisms by which CpG islands ... ...

Abstract	The majority of mammalian gene promoters are encompassed within regions of the genome called CpG islands that have an elevated level of non-methylated CpG dinucleotides. Despite over 20 years of study, the precise mechanisms by which CpG islands contribute to regulatory element function remain poorly understood. Recently it has been demonstrated that specific histone modifying enzymes are recruited directly to CpG islands through recognition of non-methylated CpG dinucleotide sequence. These enzymes then impose unique chromatin architecture on CpG islands that distinguish them from the surrounding genome. In the context of this work we discuss how CpG island elements may contribute to the function of gene regulatory elements through the utilization of chromatin and epigenetic processes.
MeSH term(s)	Animals ; Base Sequence ; Chromatin/chemistry ; Chromatin/genetics ; CpG Islands/genetics ; DNA Methylation/genetics ; DNA-Binding Proteins/chemistry ; DNA-Binding Proteins/genetics ; Epigenesis, Genetic ; F-Box Proteins ; Gene Expression Regulation ; Gene Silencing ; Genome ; Histone Demethylases/chemistry ; Histone Demethylases/genetics ; Histones/chemistry ; Histones/genetics ; Humans ; Jumonji Domain-Containing Histone Demethylases ; Oxidoreductases, N-Demethylating/genetics ; Plants/chemistry ; Plants/genetics ; Promoter Regions, Genetic ; Regulatory Elements, Transcriptional/genetics ; Trans-Activators
Chemical Substances	CXXC1 protein, human ; Chromatin ; DNA-Binding Proteins ; F-Box Proteins ; Histones ; Trans-Activators ; Histone Demethylases (EC 1.14.11.-) ; Jumonji Domain-Containing Histone Demethylases (EC 1.14.11.-) ; KDM2A protein, human (EC 1.14.11.27) ; Oxidoreductases, N-Demethylating (EC 1.5.-)
Language	English
Publishing date	2011-02-01
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1559-2308
ISSN (online)	1559-2308
DOI	10.4161/epi.6.2.13640
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