Showing papers on "Dosage compensation published in 2009"
TL;DR: The role that noncoding RNAs play as potent and specific regulators of gene expression is now widely recognized in almost all species studied to date.
340 citations
TL;DR: This review will discuss the relative contributions of sequence elements and transcriptional marks to the complete pattern of MSL complex binding and suggest that this occurs through a multi-step targeting mechanism that involves DNA sequences elements and epigenetic marks associated with transcription.
Abstract: Dosage compensation is the crucial process that equalizes gene expression from the X chromosome between males (XY) and females (XX). In Drosophila, the male-specific lethal (MSL) ribonucleoprotein complex mediates dosage compensation by upregulating transcription from the single male X chromosome approximately twofold. A key challenge is to understand how the MSL complex distinguishes the X chromosome from autosomes. Recent studies suggest that this occurs through a multi-step targeting mechanism that involves DNA sequence elements and epigenetic marks associated with transcription. This review will discuss the relative contributions of sequence elements and transcriptional marks to the complete pattern of MSL complex binding.
239 citations
TL;DR: It is shown that silencing of some X-chromosomal regions occurs outside of the usual time window and that escape from X inactivation can be highly lineage specific.
Abstract: In mammals, X-chromosome dosage compensation is achieved by inactivating one of the two X chromosomes in females. In mice, X inactivation is initially imprinted, with inactivation of the paternal X (Xp) chromosome occurring during preimplantation development. One theory is that the Xp is preinactivated in female embryos, because of its previous silence during meiosis in the male germ line. The extent to which the Xp is active after fertilization and the exact time of onset of X-linked gene silencing have been the subject of debate. We performed a systematic, single-cell transcriptional analysis to examine the activity of the Xp chromosome for a panel of X-linked genes throughout early preimplantation development in the mouse. Rather than being preinactivated, we found the Xp to be fully active at the time of zygotic gene activation, with silencing beginning from the 4-cell stage onward. X-inactivation patterns were, however, surprisingly diverse between genes. Some loci showed early onset (4–8-cell stage) of X inactivation, and some showed extremely late onset (postblastocyst stage), whereas others were never fully inactivated. Thus, we show that silencing of some X-chromosomal regions occurs outside of the usual time window and that escape from X inactivation can be highly lineage specific. These results reveal that imprinted X inactivation in mice is far less concerted than previously thought and highlight the epigenetic diversity underlying the dosage compensation process during early mammalian development.
163 citations
TL;DR: The evolutionary lability of sex determination, and the corresponding rapid rate of turn-over among different modes, makes the teleost clade an excellent model with which to test theories regarding the evolution of sex determining adaptations.
Abstract: Sex determination, due to the obvious association with reproduction and Darwinian fitness, has been traditionally assumed to be a relatively conserved trait. However, research on teleost fishes has shown that this need not be the case, as these animals display a remarkable diversity in the ways that they determine sex. These different mechanisms, which include constitutive genetic mechanisms on sex chromosomes, polygenic constitutive mechanisms, environmental influences, hermaphroditism, and unisexuality have each originated numerous independent times in the teleosts. The evolutionary lability of sex determination, and the corresponding rapid rate of turn-over among different modes, makes the teleost clade an excellent model with which to test theories regarding the evolution of sex determining adaptations. Much of the plasticity in sex determination likely results from the dynamic teleost genome, and recent advances in fish genetics and genomics have revealed the role of gene and genome duplication in fostering emergence and turn-over of sex determining mechanisms.
157 citations
TL;DR: It is shown that female preimplantation embryos have a progressive accumulation of XIST RNA on one of the two X chromosomes, starting around the 8-cell stage and is associated with transcriptional silencing of the XIST-coated chromosomal region.
Abstract: X chromosome inactivation (XCI) is the mammalian mechanism that compensates for the difference in gene dosage between XX females and XY males. Genetic and epigenetic regulatory mechanisms induce transcriptional silencing of one X chromosome in female cells. In mouse embryos, XCI is initiated at the preimplantation stage following early whole-genome activation. It is widely thought that human embryos do not employ XCI prior to implantation. Here, we show that female preimplantation embryos have a progressive accumulation of XIST RNA on one of the two X chromosomes, starting around the 8-cell stage. XIST RNA accumulates at the morula and blastocyst stages and is associated with transcriptional silencing of the XIST-coated chromosomal region. These findings indicate that XCI is initiated in female human preimplantation-stage embryos and suggest that preimplantation dosage compensation is evolutionarily conserved in placental mammals.
145 citations
TL;DR: Recent reports in birds and moths contradict this view because these animals locally compensate only a few genes on the sex chromosomes, leaving the majority with different expression levels in males and females, and warrant a re-examination of the evolutionary forces underlying dosage compensation.
141 citations
TL;DR: Almost all active genes on the X chromosome are associated with robust H4 Lys16 acetylation (H4K16ac), the histone modification catalyzed by the MSL complex, suggesting a common principle for the establishment of active and silenced chromatin domains.
Abstract: Drosophila MSL complex binds the single male X chromosome to upregulate gene expression to equal that from the two female X chromosomes. However, it has been puzzling that ~25% of transcribed genes on the X do not stably recruit MSL complex. Here, we find that almost all active genes on the X are associated with robust H4 Lys16 acetylation (H4K16ac), the histone modification catalyzed by MSL complex. The distribution of H4K16ac is much broader than that of MSL complex, and our results favor the idea that chromosome-wide H4K16ac reflects transient association of MSL complex, occurring through spreading or chromosomal looping. Our results parallel those of localized Polycomb repressive complex and its more broadly distributed H3K27me3 chromatin mark, suggesting a common principle for the establishment of active and silenced chromatin domains.
133 citations
TL;DR: It is demonstrated that condensin subunits in C. elegans form three complexes, one that functions in dosage compensation and two that function in mitosis and meiosis, illustrating the versatility of condensins to function in both gene regulation and chromosome segregation.
132 citations
TL;DR: The lack of a global mechanism of avian dosage compensation, and the pattern of gene expression difference between males and females varies a great deal for individual Z-linked genes, suggests that some genes may be individually dosage compensated, and that some less-than-global pattern of dosage compensation exists on the avian Z chromosome.
Abstract: Recent reports have suggested that birds lack a mechanism of wholesale dosage compensation for the Z sex chromosome. This discovery was rather unexpected, as all other animals investigated with chromosomal mechanisms of sex determination have some method to counteract the effects of gene dosage of the dominant sex chromosome in males and females. Despite the lack of a global mechanism of avian dosage compensation, the pattern of gene expression difference between males and females varies a great deal for individual Z-linked genes. This suggests that some genes may be individually dosage compensated, and that some less-than-global pattern of dosage compensation, such as local or temporal, exists on the avian Z chromosome. We used global gene expression profiling in males and females for both somatic and gonadal tissue at several time points in the life cycle of the chicken to assess the pattern of sex-biased gene expression on the Z chromosome. Average fold-change between males and females varied somewhat among tissue time-point combinations, with embryonic brain samples having the smallest gene dosage effects, and adult gonadal tissue having the largest degree of male bias. Overall, there were no neighborhoods of overall dosage compensation along the Z. Taken together, this suggests that dosage compensation is regulated on the Z chromosome entirely on a gene-by-gene level, and can vary during the life cycle and by tissue type. This regulation may be an indication of how critical a given gene's functionality is, as the expression level for essential genes will be tightly regulated in order to avoid perturbing important pathways and networks with differential expression levels in males and females.
131 citations
TL;DR: These findings fulfill predictions for a targeting model in which the DCC binds to recruitment sites on X and disperses to discrete sites lacking autonomous recruitment ability, and relate DCC binding to function.
Abstract: In many species, a dosage compensation complex (DCC) is targeted to X chromosomes of one sex to equalize levels of X-gene products between males (1X) and females (2X). Here we identify cis-acting regulatory elements that target the Caenorhabditis elegans X chromosome for repression by the DCC. The DCC binds to discrete, dispersed sites on X of two types. rex sites (recruitment elements on X) recruit the DCC in an autonomous, DNA sequence-dependent manner using a 12-base-pair (bp) consensus motif that is enriched on X. This motif is critical for DCC binding, is clustered in rex sites, and confers much of X-chromosome specificity. Motif variants enriched on X by 3.8-fold or more are highly predictive (95%) for rex sites. In contrast, dox sites (dependent on X) lack the X-enriched variants and cannot bind the DCC when detached from X. dox sites are more prevalent than rex sites and, unlike rex sites, reside preferentially in promoters of some expressed genes. These findings fulfill predictions for a targeting model in which the DCC binds to recruitment sites on X and disperses to discrete sites lacking autonomous recruitment ability. To relate DCC binding to function, we identified dosage-compensated and noncompensated genes on X. Unexpectedly, many genes of both types have bound DCC, but many do not, suggesting the DCC acts over long distances to repress X-gene expression. Remarkably, the DCC binds to autosomes, but at far fewer sites and rarely at consensus motifs. DCC disruption causes opposite effects on expression of X and autosomal genes. The DCC thus acts at a distance to impact expression throughout the genome.
119 citations
TL;DR: This review focuses on evolutionary aspects of dosage compensation, in light of recent advances in comparative and functional genomics that have substantially increased the authors' understanding of the molecular mechanisms of dosage Compensation and how it evolved.
Abstract: In many eukaryotic organisms, gender is determined by a pair of heteromorphic sex chromosomes. Degeneration of the non-recombining Y chromosome is a general facet of sex chromosome evolution. Selective pressure to restore expression levels of X-linked genes relative to autosomes accompanies Y-chromosome degeneration, thus driving the evolution of dosage compensation mechanisms. This review focuses on evolutionary aspects of dosage compensation, in light of recent advances in comparative and functional genomics that have substantially increased our understanding of the molecular mechanisms of dosage compensation and how it evolved. We review processes involved in sex chromosome evolution, and discuss the dynamic interaction between Y degeneration and the acquisition of dosage compensation. We compare mechanisms of dosage compensation and the origin of dosage compensation genes between different taxa and comment on sex chromosomes that apparently lack compensation mechanisms. Finally, we discuss how dosage compensation systems can also influence the evolution of well-established sex chromosomes.
TL;DR: It is shown that the ZW pair is transiently silenced, from early pachytene to early diplotene, and it is proposed that ZW inactivation is most likely achieved via spreading of heterochromatin from the W on the Z chromosome, which indicates the presence of an evolutionary force that drives meiotic sex chromosome inactivation independent of the final achievement of synapsis.
Abstract: During meiotic prophase in male mammals, the heterologous X and Y chromosomes remain largely unsynapsed, and meiotic sex chromosome inactivation (MSCI) leads to formation of the transcriptionally silenced XY body. In birds, the heterogametic sex is female, carrying Z and W chromosomes (ZW), whereas males have the homogametic ZZ constitution. During chicken oogenesis, the heterologous ZW pair reaches a state of complete heterologous synapsis, and this might enable maintenance of transcription of Z- and W chromosomal genes during meiotic prophase. Herein, we show that the ZW pair is transiently silenced, from early pachytene to early diplotene using immunocytochemistry and gene expression analyses. We propose that ZW inactivation is most likely achieved via spreading of heterochromatin from the W on the Z chromosome. Also, persistent meiotic DNA double-strand breaks (DSBs) may contribute to silencing of Z. Surprisingly, γH2AX, a marker of DSBs, and also the earliest histone modification that is associated with XY body formation in mammalian and marsupial spermatocytes, does not cover the ZW during the synapsed stage. However, when the ZW pair starts to desynapse, a second wave of γH2AX accumulates on the unsynapsed regions of Z, which also show a reappearance of the DSB repair protein RAD51. This indicates that repair of meiotic DSBs on the heterologous part of Z is postponed until late pachytene/diplotene, possibly to avoid recombination with regions on the heterologously synapsed W chromosome. Two days after entering diplotene, the Z looses γH2AX and shows reactivation. This is the first report of meiotic sex chromosome inactivation in a species with female heterogamety, providing evidence that this mechanism is not specific to spermatogenesis. It also indicates the presence of an evolutionary force that drives meiotic sex chromosome inactivation independent of the final achievement of synapsis.
TL;DR: Analysis of male:female (M:F) ratios of expression of chromosome-wide Z-linked genes in the silkworm using microarray data indicated that the two sets of the genes have functional differences, and analysis of gene expression by sex showed that M:F ratios were, some extent, associated with their expression levels.
TL;DR: Analysis of publicly available data shows that microarray data or EST data are used to detect male-biased genes in D. melanogaster and to measure their expression levels, consistent with the idea that limitations in transcription rates may prevent male- biased genes from accumulating on the X chromosome.
Abstract: In Drosophila, there is a consistent deficit of male-biased genes on the X chromosome. It has been suggested that male-biased genes may evolve from initially unbiased genes as a result of increased expression levels in males. If transcription rates are limited, a large increase in expression in the testis may be harder to achieve for single-copy X-linked genes than for autosomal genes, because they are already hypertranscribed due to dosage compensation. This hypothesis predicts that the larger the increase in expression required to make a male-biased gene, the lower the chance of this being achievable if it is located on the X chromosome. Consequently, highly expressed male-biased genes should be located on the X chromosome less often than lowly expressed male-biased genes. This pattern is observed in our analysis of publicly available data, where microarray data or EST data are used to detect male-biased genes in D. melanogaster and to measure their expression levels. This is consistent with the idea that limitations in transcription rates may prevent male-biased genes from accumulating on the X chromosome.
TL;DR: This work examines the testis transcriptome of the silkworm, Bombyx mori, and shows that the Z chromosome harbors a significantly higher number of genes expressed preferentially in testis compared to the autosomes, and hypothesizes that sexual antagonism and absence of dosage compensation have possibly led to the accumulation of many male-specific genes on the Z chromosomes.
Abstract: The role of sex chromosomes in sex determination has been well studied in diverse groups of organisms. However, the role of the genes on the sex chromosomes in conferring sexual dimorphism is still being experimentally evaluated. An unequal complement of sex chromosomes between two sexes makes them amenable to sex-specific evolutionary forces. Sex-linked genes preferentially expressed in one sex over the other offer a potential means of addressing the role of sex chromosomes in sexual dimorphism. We examined the testis transcriptome of the silkworm, Bombyx mori, which has a ZW chromosome constitution in the female and ZZ in the male, and show that the Z chromosome harbors a significantly higher number of genes expressed preferentially in testis compared to the autosomes. We hypothesize that sexual antagonism and absence of dosage compensation have possibly led to the accumulation of many male-specific genes on the Z chromosome. Further, our analysis of testis-specific paralogous genes suggests that the accumulation on the Z chromosome of genes advantageous to males has occurred primarily by translocation or tandem duplication.
TL;DR: This work explores recent advances in the study of vertebrate sex chromosomes achieved using genomic analyses using whole genome sequences from a variety of organisms.
Abstract: Sex chromosomes have evolved multiple times in many taxa. The recent explosion in the availability of whole genome sequences from a variety of organisms makes it possible to investigate sex chromosome evolution within and across genomes. Comparative genomic studies have shown that quite distant species may share fundamental properties of sex chromosome evolution, while very similar species can evolve unique sex chromosome systems. Furthermore, within-species genomic analyses can illuminate chromosome-wide sequence and expression polymorphisms. Here, we explore recent advances in the study of vertebrate sex chromosomes achieved using genomic analyses.
TL;DR: It is shown that female-detriment genes are significantly overrepresented on the Z chromosome, and female-benefit genes underrepresented, which is consistent with a dominant mode of inheritance for sexually antagonistic genes, in which male-benefit coding mutations are more likely to be fixed on theZ due to stronger male-specific selective pressures.
Abstract: Evolutionary theory predicts that sexually antagonistic loci will be preferentially sex-linked, and this association can be empirically testes with data on sex-biased gene expression with the assumption that sex-biased gene expression represents the resolution of past sexual antagonism. However, incomplete dosage compensating mechanisms and meiotic sex chromosome inactivation have hampered efforts to connect expression data to theoretical predictions regarding the genomic distribution of sexually antagonistic loci in a variety of animals. Here we use data on the underlying regulatory mechanism that produce expression sex-bias to test the genomic distribution of sexually antagonistic genes in chicken. Using this approach, which is free from problems associated with the lack of dosage compensation in birds, we show that female-detriment genes are significantly overrepresented on the Z chromosome, and female-benefit genes underrepresented. By contrast, male-effect genes show no over- or underrepresentation on the Z chromosome. These data are consistent with a dominant mode of inheritance for sexually antagonistic genes, in which male-benefit coding mutations are more likely to be fixed on the Z due to stronger male-specific selective pressures. After fixation of male-benefit alleles, regulatory changes in females evolve to minimize antagonism by reducing female expression.
TL;DR: These genes that “escape” X inactivation are of medical importance as they explain phenotypes in individuals with sex chromosome aneuploidies and may impact normal traits and disorders that differ between men and women.
Abstract: Counting chromosomes is not just simple math Although normal males and females differ in sex chromosome content (XY vs XX), X chromosome imbalance is tolerated because dosage compensation mechanisms have evolved to ensure functional equivalence In mammals this is accomplished by two processes—X chromosome inactivation that silences most genes on one X chromosome in females, leading to functional X monosomy for most genes in both sexes, and X chromosome upregulation that results in increased gene expression on the single active X in males and females, equalizing dosage relative to autosomes This review focuses on genes on the X chromosome, and how gene content, organization and expression levels can be influenced by these two processes Special attention is given to genes that are not X inactivated, and are not necessarily fully dosage compensated These genes that “escape” X inactivation are of medical importance as they explain phenotypes in individuals with sex chromosome aneuploidies and may impact normal traits and disorders that differ between men and women Moreover, escape genes give insight into how X chromosome inactivation is spread and maintained on the X
TL;DR: Recent studies have revealed major mechanistic differences in X inactivation between eutherians and marsupials, suggesting that the evolution of the X chromosome as well as developmental differences between mammals have led to diverse evolutionary strategies for dosage compensation.
Abstract: In most mammals, X-chromosome inactivation is used as the strategy to achieve dosage compensation between XX females and XY males. This process is developmentally regulated, resulting in the differential treatment of the two X chromosomes in the same nucleus and mitotic heritability of the silent state. A lack of dosage compensation in an XX embryo is believed to result in early lethality, at least in eutherians. Given its fundamental importance, X-chromosome inactivation would be predicted to be a highly conserved process in mammals. However, recent studies have revealed major mechanistic differences in X inactivation between eutherians and marsupials, suggesting that the evolution of the X chromosome as well as developmental differences between mammals have led to diverse evolutionary strategies for dosage compensation.
TL;DR: Newly formed X chromosomes are not passive players in the evolutionary process of sex chromosome differentiation, but respond adaptively to both their sex-biased transmission and to Y chromosome degeneration, possibly through demasculinization of their gene content and the evolution of dosage compensation.
Abstract: Sex chromosomes originated from ordinary autosomes, and their evolution is characterized by continuous gene loss from the ancestral Y chromosome. Here, we document a new feature of sex chromosome evolution: bursts of adaptive fixations on a newly formed X chromosome. Taking advantage of the recently formed neo-X chromosome of Drosophila miranda, we compare patterns of DNA sequence variation at genes located on the neo-X to genes on the ancestral X chromosome. This contrast allows us to draw inferences of selection on a newly formed X chromosome relative to background levels of adaptation in the genome while controlling for demographic effects. Chromosome-wide synonymous diversity on the neo-X is reduced 2-fold relative to the ancestral X, as expected under recent and recurrent directional selection. Several statistical tests employing various features of the data consistently identify 10%-15% of neo-X genes as targets of recent adaptive evolution but only 1%-3% of genes on the ancestral X. In addition, both the rate of adaptation and the fitness effects of adaptive substitutions are estimated to be roughly an order of magnitude higher for neo-X genes relative to genes on the ancestral X. Thus, newly formed X chromosomes are not passive players in the evolutionary process of sex chromosome differentiation, but respond adaptively to both their sex-biased transmission and to Y chromosome degeneration, possibly through demasculinization of their gene content and the evolution of dosage compensation.
TL;DR: Genetic compensation, which is consistent with the normal phenotype of the father, was shown through quantitative-expression analyses of genes located within the genetic region associated with the DiGeorge syndrome, a case of genetic compensation in a human genomic disorder.
Abstract: Cytogenetic studies of the parents of a girl with the DiGeorge (or velocardiofacial) syndrome, who carried a deletion at 22q11.2, revealed an unexpected rearrangement of both 22q11.2 regions in the unaffected father. He carried a 22q11.2 deletion on one copy of chromosome 22 and a reciprocal 22q11.2 duplication on the other copy of chromosome 22. Genetic compensation, which is consistent with the normal phenotype of the father, was shown through quantitative-expression analyses of genes located within the genetic region associated with the DiGeorge syndrome. This finding has implications for genetic counseling and represents a case of genetic compensation in a human genomic disorder.
TL;DR: High throughput gene expression analysis in the cerebellum of a large number of samples of Ts1Cje and euploid mice has revealed a prevailing gene dosage effect on triplicated genes, which strongly suggest that the three-copy genes are directly responsible for the phenotype present in Cerebellum.
Abstract: Background
Down syndrome is a chromosomal disorder caused by the presence of three copies of chromosome 21. The mechanisms by which this aneuploidy produces the complex and variable phenotype observed in people with Down syndrome are still under discussion. Recent studies have demonstrated an increased transcript level of the three-copy genes with some dosage compensation or amplification for a subset of them. The impact of this gene dosage effect on the whole transcriptome is still debated and longitudinal studies assessing the variability among samples, tissues and developmental stages are needed.
TL;DR: It is suggested that local DNA hypomethylation and CTCF binding are involved in the formation of a chromatin boundary, which protects the UBA1 escape gene against the chromosome-wide transcriptional silencing.
Abstract: In mammals, the dosage compensation of sex chromosomes between males and females is achieved by transcriptional inactivation of one of the two X chromosomes in females. However, a number of genes escape X-inactivation in humans. It remains poorly understood how the transcriptional activity of these 'escape genes' is maintained despite the chromosome-wide heterochromatin formation. To address this question, we analyzed a putative chromatin boundary between the inactivated RBM10 and an escape gene, UBA1/UBE1. Chromatin immunoprecipitation revealed that trimethylated histone H3 lysine 9 and H4 lysine 20 were enriched in the last exon through the proximal downstream region of RBM10, but were remarkably diminished at approximately 2 kb upstream of the UBA1 transcription start site. Whereas RNA polymerase II was not loaded onto the intergenic region, CTCF (CCCTC binding factor) was enriched around the boundary, where some CpG sites were hypomethylated specifically on inactive X. These findings suggest that local DNA hypomethylation and CTCF binding are involved in the formation of a chromatin boundary, which protects the UBA1 escape gene against the chromosome-wide transcriptional silencing.
TL;DR: Analysis of the specific pattern of histone modifications using immunofluorescence on metaphasic chromosomes of a model kangaroo, the tammar wallaby, found that all active marks are excluded from the inactive X in marsupials, so this represents a common feature of X inactivation throughout mammals.
Abstract: The inactivation of one of the two X chromosomes in female placental mammals represents a remarkable example of epigenetic silencing. X inactivation occurs also in marsupial mammals, but is phenotypically different, being incomplete, tissue-specific and paternal. Paternal X inactivation occurs also in the extraembryonic cells of rodents, suggesting that imprinted X inactivation represents a simpler ancestral mechanism. This evolved into a complex and random process in placental mammals under the control of the XIST gene, involving notably variant and modified histones. Molecular mechanisms of X inactivation in marsupials are poorly known, but occur in the absence of an XIST homologue. We analysed the specific pattern of histone modifications using immunofluorescence on metaphasic chromosomes of a model kangaroo, the tammar wallaby. We found that all active marks are excluded from the inactive X in marsupials, as in placental mammals, so this represents a common feature of X inactivation throughout mammals. However, we were unable to demonstrate the accumulation of inactive histone marks, suggesting some fundamental differences in the molecular mechanism of X inactivation between marsupial and placental mammals. A better understanding of the epigenetic mechanisms underlying X inactivation in marsupials will provide important insights into the evolution of this complex process.
TL;DR: It is shown that DCC binding is dynamically specified according to gene activity during development and that the mechanism of DCC spreading is independent of X chromosome DNA sequence, which suggests mechanisms fundamental to chromosome-scale gene regulation.
TL;DR: Both aspects of roX function are discussed and an integrated model for possible mechanisms how these RNAs might be involved in epigenetic regulation of the male X chromosome is proposed.
Abstract: The roX RNAs represent one of the paradigm examples of large non-coding RNAs involved in chromatin regulation. Interestingly, roX genes have a dual life. The RNA product is part of the MSL complex required for dosage compensation of the male X chromosome in Drosophila while the genomic location is used as a binding platform for MSL complex assembly. In this review we discuss both aspects of roX function and propose an integrated model for possible mechanisms how these RNAs might be involved in epigenetic regulation of the male X chromosome.
TL;DR: Focusing on the best studied transcripts Xist and Tsix, a current perspective on chromosome wide gene regulation by non-coding RNAs is portrayed.
Abstract: Non-coding RNAs regulate dosage compensation in mammals by controlling transcriptional silencing of one of the two X chromosomes in females. The two major transcripts involved in this process are Xist and its antisense counterpart Tsix. Expression of Xist and Tsix from the X inactivation center is mutually exclusive. Xist expression triggers chromosome wide silencing of the X chromosome from which it is transcribed. Tsix is a repressor of Xist and is specifically expressed from the other X chromosome, maintaining its activity. Here, we review non-coding RNAs that have been implicated in X chromosome inactivation. Focusing on the best studied transcripts Xist and Tsix we portray a current perspective on chromosome wide gene regulation by non-coding RNAs.
TL;DR: It is discussed how condensin-like complexes may be targeted to specific chromosomal locations for performance of their functions and how study of this model might shed light on general mechanisms of domain-scale transcriptional regulation.
Abstract: The C. elegans dosage compensation complex (DCC) reduces transcript levels from each of the two hermaphrodite X chromosomes to equalize X-linked gene expression to that of XO males. Several of the proteins that comprise the DCC are homologous to subunits of the evolutionarily conserved condensin complexes, which in most organisms function in mitotic and meiotic chromosome condensation. These include the DCC subunits MIX-1 and DPY-27, which belong to the structural maintenance of chromosomes (SMC) family of proteins. Several of the C. elegans DCC subunits also perform double duty as members of the canonical meiotic and mitotic condensin complexes. Here, we review what is known about the C. elegans DCC and how study of this model might shed light on general mechanisms of domain-scale transcriptional regulation. We discuss how condensin-like complexes may be targeted to specific chromosomal locations for performance of their functions.
TL;DR: In this article, the effects of roX mutations on heterochromatic gene expression and position effect variegation (PEV) are limited to males, and a sex-limited role for the roX RNAs in autosomal gene expression was unexpected.
Abstract: Dosage compensation modifies the chromatin of X-linked genes to assure equivalent expression in sexes with unequal X chromosome dosage. In Drosophila dosage compensation is achieved by increasing expression from the male X chromosome. The ribonucleoprotein dosage compensation complex (DCC) binds hundreds of sites along the X chromosome and modifies chromatin to facilitate transcription. Loss of roX RNA, an essential component of the DCC, reduces expression from X-linked genes. Surprisingly, loss of roX RNA also reduces expression from genes situated in proximal heterochromatin and on the small, heterochromatic fourth chromosome. Mutation of some, but not all, of the genes encoding DCC proteins produces a similar effect. Reduction of roX function suppresses position effect variegation (PEV), revealing functional alteration in heterochromatin. The effects of roX mutations on heterochromatic gene expression and PEV are limited to males. A sex-limited role for the roX RNAs in autosomal gene expression was unexpected. We propose that this reflects a difference in the heterochromatin of males and females, which serves to accommodate the heterochromatic Y chromosome present in the male nucleus. roX transcripts may thus participate in two distinct regulatory systems that have evolved in response to highly differentiated sex chromosomes: compensation of X-linked gene dosage and modulation of heterochromatin.
TL;DR: Drosophila melanogaster males have a well-characterized regulatory system that increases X-linked gene expression, and it is believed that the Y chromosome is likely to act through modulation of a process that is defective in roX1 roX2 mutants: X chromosome recognition or chromatin modification by the MSL complex.
Abstract: Drosophila melanogaster males have a well-characterized regulatory system that increases X-linked gene expression. This essential process restores the balance between X-linked and autosomal gene products in males. A complex composed of the male-specific lethal (MSL) proteins and RNA is recruited to the body of transcribed X-linked genes where it modifies chromatin to increase expression. The RNA components of this complex, roX1 and roX2 (RNA on the X1, RNA on the X2), are functionally redundant. Males mutated for both roX genes have dramatically reduced survival. We show that reversal of sex chromosome inheritance suppresses lethality in roX1 roX2 males. Genetic tests indicate that the effect on male survival depends upon the presence and source of the Y chromosome, revealing a germ line imprint that influences dosage compensation. Conventional paternal transmission of the Y chromosome enhances roX1 roX2 lethality, while maternal transmission of the Y chromosome suppresses lethality. roX1 roX2 males with both maternal and paternal Y chromosomes have very low survival, indicating dominance of the paternal imprint. In an otherwise wild-type male, the Y chromosome does not appreciably affect dosage compensation. The influence of the Y chromosome, clearly apparent in roX1 roX2 mutants, thus requires a sensitized genetic background. We believe that the Y chromosome is likely to act through modulation of a process that is defective in roX1 roX2 mutants: X chromosome recognition or chromatin modification by the MSL complex.