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Article: The upstreams and downstreams of H3K79 methylation by DOT1L

Vlaming, Hanneke / Fred van Leeuwen

Chromosoma. 2016 Sept., v. 125, no. 4

2016

Abstract: Histone modifications regulate key processes of eukaryotic genomes. Misregulation of the enzymes that place these modifications can lead to disease. An example of this is DOT1L, the enzyme that can mono-, di-, and trimethylate the nucleosome core on ... ...

Abstract	Histone modifications regulate key processes of eukaryotic genomes. Misregulation of the enzymes that place these modifications can lead to disease. An example of this is DOT1L, the enzyme that can mono-, di-, and trimethylate the nucleosome core on lysine 79 of histone H3 (H3K79). DOT1L plays a role in development and its misregulation has been implicated in several cancers, most notably leukemias caused by a rearrangement of the MLL gene. A DOT1L inhibitor is in clinical trials for these leukemias and shows promising results, yet we are only beginning to understand DOT1Lâs function and regulation in the cell. Here, we review what happens upstream and downstream of H3K79 methylation. H3K79 methylation levels are highest in transcribed genes, where H2B ubiquitination can promote DOT1L activity. In addition, DOT1L can be targeted to transcribed regions of the genome by several of its interaction partners. Although methylation levels strongly correlate with transcription, the mechanistic link between the two is unclear and probably context-dependent. Methylation of H3K79 may act through recruiting or repelling effector proteins, but we do not yet know which effectors mediate DOT1Lâs functions. Understanding DOT1L biology better will help us to understand the effects of DOT1L inhibitors and may allow the development of alternative strategies to target the DOT1L pathway.
Keywords	clinical trials ; enzymes ; genes ; histones ; lysine ; methylation ; neoplasms ; nucleosomes ; transcription (genetics) ; ubiquitination
Language	English
Dates of publication	2016-09
Size	p. 593-605.
Publishing place	Springer Berlin Heidelberg
Document type	Article
Note	Review
ZDB-ID	203083-4
ISSN	1432-0886 ; 0009-5915
ISSN (online)	1432-0886
ISSN	0009-5915
DOI	10.1007/s00412-015-0570-5
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Epigenetics Identifier screens reveal regulators of chromatin acylation and limited specificity of acylation antibodies

Leonie Kollenstart / Sophie C. van der Horst / Kees Vreeken / George M. C. Janssen / Fabrizio Martino / Hanneke Vlaming / Peter A. van Veelen / Fred van Leeuwen / Haico van Attikum

Scientific Reports, Vol 11, Iss 1, Pp 1-

2021 Volume 17

Abstract: Abstract The collection of known posttranslational modifications (PTMs) has expanded rapidly with the identification of various non-acetyl histone lysine acylations, such as crotonylation, succinylation and butyrylation, yet their regulation is still not ...

Abstract	Abstract The collection of known posttranslational modifications (PTMs) has expanded rapidly with the identification of various non-acetyl histone lysine acylations, such as crotonylation, succinylation and butyrylation, yet their regulation is still not fully understood. Through an unbiased chromatin immunoprecipitation (ChIP)-based approach called Epigenetics-IDentifier (Epi-ID), we aimed to identify regulators of crotonylation, succinylation and butyrylation in thousands of yeast mutants simultaneously. However, highly correlative results led us to further investigate the specificity of the pan-K-acyl antibodies used in our Epi-ID studies. This revealed cross-reactivity and lack of specificity of pan-K-acyl antibodies in various assays. Our findings suggest that the antibodies might recognize histone acetylation in vivo, in addition to histone acylation, due to the vast overabundance of acetylation compared to other acylation modifications in cells. Consequently, our Epi-ID screen mostly identified factors affecting histone acetylation, including known (e.g. GCN5, HDA1, and HDA2) and unanticipated (MET7, MTF1, CLB3, and RAD26) factors, expanding the repertoire of acetylation regulators. Antibody-independent follow-up experiments on the Gcn5-Ada2-Ada3 (ADA) complex revealed that, in addition to acetylation and crotonylation, ADA has the ability to butyrylate histones. Thus, our Epi-ID screens revealed limits of using pan-K-acyl antibodies in epigenetics research, expanded the repertoire of regulators of histone acetylation, and attributed butyrylation activity to the ADA complex.
Keywords	Medicine ; R ; Science ; Q
Subject code	570
Language	English
Publishing date	2021-06-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Strategy for Development of Site-Specific Ubiquitin Antibodies

Ila van Kruijsbergen / Monique P. C. Mulder / Michael Uckelmann / Tibor van Welsem / John de Widt / Aldo Spanjaard / Heinz Jacobs / Farid El Oualid / Huib Ovaa / Fred van Leeuwen

Frontiers in Chemistry, Vol

2020 Volume 8

Abstract: Protein ubiquitination is a key post-translational modification regulating a wide range of biological processes. Ubiquitination involves the covalent attachment of the small protein ubiquitin to a lysine of a protein substrate. In addition to its well- ... ...

Abstract	Protein ubiquitination is a key post-translational modification regulating a wide range of biological processes. Ubiquitination involves the covalent attachment of the small protein ubiquitin to a lysine of a protein substrate. In addition to its well-established role in protein degradation, protein ubiquitination plays a role in protein-protein interactions, DNA repair, transcriptional regulation, and other cellular functions. Understanding the mechanisms and functional relevance of ubiquitin as a signaling system requires the generation of antibodies or alternative reagents that specifically detect ubiquitin in a site-specific manner. However, in contrast to other post-translational modifications such as acetylation, phosphorylation, and methylation, the instability and size of ubiquitin−76 amino acids–complicate the preparation of suitable antigens and the generation antibodies detecting such site-specific modifications. As a result, the field of ubiquitin research has limited access to specific antibodies. This severely hampers progress in understanding the regulation and function of site-specific ubiquitination in many areas of biology, specifically in epigenetics and cancer. Therefore, there is a high demand for antibodies recognizing site-specific ubiquitin modifications. Here we describe a strategy for the development of site-specific ubiquitin antibodies. Based on a recently developed antibody against site-specific ubiquitination of histone H2B, we provide detailed protocols for chemical synthesis methods for antigen preparation and discuss considerations for screening and quality control experiments.
Keywords	ubiquitin ; histone H2B ; H2B-K123ub ; PCNA ; monoclonal antibody ; Chemistry ; QD1-999
Subject code	570
Language	English
Publishing date	2020-02-01T00:00:00Z
Publisher	Frontiers Media S.A.
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: CD4+ T cell help creates memory CD8+ T cells with innate and help-independent recall capacities

Tomasz Ahrends / Julia Busselaar / Tesa M. Severson / Nikolina Bąbała / Evert de Vries / Astrid Bovens / Lodewyk Wessels / Fred van Leeuwen / Jannie Borst

Nature Communications, Vol 10, Iss 1, Pp 1-

2019 Volume 13

Abstract: Help from CD4+ T cells is important to induce CD8+ T cell memory responses, but mechanistic insights are lacking. Here, the authors show, by transcriptomics and epigenetics, how CD4+ T cells help program memory CD8+ T cells for help-independent recall by ...

Abstract	Help from CD4+ T cells is important to induce CD8+ T cell memory responses, but mechanistic insights are lacking. Here, the authors show, by transcriptomics and epigenetics, how CD4+ T cells help program memory CD8+ T cells for help-independent recall by antigens, as well as for innate-like recall responses by IL-12/IL-18 and promoting survival by IL-15.
Keywords	Science ; Q
Language	English
Publishing date	2019-12-01T00:00:00Z
Publisher	Nature Publishing Group
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: CD4+ T cell help creates memory CD8+ T cells with innate and help-independent recall capacities

Tomasz Ahrends / Julia Busselaar / Tesa M. Severson / Nikolina Bąbała / Evert de Vries / Astrid Bovens / Lodewyk Wessels / Fred van Leeuwen / Jannie Borst

Nature Communications, Vol 10, Iss 1, Pp 1-

2019 Volume 13

Abstract	Help from CD4+ T cells is important to induce CD8+ T cell memory responses, but mechanistic insights are lacking. Here, the authors show, by transcriptomics and epigenetics, how CD4+ T cells help program memory CD8+ T cells for help-independent recall by antigens, as well as for innate-like recall responses by IL-12/IL-18 and promoting survival by IL-15.
Keywords	Science ; Q
Language	English
Publishing date	2019-12-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Decoding the chromatin proteome of a single genomic locus by DNA sequencing.

Tessy Korthout / Deepani W Poramba-Liyanage / Ila van Kruijsbergen / Kitty F Verzijlbergen / Frank P A van Gemert / Tibor van Welsem / Fred van Leeuwen

PLoS Biology, Vol 16, Iss 7, p e

2018 Volume 2005542

Abstract: Transcription, replication, and repair involve interactions of specific genomic loci with many different proteins. How these interactions are orchestrated at any given location and under changing cellular conditions is largely unknown because ... ...

Abstract	Transcription, replication, and repair involve interactions of specific genomic loci with many different proteins. How these interactions are orchestrated at any given location and under changing cellular conditions is largely unknown because systematically measuring protein-DNA interactions at a specific locus in the genome is challenging. To address this problem, we developed Epi-Decoder, a Tag-chromatin immunoprecipitation-Barcode-Sequencing (TAG-ChIP-Barcode-Seq) technology in budding yeast. Epi-Decoder is orthogonal to proteomics approaches because it does not rely on mass spectrometry (MS) but instead takes advantage of DNA sequencing. Analysis of the proteome of a transcribed locus proximal to an origin of replication revealed more than 400 interacting proteins. Moreover, replication stress induced changes in local chromatin proteome composition prior to local origin firing, affecting replication proteins as well as transcription proteins. Finally, we show that native genomic loci can be decoded by efficient construction of barcode libraries assisted by clustered regularly interspaced short palindromic repeats and CRISPR-associated protein 9 (CRISPR/Cas9). Thus, Epi-Decoder is an effective strategy to identify and quantify in an unbiased and systematic manner the proteome of an individual genomic locus by DNA sequencing.
Keywords	Biology (General) ; QH301-705.5
Subject code	612
Language	English
Publishing date	2018-07-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: The effect of acetaminophen on ubiquitin homeostasis in Saccharomyces cerevisiae.

Angelina Huseinovic / Jolanda S van Leeuwen / Tibor van Welsem / Iris Stulemeijer / Fred van Leeuwen / Nico P E Vermeulen / Jan M Kooter / J Chris Vos

PLoS ONE, Vol 12, Iss 3, p e

2017 Volume 0173573

Abstract: Acetaminophen (APAP), although considered a safe drug, is one of the major causes of acute liver failure by overdose, and therapeutic chronic use can cause serious health problems. Although the reactive APAP metabolite N-acetyl-p-benzoquinoneimine (NAPQI) ...

Abstract	Acetaminophen (APAP), although considered a safe drug, is one of the major causes of acute liver failure by overdose, and therapeutic chronic use can cause serious health problems. Although the reactive APAP metabolite N-acetyl-p-benzoquinoneimine (NAPQI) is clearly linked to liver toxicity, toxicity of APAP is also found without drug metabolism of APAP to NAPQI. To get more insight into mechanisms of APAP toxicity, a genome-wide screen in Saccharomyces cerevisiae for APAP-resistant deletion strains was performed. In this screen we identified genes related to the DNA damage response. Next, we investigated the link between genotype and APAP-induced toxicity or resistance by performing a more detailed screen with a library containing mutants of 1522 genes related to nuclear processes, like DNA repair and chromatin remodelling. We identified 233 strains that had an altered growth rate relative to wild type, of which 107 showed increased resistance to APAP and 126 showed increased sensitivity. Gene Ontology analysis identified ubiquitin homeostasis, regulation of transcription of RNA polymerase II genes, and the mitochondria-to-nucleus signalling pathway to be associated with APAP resistance, while histone exchange and modification, and vesicular transport were connected to APAP sensitivity. Indeed, we observed a link between ubiquitin levels and APAP resistance, whereby ubiquitin deficiency conferred resistance to APAP toxicity while ubiquitin overexpression resulted in sensitivity. The toxicity profile of various chemicals, APAP, and its positional isomer AMAP on a series of deletion strains with ubiquitin deficiency showed a unique resistance pattern for APAP. Furthermore, exposure to APAP increased the level of free ubiquitin and influenced the ubiquitination of proteins. Together, these results uncover a role for ubiquitin homeostasis in APAP-induced toxicity.
Keywords	Medicine ; R ; Science ; Q
Subject code	570
Language	English
Publishing date	2017-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Direct screening for chromatin status on DNA barcodes in yeast delineates the regulome of H3K79 methylation by Dot1

Hanneke Vlaming / Thom M Molenaar / Tibor van Welsem / Deepani W Poramba-Liyanage / Desiree E Smith / Arno Velds / Liesbeth Hoekman / Tessy Korthout / Sjoerd Hendriks / AF Maarten Altelaar / Fred van Leeuwen

eLife, Vol

2016 Volume 5

Abstract: Given the frequent misregulation of chromatin in cancer, it is important to understand the cellular mechanisms that regulate chromatin structure. However, systematic screening for epigenetic regulators is challenging and often relies on laborious assays ... ...

Abstract	Given the frequent misregulation of chromatin in cancer, it is important to understand the cellular mechanisms that regulate chromatin structure. However, systematic screening for epigenetic regulators is challenging and often relies on laborious assays or indirect reporter read-outs. Here we describe a strategy, Epi-ID, to directly assess chromatin status in thousands of mutants. In Epi-ID, chromatin status on DNA barcodes is interrogated by chromatin immunoprecipitation followed by deep sequencing, allowing for quantitative comparison of many mutants in parallel. Screening of a barcoded yeast knock-out collection for regulators of histone H3K79 methylation by Dot1 identified all known regulators as well as novel players and processes. These include histone deposition, homologous recombination, and adenosine kinase, which influences the methionine cycle. Gcn5, the acetyltransferase within the SAGA complex, was found to regulate histone methylation and H2B ubiquitination. The concept of Epi-ID is widely applicable and can be readily applied to other chromatin features.
Keywords	histone modifications ; H3K79 methylation ; Dot1 ; SAGA ; DNA repair ; adenosine kinase ; Medicine ; R ; Science ; Q ; Biology (General) ; QH301-705.5
Subject code	571
Language	English
Publishing date	2016-12-01T00:00:00Z
Publisher	eLife Sciences Publications Ltd
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Patterns and mechanisms of ancestral histone protein inheritance in budding yeast.

Marta Radman-Livaja / Kitty F Verzijlbergen / Assaf Weiner / Tibor van Welsem / Nir Friedman / Oliver J Rando / Fred van Leeuwen

PLoS Biology, Vol 9, Iss 6, p e

2011 Volume 1001075

Abstract: Replicating chromatin involves disruption of histone-DNA contacts and subsequent reassembly of maternal histones on the new daughter genomes. In bulk, maternal histones are randomly segregated to the two daughters, but little is known about the fine ... ...

Abstract	Replicating chromatin involves disruption of histone-DNA contacts and subsequent reassembly of maternal histones on the new daughter genomes. In bulk, maternal histones are randomly segregated to the two daughters, but little is known about the fine details of this process: do maternal histones re-assemble at preferred locations or close to their original loci? Here, we use a recently developed method for swapping epitope tags to measure the disposition of ancestral histone H3 across the yeast genome over six generations. We find that ancestral H3 is preferentially retained at the 5' ends of most genes, with strongest retention at long, poorly transcribed genes. We recapitulate these observations with a quantitative model in which the majority of maternal histones are reincorporated within 400 bp of their pre-replication locus during replication, with replication-independent replacement and transcription-related retrograde nucleosome movement shaping the resulting distributions of ancestral histones. We find a key role for Topoisomerase I in retrograde histone movement during transcription, and we find that loss of Chromatin Assembly Factor-1 affects replication-independent turnover. Together, these results show that specific loci are enriched for histone proteins first synthesized several generations beforehand, and that maternal histones re-associate close to their original locations on daughter genomes after replication. Our findings further suggest that accumulation of ancestral histones could play a role in shaping histone modification patterns.
Keywords	Biology (General) ; QH301-705.5
Subject code	612 ; 570
Language	English
Publishing date	2011-06-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: A UV-Induced Genetic Network Links the RSC Complex to Nucleotide Excision Repair and Shows Dose-Dependent Rewiring

Rohith Srivas / Thomas Costelloe / Anne-Ruxandra Carvunis / Sovan Sarkar / Erik Malta / Su Ming Sun / Marijke Pool / Katherine Licon / Tibor van Welsem / Fred van Leeuwen / Peter J. McHugh / Haico van Attikum / Trey Ideker

Cell Reports, Vol 5, Iss 6, Pp 1714-

2013 Volume 1724

Abstract: Efficient repair of UV-induced DNA damage requires the precise coordination of nucleotide excision repair (NER) with numerous other biological processes. To map this crosstalk, we generated a differential genetic interaction map centered on quantitative ... ...

Abstract	Efficient repair of UV-induced DNA damage requires the precise coordination of nucleotide excision repair (NER) with numerous other biological processes. To map this crosstalk, we generated a differential genetic interaction map centered on quantitative growth measurements of >45,000 double mutants before and after different doses of UV radiation. Integration of genetic data with physical interaction networks identified a global map of 89 UV-induced functional interactions among 62 protein complexes, including a number of links between the RSC complex and several NER factors. We show that RSC is recruited to both silenced and transcribed loci following UV damage where it facilitates efficient repair by promoting nucleosome remodeling. Finally, a comparison of the response to high versus low levels of UV shows that the degree of genetic rewiring correlates with dose of UV and reveals a network of dose-specific interactions. This study makes available a large resource of UV-induced interactions, and it illustrates a methodology for identifying dose-dependent interactions based on quantitative shifts in genetic networks.
Keywords	Biology (General) ; QH301-705.5
Language	English
Publishing date	2013-12-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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