umu.sePublications
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Hierarchical recruitment of Polycomb complexes revisited
Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
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. Vol. 8, no 5, p. 496-505
Keywords [en]
Drosophila, epigenetics, Polycomb, Polycomb targeting, Polycomb Response Elements
National Category
Developmental Biology Biochemistry and Molecular Biology
Identifiers
URN: urn:nbn:se:umu:diva-143565DOI: 10.1080/19491034.2017.1363136ISI: 000418054400008PubMedID: 28910569OAI: oai:DiVA.org:umu-143565DiVA, id: diva2:1170548
Available from: 2018-01-03 Created: 2018-01-03 Last updated: 2018-11-19Bibliographically approved
In thesis
1. Methyltransferase Ash1, histone methylation and their impact on Polycomb repression
Open this publication in new window or tab >>Methyltransferase Ash1, histone methylation and their impact on Polycomb repression
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Antagonistic interactions between Polycomb Group (PcG) and Trithorax Group (TrxG) proteins orchestrate the expression of key developmental genes. Distinct maternally loaded repressors establish the silenced state of these genes in cells where they should not be expressed and later PcG proteins sense whether a target gene is inactive and maintain the repression throughout multiple cell divisions. PcG proteins are targeted to genes by DNA elements called Polycomb Response Elements (PREs). The proteins form two major classes of complexes, namely Polycomb Repressive Complex 1 (PRC1) and Polycomb Repressive Complex 2 (PRC2). Mechanistic details of Polycomb repression are not fully understood, however, tri-methylation of Lysine 27 of histone H3 (H3K27me3) is essential for this process. Using Drosophila cell lines deficient for either PRC1 or PRC2, I investigated the role of H3K27 methylation and the interdependence of PRC1 complexes for their recruitment to PREs. My results indicate that recruitment of PcG complexes to PREs proceed via multiple pathways and that H3K27 methylation is not needed for their targeting. However, the methylation is required to stabilize interactions of PRE-anchored PcG complexes with surrounding chromatin.

TrxG proteins prevent erroneous repression of Polycomb target genes where these genes need to be expressed. Ash1 is a TrxG protein which binds Polycomb target genes when they are transcriptionally active. It contains a SET domain which methylates Lysine 36 of histone H3 (H3K36). In vitro, histone H3 methylated at K36 is a poor substrate for H3K27 methylation by PRC2. This prompted a model where Ash1 counteracts Polycomb repression through H3K36 methylation. However, this model was never tested in vivo and does not consider several experimental observations. First, in the ash1 mutant flies the bulk H3K36me2/H3K36me3 levels remain unchanged. Second, in Drosophila, there are two other H3K36-specific histone methyltransferases, NSD and Set2, which should be capable to inhibit PRC2. Third, Ash1 contains multiple evolutionary conserved domains whose roles have not been investigated. Therefore, I asked whether H3K36 methylation is critical for Ash1 to counteract Polycomb repression in vivo and whether NSD and Set2 proteins contribute to this process. I used flies lacking endogenous histone genes and complemented them with transgenic histone genes where Lysine 36 is replaced by Arginine. In these animals, I assayed erroneous repression of HOX genes as a readout for erroneous Polycomb repression. I used the same readout in the NSD or Set2 mutant flies. I also asked if other conserved domains of Ash1 are essential for its function. In addition to SET and domain, Ash1 contains three AT hook motifs as well as BAH and PHD domains. I genetically complemented ash1 loss of function animals with transgenic Ash1 variants, in each, one domain of Ash1 is deleted. I found that Ash1 is the only H3K36-specific histone methyltransferase which counteracts Polycomb repression in Drosophila. My findings suggest that the model, where Ash1 counteracts PcG repression by inhibiting PRC2 via methylation of H3K36, has to be revised. I also showed that, in vivo, Ash1 acts as a multimer and requires SET, BAH and PHD domains to counteract Polycomb repression.

This work led to two main conclusions. First, trimethylation of H3K27 is not essential for targeting PcG proteins to PREs but acts afterwards to stabilize their interaction with the chromatin of the neighboring genes. Second, while SET domain is essential for Ash1 to oppose Polycomb repression, methylation of H3K36 does not play a central role in the process.

Place, publisher, year, edition, pages
Umeå: Umeå University, 2018. p. 46
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1986
Keywords
Trithorax Group proteins, Polycomb Group proteins, PRC1, PRC2, PRE, histone methylation, histone ubiquitylation, Ash1, SET domain, H3K36, H3K27, Drosophila
National Category
Genetics Developmental Biology Other Biological Topics
Identifiers
urn:nbn:se:umu:diva-153379 (URN)978-91-7601-932-0 (ISBN)
Public defence
2018-12-18, A103, Building 6A, Umeå, 13:00 (English)
Opponent
Supervisors
Funder
Knut and Alice Wallenberg FoundationSwedish Research CouncilThe Kempe FoundationsSwedish Cancer Society
Available from: 2018-11-26 Created: 2018-11-19 Last updated: 2018-11-23Bibliographically approved

Open Access in DiVA

fulltext(705 kB)76 downloads
File information
File name FULLTEXT01.pdfFile size 705 kBChecksum SHA-512
ff5cf4300a32786ff4e85892dd9f8a0dd138eeb733f359b21843ee8f4f2cf197460e0e84286ad08ca50692a1e8f63c775fef0c7197d520dd8e4e4af8d82433c2
Type fulltextMimetype application/pdf

Other links

Publisher's full textPubMed

Authority records BETA

Dorafshan, EshaghKahn, Tatyana G.Schwartz, Yuri B.

Search in DiVA

By author/editor
Dorafshan, EshaghKahn, Tatyana G.Schwartz, Yuri B.
By organisation
Department of Molecular Biology (Faculty of Medicine)
In the same journal
Nucleus
Developmental BiologyBiochemistry and Molecular Biology

Search outside of DiVA

GoogleGoogle Scholar
Total: 76 downloads
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

doi
pubmed
urn-nbn

Altmetric score

doi
pubmed
urn-nbn
Total: 230 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf