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Decoding dosage compensation
Xinxian Deng, Christine M Disteche
Genome Biology , 2007, DOI: 10.1186/gb-2007-8-2-204
Abstract: In animals in which sex is determined by a divergent pair of sex chromosomes (XY), the resulting imbalance of gene dose between autosomes and sex chromosomes is potentially fatal. This imbalance is redressed by a process termed dosage compensation, which modulates global gene expression on the X chromosome to restore a balanced network of gene expression in the diploid cells in both sexes [1-4]. In Drosophila, dosage compensation is achieved by a twofold upregulation of expression from the single X chromosome in males. In contrast, in mammals and Caenorhabditis elegans, X-chromosome upregulation occurs in both sexes, together with a reduction of X-linked gene expression in the homogametic sex by silencing one of the two X chromosomes in mammalian females or repressing both X chromosomes in C. elegans hermaphrodites. Despite such diverse strategies, a fundamental question in the study of dosage compensation in all these species is how specific recognition of an entire X chromosome occurs. McDonel et al. [5] have recently shed light on this problem. They have discovered two clustered DNA motifs on the C. elegans X chromosome that act as a cis-acting code for recognition by the dosage-compensation complex (DCC), a complex of proteins that is responsible for the repression of the X chromosomes in hermaphrodites. This breakthrough points out the importance of DNA sequence in specifying the target of the DCC.Dosage-compensation mechanisms involve both protein complexes that act in trans and elements that are produced by the X chromosome itself, such as X inactive-specific transcript (XIST) RNA, which is essential for the onset of mammalian X inactivation. The question is how such regulatory complexes become specifically associated with, or stay with, the X chromosome. X inactivation is random in eutherian mammals, with either the paternal or maternal X chromosome silenced; however, in early mouse embryos and in marsupials, the paternal X chromosome is always inactivated.
Multiple RNA-protein interactions in Drosophila dosage compensation
Hubert Amrein
Genome Biology , 2000, DOI: 10.1186/gb-2000-1-6-reviews1030
Abstract: Dosage compensation, which ensures that the expression of X-linked genes is equal in males and females, is an essential process in organisms that have sex chromosomes. Because sex chromosomes appeared relatively late in evolution, dosage compensation evolved independently in different organisms and is accomplished by distinct mechanisms. For example, in Caenorhabditis elegans, dosage compensation occurs in the homogametic hermaphrodite (XX) by the down-regulation of virtually all genes on the two X chromosomes by about 50%. In mammals, dosage compensation also occurs in the homogametic sex (the female) by X inactivation, whereby an entire X chromosome forms a distinct, heterochromatic, transcriptionally inactive nuclear structure known as the Barr body. Consequently, each gene on the single active X chromosome in female cells and the corresponding gene on the single X chromosome in male cells are expressed at equal levels. In Drosophila, dosage compensation is achieved in the heterogametic male by a twofold chromosome-wide up-regulation (hypertranscription) of essentially all genes on the single X chromosome. In C. elegans and Drosophila, several proteins with different molecular functions involved in dosage compensation have been identified. Much attention has been dedicated to the elusive question of how the compensated or inactivated chromosomes are recognized by these proteins, and three recent papers investigating some of these aspects in Drosophila have provided new insights into this mystery [1,2,3].At least one common theme has emerged in Drosophila and mammals of how the dosage-compensated chromosomes are marked and eventually recognized by regulatory proteins: the use of non-coding RNAs transcribed from genes located on the X chromosome itself [4,5,6,7]. These RNAs, Xist (X-inactive specific transcript) in mammals, and roX1 and roX2 (RNA on the X) in Drosophila, are structurally unrelated, yet they share the intriguing property of remaining tightly associa
Targeting Determinants of Dosage Compensation in Drosophila  [PDF]
Ina K Dahlsveen,Gregor D Gilfillan,Vladimir I Shelest,Rosemarie Lamm,Peter B Becker
PLOS Genetics , 2006, DOI: 10.1371/journal.pgen.0020005
Abstract: The dosage compensation complex (DCC) in Drosophila melanogaster is responsible for up-regulating transcription from the single male X chromosome to equal the transcription from the two X chromosomes in females. Visualization of the DCC, a large ribonucleoprotein complex, on male larval polytene chromosomes reveals that the complex binds selectively to many interbands on the X chromosome. The targeting of the DCC is thought to be in part determined by DNA sequences that are enriched on the X. So far, lack of knowledge about DCC binding sites has prevented the identification of sequence determinants. Only three binding sites have been identified to date, but analysis of their DNA sequence did not allow the prediction of further binding sites. We have used chromatin immunoprecipitation to identify a number of new DCC binding fragments and characterized them in vivo by visualizing DCC binding to autosomal insertions of these fragments, and we have demonstrated that they possess a wide range of potential to recruit the DCC. By varying the in vivo concentration of the DCC, we provide evidence that this range of recruitment potential is due to differences in affinity of the complex to these sites. We were also able to establish that DCC binding to ectopic high-affinity sites can allow nearby low-affinity sites to recruit the complex. Using the sequences of the newly identified and previously characterized binding fragments, we have uncovered a number of short sequence motifs, which in combination may contribute to DCC recruitment. Our findings suggest that the DCC is recruited to the X via a number of binding sites of decreasing affinities, and that the presence of high- and moderate-affinity sites on the X may ensure that lower-affinity sites are occupied in a context-dependent manner. Our bioinformatics analysis suggests that DCC binding sites may be composed of variable combinations of degenerate motifs.
Targeting determinants of dosage compensation in Drosophila.  [cached]
Dahlsveen Ina K,Gilfillan Gregor D,Shelest Vladimir I,Lamm Rosemarie
PLOS Genetics , 2006,
Abstract: The dosage compensation complex (DCC) in Drosophila melanogaster is responsible for up-regulating transcription from the single male X chromosome to equal the transcription from the two X chromosomes in females. Visualization of the DCC, a large ribonucleoprotein complex, on male larval polytene chromosomes reveals that the complex binds selectively to many interbands on the X chromosome. The targeting of the DCC is thought to be in part determined by DNA sequences that are enriched on the X. So far, lack of knowledge about DCC binding sites has prevented the identification of sequence determinants. Only three binding sites have been identified to date, but analysis of their DNA sequence did not allow the prediction of further binding sites. We have used chromatin immunoprecipitation to identify a number of new DCC binding fragments and characterized them in vivo by visualizing DCC binding to autosomal insertions of these fragments, and we have demonstrated that they possess a wide range of potential to recruit the DCC. By varying the in vivo concentration of the DCC, we provide evidence that this range of recruitment potential is due to differences in affinity of the complex to these sites. We were also able to establish that DCC binding to ectopic high-affinity sites can allow nearby low-affinity sites to recruit the complex. Using the sequences of the newly identified and previously characterized binding fragments, we have uncovered a number of short sequence motifs, which in combination may contribute to DCC recruitment. Our findings suggest that the DCC is recruited to the X via a number of binding sites of decreasing affinities, and that the presence of high- and moderate-affinity sites on the X may ensure that lower-affinity sites are occupied in a context-dependent manner. Our bioinformatics analysis suggests that DCC binding sites may be composed of variable combinations of degenerate motifs.
Regional differences in dosage compensation on the chicken Z chromosome
Esther Melamed, Arthur P Arnold
Genome Biology , 2007, DOI: 10.1186/gb-2007-8-9-r202
Abstract: Using microarray mRNA expression analysis, we find that dosage compensated and non-compensated genes occur across the Z chromosome, but a cluster of compensated genes are found in the MHM region of chicken chromosome Zp, whereas Zq is enriched in non-compensated genes. The degree of dosage compensation among Z genes is predicted better by the level of expression of Z genes in males than in females, probably because of better compensation of genes with lower levels of expression. Compensated genes have different functional properties than non-compensated genes, suggesting that dosage compensation has evolved gene-by-gene according to selective pressures on each gene. The group of genes comprising the MHM region also resides on a primitive mammalian (platypus) sex chromosome and, thus, may represent an ancestral precursor to avian ZZ/ZW and monotreme XX/XY sex chromosome systems.The aggregation of dosage compensated genes near the MHM locus may reflect a local sex- and chromosome-specific mechanism of dosage compensation, perhaps mediated by the MHM non-coding RNA.In birds, males are homogametic (ZZ) and females are heterogametic (ZW), in contrast to the mammalian pattern of female XX homogamety and male XY heterogamety. Like the mammalian X and Y chromosomes, the euchromatic Z is large (over 500 genes) and the heterochromatic W small (probably containing tens of genes) [1-4]. In both groups, the difference in copy number of the Z or X chromosomes results in one sex having a higher genomic dose of Z or X genes.Gene dosage is considered to be critical, at least for a significant number of genes, and an imbalance in chromosomal number (aneuploidy) can result in conditions such as Turner syndrome (XO), Klinefelter syndrome (XXY), Down syndrome (Trisomy 21), and cancer [5-7]. Aneuploidy for an entire chromosome is usually lethal [8]. Because a delicate balance in gene dosage is important for proper functioning and organismal survival, numerous species have evolved mechani
Dosage compensation is less effective in birds than in mammals  [cached]
Itoh Yuichiro,Melamed Esther,Yang Xia,Kampf Kathy
Journal of Biology , 2007, DOI: 10.1186/jbiol53
Abstract: Background In animals with heteromorphic sex chromosomes, dosage compensation of sex-chromosome genes is thought to be critical for species survival. Diverse molecular mechanisms have evolved to effectively balance the expressed dose of X-linked genes between XX and XY animals, and to balance expression of X and autosomal genes. Dosage compensation is not understood in birds, in which females (ZW) and males (ZZ) differ in the number of Z chromosomes. Results Using microarray analysis, we compared the male:female ratio of expression of sets of Z-linked and autosomal genes in two bird species, zebra finch and chicken, and in two mammalian species, mouse and human. Male:female ratios of expression were significantly higher for Z genes than for autosomal genes in several finch and chicken tissues. In contrast, in mouse and human the male:female ratio of expression of X-linked genes is quite similar to that of autosomal genes, indicating effective dosage compensation even in humans, in which a significant percentage of genes escape X-inactivation. Conclusion Birds represent an unprecedented case in which genes on one sex chromosome are expressed on average at constitutively higher levels in one sex compared with the other. Sex-chromosome dosage compensation is surprisingly ineffective in birds, suggesting that some genomes can do without effective sex-specific sex-chromosome dosage compensation mechanisms.
The Status of Dosage Compensation in the Multiple X Chromosomes of the Platypus  [PDF]
Janine E. Deakin ,Timothy A. Hore,Edda Koina,Jennifer A. Marshall Graves
PLOS Genetics , 2008, DOI: 10.1371/journal.pgen.1000140
Abstract: Dosage compensation has been thought to be a ubiquitous property of sex chromosomes that are represented differently in males and females. The expression of most X-borne genes is equalized between XX females and XY males in therian mammals (marsupials and “placentals”) by inactivating one X chromosome in female somatic cells. However, compensation seems not to be strictly required to equalize the expression of most Z-borne genes between ZZ male and ZW female birds. Whether dosage compensation operates in the third mammal lineage, the egg-laying monotremes, is of considerable interest, since the platypus has a complex sex chromosome system in which five X and five Y chromosomes share considerable genetic homology with the chicken ZW sex chromosome pair, but not with therian XY chromosomes. The assignment of genes to four platypus X chromosomes allowed us to examine X dosage compensation in this unique species. Quantitative PCR showed a range of compensation, but SNP analysis of several X-borne genes showed that both alleles are transcribed in a heterozygous female. Transcription of 14 BACs representing 19 X-borne genes was examined by RNA-FISH in female and male fibroblasts. An autosomal control gene was expressed from both alleles in nearly all nuclei, and four pseudoautosomal BACs were usually expressed from both alleles in male as well as female nuclei, showing that their Y loci are active. However, nine X-specific BACs were usually transcribed from only one allele. This suggests that while some genes on the platypus X are not dosage compensated, other genes do show some form of compensation via stochastic transcriptional inhibition, perhaps representing an ancestral system that evolved to be more tightly controlled in placental mammals such as human and mouse.
Global analysis of X-chromosome dosage compensation
Gupta Vaijayanti,Parisi Michael,Sturgill David,Nuttall Rachel
Journal of Biology , 2006, DOI: 10.1186/jbiol30
Abstract: Background Drosophila melanogaster females have two X chromosomes and two autosome sets (XX;AA), while males have a single X chromosome and two autosome sets (X;AA). Drosophila male somatic cells compensate for a single copy of the X chromosome by deploying male-specific-lethal (MSL) complexes that increase transcription from the X chromosome. Male germ cells lack MSL complexes, indicating that either germline X-chromosome dosage compensation is MSL-independent, or that germ cells do not carry out dosage compensation. Results To investigate whether dosage compensation occurs in germ cells, we directly assayed X-chromosome transcripts using DNA microarrays and show equivalent expression in XX;AA and X;AA germline tissues. In X;AA germ cells, expression from the single X chromosome is about twice that of a single autosome. This mechanism ensures balanced X-chromosome expression between the sexes and, more importantly, it ensures balanced expression between the single X chromosome and the autosome set. Oddly, the inactivation of an X chromosome in mammalian females reduces the effective X-chromosome dose and means that females face the same X-chromosome transcript deficiency as males. Contrary to most current dosage-compensation models, we also show increased X-chromosome expression in X;AA and XX;AA somatic cells of Caenorhabditis elegans and mice. Conclusion Drosophila germ cells compensate for X-chromosome dose. This occurs by equilibrating X-chromosome and autosome expression in X;AA cells. Increased expression of the X chromosome in X;AA individuals appears to be phylogenetically conserved.
LTR retrotransposons and the evolution of dosage compensation in Drosophila
Lilya V Matyunina, Nathan J Bowen, John F McDonald
BMC Molecular Biology , 2008, DOI: 10.1186/1471-2199-9-55
Abstract: We show that transcription of the Drosophila melanogaster copia LTR (long terminal repeat) retrotransposon is significantly down regulated when in the hemizygous state. DNA digestion and chromatin immunoprecipitation (ChIP) analyses demonstrate that this down regulation is associated with changes in chromatin structure mediated by the histone acetyltransferase, MOF. MOF has previously been shown to play a central role in the Drosophila dosage compensation complex by binding to the hemizygous X-chromosome in males.Our results are consistent with the hypothesis that MOF originally functioned to silence retrotransposons and, over evolutionary time, was co-opted to play an essential role in dosage compensation in Drosophila.Retrotransposons are a major component of the genomes of higher eukaryotes and have been identified as a significant source of loss-of-function and regulatory mutations [1]. Over evolutionary time host genomes have developed mechanisms to mitigate the mutational potential of retrotransposons by transcriptionally silencing or otherwise blocking their transpositional activity [2]. One of the primary mechanisms by which retrotransposons are transcriptionally silenced is by methylation and/or other epigenetic mechanisms. Indeed it has been hypothesized that most, if not all, epigenetic mechanisms originally evolved as a defense against retrotransposons and have subsequently been co-opted for other essential cellular functions [3,4].Approximately 10% of the Drosophila melanogaster genome is comprised of retrotransposons, the majority of which are LTR retrotransposons. LTR retrotransposon insertions are a major source of mutations in D. melanogaster and are believed to have contributed significantly to genome evolution [5]. While histone acetylation and other epigenetic mechanisms are believed to play an essential role in dosage compensation and other vital functions in D. melanogaster, little is known about the role of these mechanisms in the regulation o
Mechanisms and Evolutionary Patterns of Mammalian and Avian Dosage Compensation  [PDF]
Philippe Julien,David Brawand,Magali Soumillon,Anamaria Necsulea,Angélica Liechti,Frédéric Schütz,Tasman Daish,Frank Grützner,Henrik Kaessmann
PLOS Biology , 2012, DOI: 10.1371/journal.pbio.1001328
Abstract: As a result of sex chromosome differentiation from ancestral autosomes, male mammalian cells only contain one X chromosome. It has long been hypothesized that X-linked gene expression levels have become doubled in males to restore the original transcriptional output, and that the resulting X overexpression in females then drove the evolution of X inactivation (XCI). However, this model has never been directly tested and patterns and mechanisms of dosage compensation across different mammals and birds generally remain little understood. Here we trace the evolution of dosage compensation using extensive transcriptome data from males and females representing all major mammalian lineages and birds. Our analyses suggest that the X has become globally upregulated in marsupials, whereas we do not detect a global upregulation of this chromosome in placental mammals. However, we find that a subset of autosomal genes interacting with X-linked genes have become downregulated in placentals upon the emergence of sex chromosomes. Thus, different driving forces may underlie the evolution of XCI and the highly efficient equilibration of X expression levels between the sexes observed for both of these lineages. In the egg-laying monotremes and birds, which have partially homologous sex chromosome systems, partial upregulation of the X (Z in birds) evolved but is largely restricted to the heterogametic sex, which provides an explanation for the partially sex-biased X (Z) expression and lack of global inactivation mechanisms in these lineages. Our findings suggest that dosage reductions imposed by sex chromosome differentiation events in amniotes were resolved in strikingly different ways.
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