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  • 1.
    Crona, Filip
    et al.
    Stockholm University, Wenner-Gren Institute, Developmental Biology, Arrhenius laboratories E3, Stockholm SE-10691, Sweden.
    Dahlberg, Olle
    Stockholm University, Wenner-Gren Institute, Developmental Biology, Arrhenius laboratories E3, Stockholm SE-10691, Sweden.
    Lundberg, Lina E
    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).
    Mannervik, Mattias
    Stockholm University, Wenner-Gren Institute, Developmental Biology, Arrhenius laboratories E3, Stockholm SE-10691, Sweden.
    Gene regulation by the lysine demethylase KDM4A in Drosophila2013In: Developmental Biology, ISSN 0012-1606, E-ISSN 1095-564X, Vol. 737, no 2, p. 453-463Article in journal (Refereed)
    Abstract [en]

    Lysine methylation of histones is associated with both transcriptionally active chromatin and with silent chromatin, depending on what residue is modified. Histone methyltransferases and demethylases ensure that histone methylations are dynamic and can vary depending on cell cycle- or developmental stage. KDM4A demethylates H3K36me3, a modification enriched in the 3' end of active genes. The genomic targets and the role of KDM4 proteins in development remain largely unknown. We therefore generated KDM4A mutant Drosophila, and identified 99 mis-regulated genes in first instar larvae. Around half of these genes were down-regulated and the other half up-regulated in dKDM4A mutants. Although heterochromatin protein 1a (HP1a) can stimulate dKDM4A demethylase activity in vitro, we find that they antagonize each other in control of dKDM4A-regulated genes. Appropriate expression levels for some dKDM4A-regulated genes rely on the demethylase activity of dKDM4A, whereas others do not. Surprisingly, although highly expressed, many demethylase-dependent and independent genes are devoid of H3K36me3 in wild-type as well as in dKDM4A mutant larvae, suggesting that some of the most strongly affected genes in dKDM4A mutant animals are not regulated by H3K36 methylation. By contrast, dKDM4A over-expression results in a global decrease in H3K36me3 levels and male lethality, which might be caused by impaired dosage compensation. Our results show that a modest increase in global H3K36me3 levels is compatible with viability, fertility, and the expression of most genes, whereas decreased H3K36me3 levels are detrimental in males.

  • 2.
    Lundberg, Lina
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Aneuploidy compensatory mechanisms and genome-wide regulation of gene expression in Drosophila melanogaster2013Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Stimulation or repression of gene expression by genome-wide regulatory mechanisms is an important epigenetic regulatory function which can act to efficiently regulate larger regions or specific groups of genes, for example by compensating for loss or gain of chromosome copy numbers. In Drosophila melanogaster there are two known chromosome-wide regulatory systems; the MSL complex, which mediates dosage compensation of the single male X-chromosome and POF, which stimulates expression from the heterochromatic 4th chromosome. POF also interacts with the heterochromatin inducing protein HP1a, which represses expression from the 4th chromosome but which also has been assigned stimulatory functions. In addition to these two, there is another more elusive and less well-characterized genome-wide mechanism called buffering, which can act to balance transcriptional output of aneuploidy regions of the genome (i.e. copy number variation).

    In my thesis, I describe the presence of a novel physical link between dosage compensation and heterochromatin; mediate by two female-specific POF binding sites, proximal to roX1 and roX2 on the X chromosome (the two non-coding RNAs in the MSL complex). These sites can also provide clues to the mechanisms behind targeting of chromosome-specific proteins. Furthermore, to clarify the conflicting reports about the function of HP1a, I have suggested a mechanism in which HP1a has adopted its function to different genomic locations and gene types. Different binding mechanisms to the promoter vs. the exon of genes allows HP1a to adopt opposite functions; at the promoter, HP1a binding opens up the chromatin structure and stimulates gene expression, whereas the binding to exons condense the chromatin and thus, represses expression. This also causes long genes to be more bound and repressed by HP1a. Moreover, I show that buffering of monosomic regions is a weak but significant response to loss of chromosomal copy numbers, and that this is mediated via a general mechanism which mainly acts on differentially expressed genes, where the effect becomes stronger for long genes. I also show that POF is the factor which compensates for copy number loss of chromosome 4.

  • 3.
    Lundberg, Lina E
    et al.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Figueiredo, Margarida L A
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Stenberg, Per
    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).
    Buffering and proteolysis are induced by segmental monosomy in Drosophila melanogaster2012In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 40, no 13, p. 5926-5937Article in journal (Refereed)
    Abstract [en]

    Variation in the number of individual chromosomes (chromosomal aneuploidy) or chromosome segments (segmental aneuploidy) is associated with developmental abnormalities and reduced fitness in all species examined; it is the leading cause of miscarriages and mental retardation and a hallmark of cancer. However, despite their documented importance in disease, the effects of aneuploidies on the transcriptome remain largely unknown. We have examined the expression effects of seven heterozygous chromosomal deficiencies, both singly and in all pairwise combinations, in Drosophila melanogaster. The results show that genes in one copy are buffered, i.e. expressed more strongly than the expected 50% of wild-type level, the buffering is general and not influenced by other monosomic regions. Furthermore, long genes are significantly more highly buffered than short genes and gene length appears to be the primary determinant of the buffering degree. For short genes the degree of buffering depends on expression level and expression pattern. Furthermore, the results show that in deficiency heterozygotes the expression of genes involved in proteolysis is enhanced and negatively correlates with the degree of buffering. Thus, enhanced proteolysis appears to be a general response to aneuploidy.

  • 4.
    Lundberg, Lina E
    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).
    Johansson, Anna-Mia
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Faucillion, Marie-Line
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Josupeit, Rafael
    Division of Tumor Virology, German Cancer Research Center.
    Larsson, Jan
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Targeting of Painting of fourth to roX1 and roX2 proximal sites links dosage compensation to heterochromatin in Drosophila melanogasterManuscript (preprint) (Other academic)
    Abstract [en]

    In Drosophila melanogaster, two chromosome‐specific targeting and regulatory systems have been described. The male‐specific lethal (MSL) complex supports dosage compensation by stimulating gene expression from the male X‐chromosome and the protein Painting of fourth (POF) specifically targets and stimulates expression from the heterochromatic 4th chromosome. The targeting sites of both systems are well characterized, but the principles underlying the targeting mechanisms have remained elusive. Here we present an original observation, namely that POF specifically targets two loci on the X‐chromosome, PoX1 and PoX2 (POF‐on‐X). PoX1 and PoX2 are located close to the roX1 and roX2 genes, which encode ncRNAs important for the correct targeting and spreading of the MSL‐complex. We also found that the targeting of POF to PoX1 and PoX2 is largely dependent on roX expression and identified a high‐affinity target region which ectopically recruits POF. The results presented support a model linking the MSL‐complex to POF and dosage compensation to regulation of heterochromatin.

  • 5.
    Lundberg, Lina E
    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).
    Johansson, Anna-Mia
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Faucillion, Marie-Line
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Josupeit, Rafael
    German Cancer Research Center (DKFZ).
    Larsson, Jan
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Targeting of painting of fourth to roX1 and roX2 proximal sites suggests evolutionary links between dosage compensation and the regulation of the 4th chromosome in Drosophila melanogaster2013In: G3: Genes, Genomes, Genetics, ISSN 2160-1836, E-ISSN 2160-1836, Vol. 3, no 8, p. 1325-1334Article in journal (Refereed)
    Abstract [en]

    In Drosophila melanogaster, two chromosome-specific targeting and regulatory systems have been described. The male-specific lethal (MSL) complex supports dosage compensation by stimulating gene expression from the male X-chromosome and the protein Painting of fourth (POF) specifically targets and stimulates expression from the heterochromatic 4(th) chromosome. The targeting sites of both systems are well characterized, but the principles underlying the targeting mechanisms have remained elusive. Here we present an original observation, namely that POF specifically targets two loci on the X-chromosome, PoX1 and PoX2 (POF-on-X). PoX1 and PoX2 are located close to the roX1 and roX2 genes, which encode ncRNAs important for the correct targeting and spreading of the MSL-complex. We also found that the targeting of POF to PoX1 and PoX2 is largely dependent on roX expression and identified a high-affinity target region which ectopically recruits POF. The results presented support a model linking the MSL-complex to POF and dosage compensation to regulation of heterochromatin.

  • 6.
    Lundberg, Lina E
    et al.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Stenberg, Per
    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).
    HP1a, Su(var)3-9, SETDB1 and POF stimulate or repress gene expression depending on genomic position, gene length and expression pattern in Drosophila melanogaster2013In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 41, no 8, p. 4481-4494Article in journal (Refereed)
    Abstract [en]

    Heterochromatin protein 1a (HP1a) is a chromatin-associated protein important for the formation and maintenance of heterochromatin. In Drosophila, the two histone methyltransferases SETDB1 and Su(var)3-9 mediate H3K9 methylation marks that initiates the establishment and spreading of HP1a-enriched chromatin. Although HP1a is generally regarded as a factor that represses gene transcription, several reports have linked HP1a binding to active genes, and in some cases, it has been shown to stimulate transcriptional activity. To clarify the function of HP1a in transcription regulation and its association with Su(var)3-9, SETDB1 and the chromosome 4-specific protein POF, we conducted genome-wide expression studies and combined the results with available binding data in Drosophila melanogaster. The results suggest that HP1a, SETDB1 and Su(var)3-9 repress genes on chromosome 4, where non-ubiquitously expressed genes are preferentially targeted, and stimulate genes in pericentromeric regions. Further, we showed that on chromosome 4, Su(var)3-9, SETDB1 and HP1a target the same genes. In addition, we found that transposons are repressed by HP1a and Su(var)3-9 and that the binding level and expression effects of HP1a are affected by gene length. Our results indicate that genes have adapted to be properly expressed in their local chromatin environment.

  • 7.
    Stenberg, Per
    et al.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Lundberg, Lina E.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Johansson, Anna-Mia
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Rydén, Patrik
    Umeå University, Faculty of Science and Technology, Department of Mathematics and Mathematical Statistics. Umeå University, Faculty of Social Sciences, Department of Statistics.
    Svensson, Malin J.
    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).
    Buffering of segmental and chromosomal aneuploidies in Drosophila melanogaster2009In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 5, no 5Article in journal (Refereed)
    Abstract [en]

    Chromosomal instability, which involves the deletion and duplication of chromosomes or chromosome parts, is a common feature of cancers, and deficiency screens are commonly used to detect genes involved in various biological pathways. However, despite their importance, the effects of deficiencies, duplications, and chromosome losses on the regulation of whole chromosomes and large chromosome domains are largely unknown. Therefore, to explore these effects, we examined expression patterns of genes in several Drosophila deficiency hemizygotes and a duplication hemizygote using microarrays. The results indicate that genes expressed in deficiency hemizygotes are significantly buffered, and that the buffering effect is general rather than being mainly mediated by feedback regulation of individual genes. In addition, differentially expressed genes in haploid condition appear to be generally more strongly buffered than ubiquitously expressed genes in haploid condition, but, among genes present in triploid condition, ubiquitously expressed genes are generally more strongly buffered than differentially expressed genes. Furthermore, we show that the 4th chromosome is compensated in response to dose differences. Our results suggest general mechanisms have evolved that stimulate or repress gene expression of aneuploid regions as appropriate, and on the 4th chromosome of Drosophila this compensation is mediated by Painting of Fourth (POF).

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