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. 2016 May 23;26(10):1339-45.
doi: 10.1016/j.cub.2016.03.050. Epub 2016 May 5.

Male-Killing Spiroplasma Alters Behavior of the Dosage Compensation Complex During Drosophila Melanogaster Embryogenesis

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Male-Killing Spiroplasma Alters Behavior of the Dosage Compensation Complex During Drosophila Melanogaster Embryogenesis

Becky Cheng et al. Curr Biol. .
Free PMC article


Numerous arthropods harbor maternally transmitted bacteria that induce the preferential death of males [1-7]. This sex-specific lethality benefits the bacteria because males are "dead ends" regarding bacterial transmission, and their absence may result in additional resources for their viable female siblings who can thereby more successfully transmit the bacteria [5]. Although these symbionts disrupt a range of developmental processes [8-10], the underlying cellular mechanisms are largely unknown. It was previously shown that mutations in genes of the dosage compensation pathway of Drosophila melanogaster suppressed male killing caused by the bacterium, Spiroplasma [10]. This result suggested that dosage compensation is a target of Spiroplasma. However, it remains unclear how this pathway is affected, and whether the underlying interactions require the male-specific cellular environment. Here, we investigated the cellular basis of male embryonic lethality in D. melanogaster induced by Spiroplasma. We found that the dosage compensation complex (DCC), which acetylates X chromatin in males [11], becomes mis-localized to ectopic regions of the nucleus immediately prior to the killing phase. This effect was accompanied by inappropriate histone acetylation and genome-wide mis-regulation of gene expression. Artificially induced formation of the DCC in infected females, through transgenic expression of the DCC-specific gene msl-2, resulted in mis-localization of this complex to non-X regions and early Spiroplasma-induced death, mirroring the killing effects in males. These findings strongly suggest that Spiroplasma initiates male killing by targeting the dosage compensation machinery directly and independently of other cellular features characteristic of the male sex.


Figure 1
Figure 1. Spiroplasma-infected male embryos exhibit mis-localized MOF and H4K16ac
(A,B) Both control (uninfected) and infected embryos at 2-3hrs after egg deposition (AED) show very little MOF or H4K16ac signals. (C,D) At 5-6hrs AED, MOF and H4K16ac signals become bright and co-localize to a single focus in each nucleus of control embryos. The H4K16ac signals co-localizes with X sequences and overlap with MSL3 (see Figures S1 and S2 respectively). In contrast, these signals, although still overlapping, become distributed across nuclei in infected embryos (yellow arrows in right panel). Some nuclei in infected embryos appear hyper-condensed (white arrow). (E,F) At 9-11hrs AED, MOF and H4K16ac signals persist as bright foci in the nuclei of control embryos. However, in infected embryos these signals are barely visible in most nuclei, and more nuclei are hyper-condensed (white arrow). Scale bar equals 15 μm in wide panel F and 5 μm in the high magnification panel under F.
Figure 2
Figure 2. Spiroplasma-infected male embryos exhibit genome-wide misregulation of gene expression
(A) Scatterplots show averaged FPKM values between corresponding replicates for expressed genes in wild type embryos plotted against those of Spiroplasma-infected embryos for both time points. Values are shown in log scale. Red arrow indicates a higher clustering of genes that appear over-expressed in infected embryos. (B) Chromosome maps depicting the positions of significantly mis-expressed genes in Spiroplasma-infected embryos relative to uninfected embryos. Peaks above the horizontal lines represent genes that are significantly over-expressed in Spiroplasma-infected embryos, and peak height reflects expression ratio on the log scale. Red dot corresponds to the chromosome centromeres (C) The number of significantly mis-expressed genes on the X vs. the autosomes (non-sex chromosomes) and their general fold change values between Spiroplasma-infected and uninfected embryos. The patterns in B and C reflect an enrichment of over-expressed genes on all chromosomes and for both developmental times. (D) A Venn diagram depicting the number of over-expressed genes (up arrow) and under-expressed (down arrow) in Spiroplasma-infected embryos that are unique to each developmental time point and those common between these times. See Table S1 for raw data, and Figure S4 for ontogeny groupings of mis-expressed genes common between 2-3hrs and 5-6hrs AED.
Figure 3
Figure 3. Spiroplasma infection causes death of females expressing low levels of MSL-2 and mis-localized DCC during female embryogenesis
(A) The number of F1 progeny carrying the hsp83-MSL-2 transgene (+Tr) and their siblings without the transgene (no Tr) produced from either uninfected (control) or Spiroplasma-infected mothers. Red asterisk indicates a significant difference between transgenic and non-transgenic females infected by Spiroplasma. (B) Transgenic male and female embryos that are either uninfected or Spiroplasma-infected. Uninfected embryos of both sexes show distinct MOF localization, whereas in infected embryos MOF fails to concentrate and becomes distributed lightly across nuclei. Uninfected females do not exhibit foci of MOF or H4K16ac (see Figure S3). Scale bar equals 5 μm.

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