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The role of H3K36 methylation and associated methyltransferases in chromosome-specific gene regulation
Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet). (Jan Larsson)ORCID-id: 0000-0003-1195-2341
Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).ORCID-id: 0000-0003-4790-3920
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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. Vol. 7, nr 40, artikel-id eabh4390
Nationell ämneskategori
Genetik
Forskningsämne
genetik
Identifikatorer
URN: urn:nbn:se:umu:diva-188176DOI: 10.1126/sciadv.abh4390ISI: 000703091100019PubMedID: 34597135Scopus ID: 2-s2.0-85116655009OAI: oai:DiVA.org:umu-188176DiVA, id: diva2:1600277
Forskningsfinansiär
Knut och Alice Wallenbergs Stiftelse, 2014.0018Cancerfonden, 2017/342Vetenskapsrådet, 2016-03306Vetenskapsrådet, 2017-03918Tillgänglig från: 2021-10-04 Skapad: 2021-10-04 Senast uppdaterad: 2022-12-19Bibliografiskt 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, HenrikGlotov, AlexanderDorafshan, EshaghSchwartz, Yuri B.Larsson, Jan

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