Dosage compensation in Drosophila melanogaster: epigenetic fine-tuning of chromosome-wide transcription

Conrad, Thomas; Akhtar, Asifa

doi:10.1038/nrg3124

Cited by 245 publications

(243 citation statements)

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“…Dosage compensation equalizes X chromosome transcript levels between XX females and single X males. Although strategies differ, dosage-compensation mechanisms have been found in mammals, Drosophila, and C. elegans (Meyer 2010;Conrad and Akhtar 2012;Disteche 2012;Ferrari et al 2014). Mammalian females inactivate most of the genes on one of their two X chromosomes to match transcriptional output from the single male X (Pollex and Heard 2012;Dupont and Gribnau 2013).…”

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confidence: 99%

Sex-Biased Gene Expression and Evolution of the X Chromosome in Nematodes

et al. 2014

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Studies of X chromosome evolution in various organisms have indicated that sex-biased genes are nonrandomly distributed between the X and autosomes. Here, to extend these studies to nematodes, we annotated and analyzed X chromosome gene content in four Caenorhabditis species and in Pristionchus pacificus. Our gene expression analyses comparing young adult male and female mRNAseq data indicate that, in general, nematode X chromosomes are enriched for genes with high female-biased expression and depleted of genes with high male-biased expression. Genes with low sex-biased expression do not show the same trend of X chromosome enrichment and depletion. Combined with the observation that highly sex-biased genes are primarily expressed in the gonad, differential distribution of sex-biased genes reflects differences in evolutionary pressures linked to tissue-specific regulation of X chromosome transcription. Our data also indicate that X dosage imbalance between males (XO) and females (XX) is influential in shaping both expression and gene content of the X chromosome. Predicted upregulation of the single male X to match autosomal transcription (Ohno's hypothesis) is supported by our observation that overall transcript levels from the X and autosomes are similar for highly expressed genes. However, comparison of differentially located one-to-one orthologs between C. elegans and P. pacificus indicates lower expression of X-linked orthologs, arguing against X upregulation. These contradicting observations may be reconciled if X upregulation is not a global mechanism but instead acts locally on a subset of tissues and X-linked genes that are dosage sensitive. IN an XY sex-determination system, male and female genomes are identical with the exception of the male-specific Y chromosome, which bears few genes (Charlesworth et al. 2005). This is particularly true when the Y chromosome is thought to be completely lost, as is the case for C. elegans and many other nematodes (Walton 1940). Because gene content is the same, phenotypic differences between males and females, termed "sexual dimorphisms," must be caused by differential gene expression between the two sexes (Connallon and Knowles 2005;Ellegren and Parsch 2007). Throughout the article, such differentially expressed genes are referred to as "sex biased." As males and females have different fitness optima, a trait that is beneficial to one sex can be harmful to the other (termed sexual antagonism) (Rice and Chippindale 2001;Arnqvist 2004;Connallon and Knowles 2005;Ellegren and Parsch 2007;Mank et al. 2008a;Rice 1984). The evolution of sex-biased gene expression is thought to mediate the effects of sexual antagonism and allow for achievement of sex-specific fitness. Previous studies have indicated that anywhere between 30 and 60% of metazoan genes may be sex biased Parisi et al. 2004;Reinke et al. 2004;Yang et al. 2006;Reinius et al. 2008;Small et al. 2009;Innocenti and Morrow 2010;Assis et al. 2012;Reinius et al. 2012;Thomas et al. 2012). Genes with sex-biased exp...

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Sex-Biased Gene Expression and Evolution of the X Chromosome in Nematodes

et al. 2014

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“…In flies, Xlinked genes are upregulated 2-fold in males; a consequence of the recruitment of the fly DCC, the male-specific lethal (MSL) complex onto the X chromosome. 32 Consequent to this loading, the male X chromosome shows a specific 3D conformation. 33 Fly DCC activates Xlinked gene transcription via H4K16 acetylation 34 and co-purifies with 2 nucleoporins, MTOR/TPR and NUP153.…”

Section: A Nuclear Organizationmentioning

confidence: 99%

Linking dosage compensation and X chromosome nuclear organization inC. elegans

Sharma

Meister

2015

Nucleus

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A nimal sex is determined by the number of X chromosomes in many species, creating unequal gene dosage (aneuploidy) between sexes. Dosage Compensation mechanisms equalize this dosage difference by regulating X-linked gene expression. In the nematode C. elegans the current model suggests that DC is achieved by a 2-fold transcriptional downregulation in hermaphrodites mediated by the Dosage Compensation Complex (DCC), which restricts access to RNA Polymerase II by an unknown mechanism. Taking a nuclear organization point of view, we showed that the male X chromosome resides in the pore proximal subnuclear compartment whereas the DCC bound to the X, inhibits this spatial organization in the hermaphrodites. Here we discuss our results and propose a model that reassigns the role of DCC from repression of genes to inhibition of activation.

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“…Loss and silencing of Y-linked genes drives the evolution of dosage compensation on the X chromosome, which is often mediated by chromosomewide epigenetic modifications. Drosophila males, for example, acquire a hyperactive chromatin conformation of their single X, while one of the two X's in female mammals becomes heterochromatic [4,5].…”

Section: Introductionmentioning

confidence: 99%

Ancestral chromatin configuration constrains chromatin evolution on differentiating sex chromosomes inDrosophila

Zhou

Bachtrog

2015

Preprint

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Sex chromosomes evolve distinctive types of chromatin from a pair of ancestral autosomes that are usually euchromatic. In Drosophila, the dosage-compensated X becomes enriched for hyperactive chromatin in males (mediated by H4K16ac), while the Y chromosome acquires silencing heterochromatin (enriched for H3K9me2/3). Drosophila autosomes are typically mostly euchromatic but the small dot chromosome has evolved a heterochromatinlike milieu (enriched for H3K9me2/3) that permits the normal expression of dot-linked genes, but which is different from typical pericentric heterochromatin. In Drosophila busckii, the dot chromosomes have fused to the ancestral sex chromosomes, creating a pair of 'neo-sex' chromosomes. Here we collect genomic, transcriptomic and epigenomic data from D. busckii, to investigate the evolutionary trajectory of sex chromosomes from a largely heterochromatic ancestor. We show that the neo-sex chromosomes formed <1 million years ago, but nearly 60% of neo-Y linked genes have already become non-functional. Expression levels are generally lower for the neo-Y alleles relative to their neo-X homologs, and the silencing heterochromatin mark H3K9me2, but not H3K9me3, is significantly enriched on silenced neo-Y genes. Despite rampant neo-Y degeneration, we find that the neo-X is deficient for the canonical histone modification mark of dosage compensation (H4K16ac), relative to autosomes or the compensated ancestral X chromosome, possibly reflecting constraints imposed on evolving hyperactive chromatin in an originally heterochromatic environment. Yet, neo-X genes are transcriptionally more active in males, relative to females, suggesting the evolution of incipient dosage compensation on the neo-X. Our data show that Y degeneration proceeds quickly after sex chromosomes become established through genomic and epigenetic changes, and are consistent with the idea that the evolution of sex-linked chromatin is influenced by its ancestral configuration. Data Availability Statement: All sequencing reads, the genome sequence assembly and annotation generated in this study are deposited at the National Center for Biotechnology Information Short Reads Archive (www.ncbi.nlm.nih.gov/sra) under the Bioproject accession no. PRJNA274996.Funding: This work was funded by NIH grants (R01GM076007, R01GM093182 and R01GM101255) to DB. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Author SummaryDNA is packaged with proteins into two general types of chromatin: the transcriptionally active euchromatin and repressive heterochromatin. Sex chromosomes typically evolve from a pair of euchromatic autosomes. The Y chromosome of Drosophila is gene poor and almost entirely heterochromatic; the X chromosome, in contrast, has evolved a hyperactive euchromatin structure and globally up-regulates its gene expression, to compensate for loss of activity from the homologous genes on the Y chromosome. The evolutionary trajectory along which sex chromosomes...

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Dosage compensation in Drosophila melanogaster: epigenetic fine-tuning of chromosome-wide transcription

Cited by 245 publications

References 152 publications

Sex-Biased Gene Expression and Evolution of the X Chromosome in Nematodes

Sex-Biased Gene Expression and Evolution of the X Chromosome in Nematodes

Linking dosage compensation and X chromosome nuclear organization inC. elegans

Ancestral chromatin configuration constrains chromatin evolution on differentiating sex chromosomes inDrosophila

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