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Towards forecasting epigenetic repression
Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
2024 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Multicellular organisms form many different cell types from one genome, which requires differential gene activity. The Polycomb system upholds the correct gene expression programs by epigenetically silencing genes that encode critical transcription regulators. It is defined by the protein complexes Polycomb Repressive Complexes 1 and 2 (PRC1 and PRC2). PRC2 methylates lysine 27 on histone H3 (H3K27) on nucleosomes. This is necessary for the repression, but it is not known why. In Drosophila melanogaster both PRC1 and PRC2 bind to DNA elements called PREs near the target genes. In human cells, PRC2 are tethered to CpG islands, but PRC1 tethering is not well understood. In paper I of the thesis we uncover the first comprehensive catalogue of DNA elements, Polycomb Tethering Elements (PTEs), that target PRC1 to human developmental genes. PTEs and CpG islands may be intermixed—forming a PRE equivalent—or offset from each other. Genes equipped with PTEs have low transcription and are stochastically reactivated upon deletion of their PTE. In paper II, we used a computational model to stochastically simulate both the random and targeted methylation by PRC2, to understand the dynamics of H3K27 methylation. The model was constrained by data, such as the levels of methylation in cells, allosteric stimulation of PRC2 by H3K27 trimethylation, and the differing catalytic efficiency of each successive methyl transfer to H3K27. We used it to investigate PRC2’s allosteric stimulation, the relationship between the rates of methylation and demethylation and cell cycle length, and how the rapid embryonic development of D. melanogaster affects the maternal contribution of H3K27me3 to the embryo. In paper III we used polymer modelling to investigate how chromatin folding by PRC1-H3K27me3 interactions affects contacts inside loci repressed by the Polycomb system. With these three studies, this thesis combines experimental and computational methods to further our understanding of epigenetic repression by the Polycomb system.

Place, publisher, year, edition, pages
Umeå: Umeå University, 2024. , p. 43
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 2293
Keywords [en]
epigenetics, Polycomb, PRC1, PRC2, H3K27 methylation, Monte-Carlo simulation, chromatin structure, Drosophila
National Category
Cell and Molecular Biology Bioinformatics and Systems Biology
Research subject
molecular biotechnology (dept of molecular biology)
Identifiers
URN: urn:nbn:se:umu:diva-222738ISBN: 978-91-8070-334-5 (print)ISBN: 978-91-8070-335-2 (electronic)OAI: oai:DiVA.org:umu-222738DiVA, id: diva2:1847172
Public defence
2024-04-26, Hörsal NAT.D.410, Naturvetarhuset, Umeå, 13:00 (English)
Opponent
Supervisors
Available from: 2024-04-05 Created: 2024-03-26 Last updated: 2024-03-27Bibliographically approved
List of papers
1. DNA elements tether canonical Polycomb Repressive Complex 1 to human genes
Open this publication in new window or tab >>DNA elements tether canonical Polycomb Repressive Complex 1 to human genes
2023 (English)In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 51, no 21, p. 11613-11633Article in journal (Refereed) Published
Abstract [en]

Development of multicellular animals requires epigenetic repression by Polycomb group proteins. The latter assemble in multi-subunit complexes, of which two kinds, Polycomb Repressive Complex 1 (PRC1) and Polycomb Repressive Complex 2 (PRC2), act together to repress key developmental genes. How PRC1 and PRC2 recognize specific genes remains an open question. Here we report the identification of several hundreds of DNA elements that tether canonical PRC1 to human developmental genes. We use the term tether to describe a process leading to a prominent presence of canonical PRC1 at certain genomic sites, although the complex is unlikely to interact with DNA directly. Detailed analysis indicates that sequence features associated with PRC1 tethering differ from those that favour PRC2 binding. Throughout the genome, the two kinds of sequence features mix in different proportions to yield a gamut of DNA elements that range from those tethering predominantly PRC1 or PRC2 to ones capable of tethering both complexes. The emerging picture is similar to the paradigmatic targeting of Polycomb complexes by Polycomb Response Elements (PREs) of Drosophila but providing for greater plasticity. [GRAPHICS]

Place, publisher, year, edition, pages
Oxford University Press, 2023
National Category
Genetics Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-217905 (URN)10.1093/nar/gkad889 (DOI)001085441300001 ()37855680 (PubMedID)2-s2.0-85179432173 (Scopus ID)
Funder
Swedish Cancer Society, 19 0003PjSwedish Cancer Society, 22 2285 PjSwedish Research Council, 2021-04435Knut and Alice Wallenberg Foundation, 2014.0018
Available from: 2023-12-20 Created: 2023-12-20 Last updated: 2024-03-26Bibliographically approved
2. Forecasting histone methylation by Polycomb complexes with minute-scale precision
Open this publication in new window or tab >>Forecasting histone methylation by Polycomb complexes with minute-scale precision
2023 (English)In: Science Advances, E-ISSN 2375-2548, Vol. 9, no 51, article id eadj8198Article in journal (Refereed) Published
Abstract [en]

Animals use the Polycomb system to epigenetically repress developmental genes. The repression requires trimethylation of lysine 27 of histone H3 (H3K27me3) by Polycomb Repressive Complex 2 (PRC2), but the dynamics of this process is poorly understood. To bridge the gap, we developed a computational model that forecasts H3K27 methylation in Drosophila with high temporal resolution and spatial accuracy of contemporary experimental techniques. Using this model, we show that pools of methylated H3K27 in dividing cells are defined by the effective concentration of PRC2 and the replication frequency. We find that the allosteric stimulation by preexisting H3K27me3 makes PRC2 better in methylating developmental genes as opposed to indiscriminate methylation throughout the genome. Applied to Drosophila development, our model argues that, in this organism, the intergenerationally inherited H3K27me3 does not “survive” rapid cycles of embryonic chromatin replication and is unlikely to transmit the memory of epigenetic repression to the offspring. Our model is adaptable to other organisms, including mice and humans.

Place, publisher, year, edition, pages
American Association for the Advancement of Science (AAAS), 2023
National Category
Genetics Developmental Biology
Identifiers
urn:nbn:se:umu:diva-220447 (URN)10.1126/sciadv.adj8198 (DOI)001142517100015 ()38134278 (PubMedID)2-s2.0-85181178114 (Scopus ID)
Funder
Swedish Research Council, 2021-04435Swedish Research Council, 2021-04080Swedish Cancer Society, 222285 Pj
Available from: 2024-02-14 Created: 2024-02-14 Last updated: 2024-03-26Bibliographically approved
3. Chromatin folding by interactions between PRC1 and histone H3 tri-methylated at lysine 27
Open this publication in new window or tab >>Chromatin folding by interactions between PRC1 and histone H3 tri-methylated at lysine 27
(English)Manuscript (preprint) (Other academic)
National Category
Biochemistry and Molecular Biology Genetics
Identifiers
urn:nbn:se:umu:diva-222731 (URN)
Available from: 2024-03-26 Created: 2024-03-26 Last updated: 2024-03-27

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Lundkvist, Moa J.

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