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Methylation of lysine 36 on histone H3 is required to control transposon activities in somatic cells
Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet).
Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet).ORCID-id: 0000-0003-4373-6790
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. Vol. 6, nr 8, artikel-id e202201832
Nationell ämneskategori
Genetik Bioinformatik och systembiologi Biokemi och molekylärbiologi
Identifikatorer
URN: urn:nbn:se:umu:diva-201601DOI: 10.26508/lsa.202201832ISI: 000994281600003PubMedID: 37169594Scopus ID: 2-s2.0-85159740379OAI: oai:DiVA.org:umu-201601DiVA, id: diva2:1718172
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
Ingår i avhandling
1. Jack of all trades, master of none: the multifaceted nature of H3K36 methylation
Öppna denna publikation i ny flik eller fönster >>Jack of all trades, master of none: the multifaceted nature of H3K36 methylation
2023 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Alternativ titel[sv]
Molekylär mångsysslare : komplexiteten kring H3K36 metylering
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
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:nbn:se:umu:diva-201602 (URN)978-91-7855-952-7 (ISBN)978-91-7855-953-4 (ISBN)
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

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Lindehell, HenrikSchwartz, Yuri B.Larsson, Jan

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