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  • 1.
    Lindehell, Henrik
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Jack of all trades, master of none: the multifaceted nature of H3K36 methylation2023Doctoral thesis, comprehensive summary (Other academic)
    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.

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  • 2.
    Lindehell, Henrik
    et al.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Glotov, Alexander
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Dorafshan, Eshagh
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Schwartz, Yuri B.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Larsson, Jan
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    The role of H3K36 methylation and associated methyltransferases in chromosome-specific gene regulation2021In: Science Advances, E-ISSN 2375-2548, Vol. 7, no 40, article id eabh4390Article in journal (Refereed)
    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.

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  • 3.
    Lindehell, Henrik
    et al.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Kim, Maria
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Larsson, Jan
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Proximity ligation assays of protein and RNA interactions in the male-specific lethal complex on Drosophila melanogaster polytene chromosomes2015In: Chromosoma, ISSN 0009-5915, E-ISSN 1432-0886, Vol. 124, no 3, p. 385-395Article in journal (Refereed)
    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.

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  • 4.
    Lindehell, Henrik
    et al.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Schwartz, Yuri B.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Larsson, Jan
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Methylation of lysine 36 on histone H3 is required to control transposon activities in somatic cells2023In: Life Science Alliance, E-ISSN 2575-1077, Vol. 6, no 8, article id e202201832Article in journal (Refereed)
    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.

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  • 5.
    Mendoza-Garcia, Patricia
    et al.
    Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, University of Gothenburg, SE-405 30 Gothenburg, Sweden.
    Basu, Swaraj
    Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, University of Gothenburg, SE-405 30 Gothenburg, Sweden.
    Sukumar, Sanjay Kumar
    Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, University of Gothenburg, SE-405 30 Gothenburg, Sweden.
    Arefin, Badrul
    Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, University of Gothenburg, SE-405 30 Gothenburg, Sweden.
    Wolfstetter, Georg
    Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, University of Gothenburg, SE-405 30 Gothenburg, Sweden.
    Anthonydhason, Vimala
    Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, University of Gothenburg, SE-405 30 Gothenburg, Sweden.
    Molander, Linnea
    Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, University of Gothenburg, SE-405 30 Gothenburg, Sweden.
    Uçkun, Ezgi
    Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, University of Gothenburg, SE-405 30 Gothenburg, Sweden.
    Lindehell, Henrik
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). Department of Molecular Biology, Umeå University, SE-901 87 Umeå, Sweden.
    Lebrero-Fernandez, Cristina
    Department of Microbiology and Immunology, Institute of Biomedicine, University of Gothenburg, SE-405 30 Gothenburg, Sweden.
    Larsson, Jan
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). Department of Molecular Biology, Umeå University, SE-901 87 Umeå, Sweden.
    Larsson, Erik
    Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, University of Gothenburg, SE-405 30 Gothenburg, Sweden.
    Bemark, Mats
    Department of Microbiology and Immunology, Institute of Biomedicine, University of Gothenburg, SE-405 30 Gothenburg, Sweden;Department of Clinical Immunology and Transfusion Medicine, Sahlgrenska University Hospital, Region Västra Götaland, SE-41346 Gothenburg, Sweden.
    Palmer, Ruth H.
    Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, University of Gothenburg, SE-405 30 Gothenburg, Sweden.
    DamID transcriptional profiling identifies the Snail/Scratch transcription factor Kahuli as an Alk target in the Drosophila visceral mesoderm2021In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 148, no 23, article id dev199465Article in journal (Refereed)
    Abstract [en]

    Development of the Drosophila visceral muscle depends on Anaplastic Lymphoma Kinase (Alk) receptor tyrosine kinase (RTK) signaling, which specifies founder cells (FCs) in the circular visceral mesoderm (VM). Although Alk activation by its ligand Jelly Belly (Jeb) is well characterized, few target molecules have been identified. Here, we used targeted DamID (TaDa) to identify Alk targets in embryos overexpressing Jeb versus embryos with abrogated Alk activity, revealing differentially expressed genes, including the Snail/Scratch family transcription factor Kahuli (Kah). We confirmed Kah mRNA and protein expression in the VM, and identified midgut constriction defects in Kah mutants similar to those of pointed (pnt). ChIP and RNA-Seq data analysis defined a Kah target-binding site similar to that of Snail, and identified a set of common target genes putatively regulated by Kah and Pnt during midgut constriction. Taken together, we report a rich dataset of Alk-responsive loci in the embryonic VM and functionally characterize the role of Kah in the regulation of embryonic midgut morphogenesis.

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1 - 5 of 5
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