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Jack of all trades, master of none: the multifaceted nature of H3K36 methylation
Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet). (Jan Larsson)
2023 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)Alternativ titel
Molekylär mångsysslare : komplexiteten kring H3K36 metylering (Svenska)
Abstract [en]

Post-translational modifications of histones enable differential transcriptional control of the genome between cell types and developmental stages, and in response to environmental factors. The methylation of Histone 3 Lysine 36 (H3K36) is one the most complex and well-studied histone modifications and is known to be involved in a wide range of molecular processes. Commonly associated with active genes and transcriptional elongation, H3K36 methylation also plays a key role in DNA repair, repression of cryptic transcription, and guiding additional post-translational modifications to histones, genomic DNA, and RNA. In Drosophila melanogaster, trimethylated H3K36 has also been linked to dosage compensation of the single male X chromosome as a binding substrate for the Male-Specific Lethal (MSL) complex. However, this model has been challenged by structural and biochemical studies demonstrating higher MSL complex affinity for other methylated lysines. There is an additional system of chromosome-specific gene regulation in D. melanogaster where transcription from the small heterochromatic fourth chromosome is increased by Painting of fourth (POF), a protein specifically binding nascent RNA on the fourth chromosome. The fourth chromosome is thought to have been an ancestral X chromosome that reverted into an autosome. POF mediating high transcription levels from an autosome is believed to be a remnant of an ancient sex-chromosome dosage compensation mechanism. 

Proximity ligation assays revealed no interaction between MSL complex components and methylated H3K36. This finding was corroborated by RNA sequencing of H3K36 methylation impaired mutants: the transcriptional output of the male X chromosome was unaffected in mutants where Lysine 36 on Histone 3 was replaced by an Arginine, abolishing methylation of this site. However, we found that knocking out Set2, which encodes the methyltransferase responsible for H3K36 trimethylation, significantly reduced X-linked transcription relative to autosomal transcription. This strongly suggests the existence of previously unrecognized alternate Set2 substrates. Interestingly, we also found that Ash1- and NSD-mediated methylation of H3K36 was required to maintain high expression from chromosome four. 

Recent studies have also implicated H3K36 methylation in the silencing of transposon activity in somatic cells. By analyzing the transcription of transposable elements and Piwi-interacting RNAs (piRNAs), we identified dimethylation of H3K36 by Set2 as the main methylation mark involved in this process and showed that dual-stranded piRNA clusters are preferentially activated upon disturbing the methylation machinery. These findings extends the long list of processes dependent on functional H3K36 methylation.

Ort, förlag, år, upplaga, sidor
Umeå: Umeå universitet , 2023. , s. 47
Nyckelord [en]
H3K36, histone methylation, dosage compensation, chromosome-specific gene regulation, transposable elements, PIWI/piRNA biosynthesis, Set2, Ash1, NSD, Histone 3.3, post-translational modifications, histone modifications, epigenetics, proximity ligation assay, Drosophila
Nationell ämneskategori
Biokemi och molekylärbiologi Genetik Bioinformatik (beräkningsbiologi)
Forskningsämne
genetik; molekylärbiologi; biofarmaci
Identifikatorer
URN: urn:nbn:se:umu:diva-201602ISBN: 978-91-7855-952-7 (tryckt)ISBN: 978-91-7855-953-4 (digital)OAI: oai:DiVA.org:umu-201602DiVA, id: diva2:1720412
Disputation
2023-01-27, Astrid Fagraeus-salen (A103), byggnad 6A, Umeå, 09:00 (Engelska)
Opponent
Handledare
Tillgänglig från: 2023-01-05 Skapad: 2022-12-19 Senast uppdaterad: 2023-01-02Bibliografiskt granskad
Delarbeten
1. Proximity ligation assays of protein and RNA interactions in the male-specific lethal complex on Drosophila melanogaster polytene chromosomes
Öppna denna publikation i ny flik eller fönster >>Proximity ligation assays of protein and RNA interactions in the male-specific lethal complex on Drosophila melanogaster polytene chromosomes
2015 (Engelska)Ingår i: Chromosoma, ISSN 0009-5915, E-ISSN 1432-0886, Vol. 124, nr 3, s. 385-395Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

In Drosophila, the male-specific lethal (MSL) complex specifically targets the male X chromosome and participates in a twofold increase in expression output leading to functional dosage compensation. The complex includes five proteins and two non-coding RNAs (ncRNAs). A number of additional associated factors have also been identified. However, the components' roles and interactions have not been fully elucidated. The in situ proximity ligation assay (PLA) provides a sensitive means to determine whether proteins and other factors have bound to chromosomes in close proximity to each other, and thus may interact. Thus, we modified, tested, and applied the assay to probe interactions of MSL complex components on polytene chromosomes. We show that in situ PLA can detect and map both protein-protein and protein-ncRNA interactions on polytene chromosomes at high resolution. We further show that all five protein components of the MSL complex are in close proximity to each other, and the ncRNAs roX1 and roX2 bind the complex in close proximity to MLE. Our results also indicate that JIL1, a histone H3 Ser10 kinase enriched on the male X chromosome, interacts with MSL1 and MSL2, but not MSL3 of the MSL complex. In addition, we corroborate proposed interactions of the MSL complex with both CLAMP and TopoII.

Nyckelord
dosage compensation, protein interaction, polytene chromosomes, MSL-complex
Nationell ämneskategori
Genetik
Forskningsämne
genetik
Identifikatorer
urn:nbn:se:umu:diva-100658 (URN)10.1007/s00412-015-0509-x (DOI)000360288200009 ()25694028 (PubMedID)2-s2.0-84940451246 (Scopus ID)
Forskningsfinansiär
Vetenskapsrådet, 621-2012-2165Cancerfonden, 2011/382
Tillgänglig från: 2015-03-06 Skapad: 2015-03-05 Senast uppdaterad: 2023-03-24Bibliografiskt granskad
2. The role of H3K36 methylation and associated methyltransferases in chromosome-specific gene regulation
Öppna denna publikation i ny flik eller fönster >>The role of H3K36 methylation and associated methyltransferases in chromosome-specific gene regulation
Visa övriga...
2021 (Engelska)Ingår i: Science Advances, E-ISSN 2375-2548, Vol. 7, nr 40, artikel-id eabh4390Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

In Drosophila, two chromosomes require special mechanisms to balance their transcriptional output to the rest of the genome. These are the male-specific lethal complex targeting the male X chromosome and Painting of fourth targeting chromosome 4. Here, we explore the role of histone H3 methylated at lysine-36 (H3K36) and the associated methyltransferases—Set2, NSD, and Ash1—in these two chromosome-specific systems. We show that the loss of Set2 impairs the MSL complex–mediated dosage compensation; however, the effect is not recapitulated by H3K36 replacement and indicates an alternative target of Set2. Unexpectedly, balanced transcriptional output from the fourth chromosome requires intact H3K36 and depends on the additive functions of NSD and Ash1. We conclude that H3K36 methylation and the associated methyltransferases are important factors to balance transcriptional output of the male X chromosome and the fourth chromosome. Furthermore, our study highlights the pleiotropic effects of these enzymes.

Ort, förlag, år, upplaga, sidor
American Association for the Advancement of Science, 2021
Nationell ämneskategori
Genetik
Forskningsämne
genetik
Identifikatorer
urn:nbn:se:umu:diva-188176 (URN)10.1126/sciadv.abh4390 (DOI)000703091100019 ()34597135 (PubMedID)2-s2.0-85116655009 (Scopus ID)
Forskningsfinansiär
Knut och Alice Wallenbergs Stiftelse, 2014.0018Cancerfonden, 2017/342Vetenskapsrådet, 2016-03306Vetenskapsrådet, 2017-03918
Tillgänglig från: 2021-10-04 Skapad: 2021-10-04 Senast uppdaterad: 2022-12-19Bibliografiskt granskad
3. Methylation of lysine 36 on histone H3 is required to control transposon activities in somatic cells
Öppna denna publikation i ny flik eller fönster >>Methylation of lysine 36 on histone H3 is required to control transposon activities in somatic cells
2023 (Engelska)Ingår i: Life Science Alliance, E-ISSN 2575-1077, Vol. 6, nr 8, artikel-id e202201832Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Transposable elements constitute a substantial portion of most eukaryotic genomes and their activity can lead to developmental and neuronal defects. In the germline, transposon activity is antagonized by the PIWI-interacting RNA pathway tasked with repression of transposon transcription and degrading transcripts that have already been produced. However, most of the genes required for transposon control are not expressed outside the germline, prompting the question: what causes deleterious transposons activity in the soma and how is it managed? Here, we show that disruptions of the Histone 3 lysine 36 methylation machinery led to increased transposon transcription in Drosophila melanogaster brains and that there is division of labour for the repression of transposable elements between the different methyltransferases Set2, NSD, and Ash1. Furthermore, we show that disruption of methylation leads to somatic activation of key genes in the PIWI-interacting RNA pathway and the preferential production of RNA from dual-strand piRNA clusters.

Ort, förlag, år, upplaga, sidor
NLM (Medline), 2023
Nationell ämneskategori
Genetik Bioinformatik och systembiologi Biokemi och molekylärbiologi
Identifikatorer
urn:nbn:se:umu:diva-201601 (URN)10.26508/lsa.202201832 (DOI)000994281600003 ()37169594 (PubMedID)2-s2.0-85159740379 (Scopus ID)
Forskningsfinansiär
Vetenskapsrådet, 2020-03561Vetenskapsrådet, 2021-04435Vetenskapsrådet, 2020-03561Cancerfonden, 20 0779 PjFCancerfonden, 22 2285 Pj
Anmärkning

Originally included in thesis in manuscript form. 

Tillgänglig från: 2022-12-12 Skapad: 2022-12-12 Senast uppdaterad: 2023-09-05Bibliografiskt granskad

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Lindehell, Henrik

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