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Kahn, Tatyana G.
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Publications (10 of 20) Show all publications
Dorafshan, E., Kahn, T. G., Glotov, A., Savitsky, M., Walther, M., Reuter, G. & Schwartz, Y. B. (2019). Ash1 counteracts Polycomb repression independent of histone H3 lysine 36 methylation. EMBO Reports, 20(4), Article ID e46762.
Open this publication in new window or tab >>Ash1 counteracts Polycomb repression independent of histone H3 lysine 36 methylation
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2019 (English)In: EMBO Reports, ISSN 1469-221X, E-ISSN 1469-3178, Vol. 20, no 4, article id e46762Article in journal (Refereed) Published
Abstract [en]

Polycomb repression is critical for metazoan development. Equally important but less studied is the Trithorax system, which safeguards Polycomb target genes from the repression in cells where they have to remain active. It was proposed that the Trithorax system acts via methylation of histone H3 at lysine 4 and lysine 36 (H3K36), thereby inhibiting histone methyltransferase activity of the Polycomb complexes. Here we test this hypothesis by asking whether the Trithorax group protein Ash1 requires H3K36 methylation to counteract Polycomb repression. We show that Ash1 is the only Drosophila H3K36-specific methyltransferase necessary to prevent excessive Polycomb repression of homeotic genes. Unexpectedly, our experiments reveal no correlation between the extent of H3K36 methylation and the resistance to Polycomb repression. Furthermore, we find that complete substitution of the zygotic histone H3 with a variant in which lysine 36 is replaced by arginine does not cause excessive repression of homeotic genes. Our results suggest that the model, where the Trithorax group proteins methylate histone H3 to inhibit the histone methyltransferase activity of the Polycomb complexes, needs revision.

Place, publisher, year, edition, pages
WILEY, 2019
Keywords
Ash1, Drosophila, Polycomb, Trithorax
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-158742 (URN)10.15252/embr.201846762 (DOI)000463235300017 ()30833342 (PubMedID)
Available from: 2019-05-20 Created: 2019-05-20 Last updated: 2019-05-20Bibliographically approved
Cameron, S. R., Nandi, S., Kahn, T. G., Barrasa, J. I., Stenberg, P. & Schwartz, Y. B. (2018). PTE, a novel module to target Polycomb Repressive Complex 1 to the human cyclin D2 (CCND2) oncogene. Journal of Biological Chemistry, 293(37), 14342-14358
Open this publication in new window or tab >>PTE, a novel module to target Polycomb Repressive Complex 1 to the human cyclin D2 (CCND2) oncogene
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2018 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 293, no 37, p. 14342-14358Article in journal (Refereed) Published
Abstract [en]

Polycomb group proteins are essential epigenetic repressors. They form multiple protein complexes of which two kinds, PRC1 and PRC2, are indispensable for repression. Although much is known about their biochemical properties, how mammalian PRC1 and PRC2 are targeted to specific genes is poorly understood. Here, we establish the cyclin D2 (CCND2) oncogene as a simple model to address this question. We provide the evidence that the targeting of PRC1 to CCND2 involves a dedicated PRC1-targeting element (PTE). The PTE appears to act in concert with an adjacent cytosine-phosphate-guanine (CpG) island to arrange for the robust binding of PRC1 and PRC2 to repressed CCND2. Our findings pave the way to identify sequence-specific DNA-binding proteins implicated in the targeting of mammalian PRC1 complexes and provide novel link between polycomb repression and cancer.

Place, publisher, year, edition, pages
American Society for Biochemistry and Molecular Biology, 2018
Keywords
polycomb, epigenetics, gene silencing, chromatin, oncogene, cyclin D2, polycomb targeting, PRC1
National Category
Medical Genetics
Identifiers
urn:nbn:se:umu:diva-152251 (URN)10.1074/jbc.RA118.005010 (DOI)000444671500015 ()30068546 (PubMedID)
Funder
Åke Wiberg FoundationMagnus Bergvall FoundationSwedish Cancer SocietySwedish Research CouncilKnut and Alice Wallenberg FoundationThe Kempe Foundations
Available from: 2018-10-04 Created: 2018-10-04 Last updated: 2019-02-12Bibliographically approved
Dorafshan, E., Kahn, T. G. & Schwartz, Y. B. (2017). Hierarchical recruitment of Polycomb complexes revisited. Nucleus, 8(5), 496-505
Open this publication in new window or tab >>Hierarchical recruitment of Polycomb complexes revisited
2017 (English)In: Nucleus, ISSN 1949-1034, E-ISSN 1949-1042, Vol. 8, no 5, p. 496-505Article in journal (Refereed) Published
Abstract [en]

Polycomb Group (PcG) proteins epigenetically repress key developmental genes and thereby control alternative cell fates. PcG proteins act as complexes that can modify histones and these histone modifications play a role in transmitting the memory of the repressed state as cells divide. Here we consider mainstream models that link histone modifications to hierarchical recruitment of PcG complexes and compare them to results of a direct test of interdependence between PcG complexes for recruitment to Drosophila genes. The direct test indicates that PcG complexes do not rely on histone modifications to recognize their target genes but use them to stabilize the interactions within large chromatin domains. It also shows that multiple strategies are used to coordinate the targeting of PcG complexes to different genes, which may make the repression of these genes more or less robust.

Place, publisher, year, edition, pages
Taylor & Francis Group, 2017
Keywords
Drosophila, epigenetics, Polycomb, Polycomb targeting, Polycomb Response Elements
National Category
Developmental Biology Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-143565 (URN)10.1080/19491034.2017.1363136 (DOI)000418054400008 ()28910569 (PubMedID)
Available from: 2018-01-03 Created: 2018-01-03 Last updated: 2018-11-19Bibliographically approved
Kahn, T. G., Dorafshan, E., Schultheis, D., Zare, A., Stenberg, P., Reim, I., . . . Schwartz, Y. B. (2016). Interdependence of PRC1 and PRC2 for recruitment to Polycomb Response Elements. Nucleic Acids Research, 44(21), 10132-10149
Open this publication in new window or tab >>Interdependence of PRC1 and PRC2 for recruitment to Polycomb Response Elements
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2016 (English)In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 44, no 21, p. 10132-10149Article in journal (Refereed) Published
Abstract [en]

Polycomb Group (PcG) proteins are epigenetic repressors essential for control of development and cell differentiation. They form multiple complexes of which PRC1 and PRC2 are evolutionary conserved and obligatory for repression. The targeting of PRC1 and PRC2 is poorly understood and was proposed to be hierarchical and involve tri-methylation of histone H3 (H3K27me3) and/or monoubiquitylation of histone H2A (H2AK118ub). Here, we present a strict test of this hypothesis using the Drosophila model. We discover that neither H3K27me3 nor H2AK118ub is required for targeting PRC complexes to Polycomb Response Elements (PREs). We find that PRC1 can bind PREs in the absence of PRC2 but at many PREs PRC2 requires PRC1 to be targeted. We show that one role of H3K27me3 is to allow PcG complexes anchored at PREs to interact with surrounding chromatin. In contrast, the bulk of H2AK118ub is unrelated to PcG repression. These findings radically change our view of how PcG repression is targeted and suggest that PRC1 and PRC2 can communicate independently of histone modifications.

Keywords
Epigenetics, Gene regulation, Polycomb repression mechanisms, Polycomb Response Elements
National Category
Genetics Biochemistry and Molecular Biology
Research subject
Genetics; Molecular Biology
Identifiers
urn:nbn:se:umu:diva-128511 (URN)10.1093/nar/gkw701 (DOI)000393979400015 ()27557709 (PubMedID)
Available from: 2016-12-06 Created: 2016-12-06 Last updated: 2018-11-19Bibliographically approved
Lee, H.-G., Kahn, T. G., Simcox, A., Schwartz, Y. B. & Pirrotta, V. (2015). Genome-wide activities of Polycomb complexes control pervasive transcription. Genome Research, 25(8), 1170-1181
Open this publication in new window or tab >>Genome-wide activities of Polycomb complexes control pervasive transcription
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2015 (English)In: Genome Research, ISSN 1088-9051, E-ISSN 1549-5469, Vol. 25, no 8, p. 1170-1181Article in journal (Refereed) Published
Abstract [en]

Polycomb group (PcG) complexes PRC1 and PRC2 are well known for silencing specific developmental genes. PRC2 is a methyltransferase targeting histone H3K27 and producing H3K27me3, essential for stable silencing. Less well known but quantitatively much more important is the genome-wide role of PRC2 that dimethylates similar to 70% of total H3K27. We show that H3K27me2 occurs in inverse proportion to transcriptional activity in most non-PcG target genes and intergenic regions and is governed by opposing roaming activities of PRC2 and complexes containing the H3K27 demethylase UTX. Surprisingly, loss of H3K27me2 results in global transcriptional derepression proportionally greatest in silent or weakly transcribed intergenic and genic regions and accompanied by an increase of H3K27ac and H3K4me1. H3K27me2 therefore sets a threshold that prevents random, unscheduled transcription all over the genome and even limits the activity of highly transcribed genes. PRC1-type complexes also have global roles. Unexpectedly, we find a pervasive distribution of histone H2A ubiquitylated at lysine 118 (H2AK118ub) outside of canonical PcG target regions, dependent on the RING/Sce subunit of PRC1-type complexes. We show, however, that H2AK118ub does not mediate the global PRC2 activity or the global repression and is predominantly produced by a new complex involving L(3) 73Ah, a homolog of mammalian PCGF3.

National Category
Biochemistry and Molecular Biology Medical Genetics
Identifiers
urn:nbn:se:umu:diva-107857 (URN)10.1101/gr.188920.114 (DOI)000358957500009 ()25986499 (PubMedID)
Available from: 2015-10-08 Created: 2015-08-28 Last updated: 2018-06-07Bibliographically approved
diva2:746860
Open this publication in new window or tab >>Combinatorial Interactions Are Required for the Efficient Recruitment of Pho Repressive Complex (PhoRC) to Polycomb Response Elements
2014 (English)In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 10, no 7, p. e1004495-Article in journal (Refereed) Published
Abstract [en]

Polycomb Group (PcG) proteins are epigenetic repressors that control metazoan development and cell differentiation. In Drosophila, PcG proteins form five distinct complexes targeted to genes by Polycomb Response Elements (PREs). Of all PcG complexes PhoRC is the only one that contains a sequence-specific DNA binding subunit (PHO or PHOL), which led to a model that places PhoRC at the base of the recruitment hierarchy. Here we demonstrate that in vivo PHO is preferred to PHOL as a subunit of PhoRC and that PHO and PHOL associate with PREs and a subset of transcriptionally active promoters. Although the binding to the promoter sites depends on the quality of recognition sequences, the binding to PREs does not. Instead, the efficient recruitment of PhoRC to PREs requires the SFMBT subunit and crosstalk with Polycomb Repressive Complex 1. We find that human YY1 protein, the ortholog of PHO, binds sites at active promoters in the human genome but does not bind most PcG target genes, presumably because the interactions involved in the targeting to Drosophila PREs are lost in the mammalian lineage. We conclude that the recruitment of PhoRC to PREs is based on combinatorial interactions and propose that such a recruitment strategy is important to attenuate the binding of PcG proteins when the target genes are transcriptionally active. Our findings allow the appropriate placement of PhoRC in the PcG recruitment hierarchy and provide a rationale to explain why YY1 is unlikely to serve as a general recruiter of mammalian Polycomb complexes despite its reported ability to participate in PcG repression in flies.

Place, publisher, year, edition, pages
PLOS, 2014
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-92952 (URN)10.1371/journal.pgen.1004495 (DOI)000339902600043 ()
Available from: 2014-09-15 Created: 2014-09-09 Last updated: 2018-06-07Bibliographically approved
Park, S. Y., Schwartz, Y. B., Kahn, T. G., Asker, D. & Pirrotta, V. (2012). Regulation of Polycomb group genes Psc and Su(z)2 in Drosophila melanogaster. Mechanisms of Development, 128(11-12), 536-547
Open this publication in new window or tab >>Regulation of Polycomb group genes Psc and Su(z)2 in Drosophila melanogaster
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2012 (English)In: Mechanisms of Development, ISSN 0925-4773, E-ISSN 1872-6356, Vol. 128, no 11-12, p. 536-547Article in journal (Refereed) Published
Abstract [en]

Certain Polycomb group (PcG) genes are themselves targets of PcG complexes. Two of these constitute the Drosophila Psc-Su(z)2 locus, a region whose chromatin is enriched for H3K27me3 and contains several putative Polycomb response elements (PREs) that bind PcG proteins. To understand how PcG mechanisms regulate this region, the repressive function of the PcG protein binding sites was analyzed using reporter gene constructs. We find that at least two of these are functional PREs that can silence a reporter gene in a PcG-dependent manner. One of these two can also display anti-silencing activity, dependent on the context. A PcG protein binding site near the Psc promoter behaves not as a silencer but as a down-regulation module that is actually stimulated by the Pc gene product but not by other PcG products. Deletion of one of the PREs increases the expression level of Psc and Su(z)2 by twofold at late embryonic stages. We present evidence suggesting that the Psc-Su(z)2 locus is flanked by insulator elements that may protect neighboring genes from inappropriate silencing. Deletion of one of these regions results in extension of the domain of H3K27me3 into a region containing other genes, whose expression becomes silenced in the early embryo.

Place, publisher, year, edition, pages
Elsevier Ireland Ltd., 2012
Keywords
Polycomb autoregulation, Polycomb response elements, PcG proteins, Silencing, H3K27 trimethylation, Insulators
National Category
Developmental Biology
Identifiers
urn:nbn:se:umu:diva-58146 (URN)10.1016/j.mod.2012.01.004 (DOI)000301132100002 ()22289633 (PubMedID)
Note

Ett corrigendum har publicerats: / A corrigendum has been published:

Park, S. Y., Schwartz, Y. B., Kahn, T. G., Asker, D., & Pirrotta, V. (2018). Corrigendum to “Regulation of Polycomb group genes Psc and Su(z)2 in Drosophila melanogaster” [Mech. Dev. 128 (2012) 536–547]. Mechanisms of Development, 149, 53. doi:https://doi.org/10.1016/j.mod.2017.01.002

Available from: 2012-08-27 Created: 2012-08-27 Last updated: 2018-06-08Bibliographically approved
Schwartz, Y. B., Kahn, T. G., Stenberg, P., Ohno, K., Bourgon, R. & Pirrotta, V. (2010). Alternative Epigenetic Chromatin States of Polycomb Target Genes. PLoS Genetics, 6(1), e1000805
Open this publication in new window or tab >>Alternative Epigenetic Chromatin States of Polycomb Target Genes
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2010 (English)In: PLoS Genetics, ISSN 1553-7390, Vol. 6, no 1, p. e1000805-Article in journal (Refereed) Published
Abstract [en]

Polycomb (PcG) regulation has been thought to produce stable long-term gene silencing. Genomic analyses in Drosophila and mammals, however, have shown that it targets many genes, which can switch state during development. Genetic evidence indicates that critical for the active state of PcG target genes are the histone methyltransferases Trithorax (TRX) and ASH1. Here we analyze the repertoire of alternative states in which PcG target genes are found in different Drosophila cell lines and the role of PcG proteins TRX and ASH1 in controlling these states. Using extensive genome-wide chromatin immunoprecipitation analysis, RNAi knockdowns, and quantitative RT-PCR, we show that, in addition to the known repressed state, PcG targets can reside in a transcriptionally active state characterized by formation of an extended domain enriched in ASH1, the N-terminal, but not C-terminal moiety of TRX and H3K27ac. ASH1/TRX N-ter domains and transcription are not incompatible with repressive marks, sometimes resulting in a "balanced" state modulated by both repressors and activators. Often however, loss of PcG repression results instead in a "void" state, lacking transcription, H3K27ac, or binding of TRX or ASH1. We conclude that PcG repression is dynamic, not static, and that the propensity of a target gene to switch states depends on relative levels of PcG, TRX, and activators. N-ter TRX plays a remarkable role that antagonizes PcG repression and preempts H3K27 methylation by acetylation. This role is distinct from that usually attributed to TRX/MLL proteins at the promoter. These results have important implications for Polycomb gene regulation, the "bivalent" chromatin state of embryonic stem cells, and gene expression in development.

Place, publisher, year, edition, pages
Public Library of Science, 2010
National Category
Genetics
Identifiers
urn:nbn:se:umu:diva-43197 (URN)10.1371/journal.pgen.1000805 (DOI)000274194300013 ()
Available from: 2011-04-22 Created: 2011-04-22 Last updated: 2018-06-08Bibliographically approved
Shwartz, Y. B., Kahn, T. G. & Pirrotta, V. (2010). [Polycomb and trithorax control genome expression by determining the alternative epigenetic states of chromatin for key developmental regulators].. Journal Genetika, 46(10), 1413-1416
Open this publication in new window or tab >>[Polycomb and trithorax control genome expression by determining the alternative epigenetic states of chromatin for key developmental regulators].
2010 (Russian)In: Journal Genetika, ISSN 0016-6758, Vol. 46, no 10, p. 1413-1416Article in journal (Refereed) Published
Abstract [en]

The Polycomb (PcG) and Trithorax (TrxG) group proteins are essential for development in all multicellular organisms. Mutations of the PcG and TrxG genes act as early embryonic lethals, while their overexpression correlates with malignancies. Comparative genome analysis showed that PcG and TrxG form a binary regulatory system that functions as an epigenetic rheostat to determine the threshold levels of extracellular signals affecting the expression levels of key developmental genes.

National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-46246 (URN)21254568 (PubMedID)
Note
Article in Russian.Available from: 2011-08-29 Created: 2011-08-29 Last updated: 2018-06-08Bibliographically approved
Schaaf, C. A., Misulovin, Z., Sahota, G., Siddiqui, A. M., Schwartz, Y. B., Kahn, T. G., . . . Dorsett, D. (2009). Regulation of the Drosophila Enhancer of split and invected-engrailed gene complexes by sister chromatid cohesion proteins. PloS one, 4(7), e6202
Open this publication in new window or tab >>Regulation of the Drosophila Enhancer of split and invected-engrailed gene complexes by sister chromatid cohesion proteins
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2009 (English)In: PloS one, ISSN 1932-6203, Vol. 4, no 7, p. e6202-Article in journal (Refereed) Published
Abstract [en]

The cohesin protein complex was first recognized for holding sister chromatids together and ensuring proper chromosome segregation. Cohesin also regulates gene expression, but the mechanisms are unknown. Cohesin associates preferentially with active genes, and is generally absent from regions in which histone H3 is methylated by the Enhancer of zeste [E(z)] Polycomb group silencing protein. Here we show that transcription is hypersensitive to cohesin levels in two exceptional cases where cohesin and the E(z)-mediated histone methylation simultaneously coat the entire Enhancer of split and invected-engrailed gene complexes in cells derived from Drosophila central nervous system. These gene complexes are modestly transcribed, and produce seven of the twelve transcripts that increase the most with cohesin knockdown genome-wide. Cohesin mutations alter eye development in the same manner as increased Enhancer of split activity, suggesting that similar regulation occurs in vivo. We propose that cohesin helps restrain transcription of these gene complexes, and that deregulation of similarly cohesin-hypersensitive genes may underlie developmental deficits in Cornelia de Lange syndrome.

Identifiers
urn:nbn:se:umu:diva-46231 (URN)10.1371/journal.pone.0006202 (DOI)19587787 (PubMedID)
Available from: 2011-08-29 Created: 2011-08-29 Last updated: 2018-06-08Bibliographically approved
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