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At least 19 recordsLinked to original sources
PubMed1998

Modulation of MSL1 abundance in female Drosophila contributes to the sex specificity of dosage compensation.

Dosage compensation in Drosophila is the mechanism by which X-linked gene expression is made equal in males and females. Proper regulation of this process is critical to the survival of both sexes. Males must turn the male-specific lethal (msl)-mediated pathway of dosage compensation on and females must keep it off. The msl2 gene is the primary target of negative regulation in females. Preventing production of MSL2 protein is sufficient to prevent dosage compensation; however, ectopic expression of MSL2 protein in females is not sufficient to induce an insurmountable level of dosage compensation, suggesting that an additional component is limiting in females. A candidate for this limiting factor is MSL1, because the amount of MSL1 protein in females is reduced compared to males. We have identified two levels of negative regulation of msl1 in females. The predominant regulation is at the level of protein stability, while a second regulatory mechanism functions at the level of protein synthesis. Overcoming these control mechanisms by overexpressing both MSL1 and MSL2 in females results in 100% female-specific lethality.

3' Untranslated Regions↗
PubMedDate not supplied

Sex chromosomes: evolving dosage compensation.

Dosage compensation of some X-linked genes varies among mammals. Inactivation of an X-linked copy of a gene in females appears to correlate with lack of an active homologue on the Y chromosome, implying that dosage compensation evolves in response to the loss of function of genes on the Y.

ATP Binding Cassette Transporter, Subfamily D, Mem↗
PubMed2005

Chromatin mechanisms in Drosophila dosage compensation.

Dosage compensation ensures that males and females equalize the expression of the X-linked genes and therefore provides an exquisite model system to study chromosome-wide transcription regulation. In Drosophila, this is achieved by hyper-transcription of the genes on the male X chromosome. This process requires an RNA/protein-containing dosage compensation complex. Here, we discuss the current status of the known Drosophila complex members as well as the recent views on targeting, assembly and spreading mechanisms.

Acetyltransferases↗
PubMed2006

Non-coding RNA in fly dosage compensation.

Dosage compensation modulates global expression of an X chromosome and is necessary to restore the balance between X-chromosome and autosome expression in both sexes. A central question in the field is how this regulation is directed. Large non-coding RNAs, such as Xist in mammals and roX in flies, have pivotal roles in targeting chromosome-wide modification for dosage compensation. Several recent studies in Drosophila provide new insight into the principles of X-chromosome recognition and the function of non-coding RNA in this process.

Animals↗
PubMed2000

Evolution of dosage compensation in Diptera: the gene maleless implements dosage compensation in Drosophila (Brachycera suborder) but its homolog in Sciara (Nematocera suborder) appears to play no role in dosage compensation.

In Drosophila melanogaster and in Sciara ocellaris dosage compensation occurs by hypertranscription of the single male X chromosome. This article reports the cloning and characterization in S. ocellaris of the gene homologous to maleless (mle) of D. melanogaster, which implements dosage compensation. The Sciara mle gene produces a single transcript, encoding a helicase, which is present in both male and female larvae and adults and in testes and ovaries. Both Sciara and Drosophila MLE proteins are highly conserved. The affinity-purified antibody to D. melanogaster MLE recognizes the S. ocellaris MLE protein. In contrast to Drosophila polytene chromosomes, where MLE is preferentially associated with the male X chromosome, in Sciara MLE is found associated with all chromosomes. Anti-MLE staining of Drosophila postblastoderm male embryos revealed a single nuclear dot, whereas Sciara male and female embryos present multiple intranuclear staining spots. This expression pattern in Sciara is also observed before blastoderm stage, when dosage compensation is not yet set up. The affinity-purified antibodies against D. melanogaster MSL1, MSL3, and MOF proteins involved in dosage compensation also revealed no differences in the staining pattern between the X chromosome and the autosomes in both Sciara males and females. These results lead us to propose that different proteins in Drosophila and Sciara would implement dosage compensation.

Amino Acid Sequence↗
PubMed2003

MOF-regulated acetylation of MSL-3 in the Drosophila dosage compensation complex.

Dosage compensation ensures equal expression of X-linked genes in males and females. In Drosophila, equalization is achieved by hypertranscription of the male X chromosome. This process requires an RNA/protein containing dosage compensation complex (DCC). Here we use RNA interference of individual DCC components to define the order of complex assembly in Schneider cells. We show that interaction of MOF with MSL-3 leads to specific acetylation of MSL-3 at a single lysine residue adjacent to one of its chromodomains. We observe that localization of MSL-3 to the X chromosome is RNA dependent and acetylation sensitive. We find that the acetylation status of MSL-3 determines its interaction with roX2 RNA. Furthermore, we find that RPD3 interacts with MSL-3 and that MSL-3 can be deacetylated by the RPD3 complex. We propose that regulated acetylation of MSL-3 may provide a mechanistic explanation for spreading of the dosage compensation complex along the male X chromosome.

Acetylation↗
PubMed2000

The evolution of dosage-compensation mechanisms.

Dosage compensation is the process by which the expression levels of sex-linked genes are altered in one sex to offset a difference in sex-chromosome number between females and males of a heterogametic species. Degeneration of a sex-limited chromosome to produce heterogamety is a common, perhaps unavoidable, feature of sex-chromosome evolution. Selective pressure to equalize sex-linked gene expression in the two sexes accompanies degeneration, thereby driving the evolution of dosage-compensation mechanisms. Studies of model species indicate that what appear to be very different mechanisms have evolved in different lineages: the male X chromosome is hypertranscribed in drosophilid flies, both hermaphrodite X chromosomes are downregulated in the nematode Caenorhabditis elegans, and one X is inactivated in mammalian females. Moreover, comparative genomic studies demonstrate that the trans-acting factors (proteins and non-coding RNAs) that have been shown to mediate dosage compensation are unrelated among the three lineages. Some tantalizing similarities in the fly and mammalian mechanisms, however, remain to be explained.

Animals↗
PubMed2004

Functional integration of the histone acetyltransferase MOF into the dosage compensation complex.

Dosage compensation in flies involves doubling the transcription of genes on the single male X chromosome to match the combined expression level of the two female X chromosomes. Crucial for this activation is the acetylation of histone H4 by the histone acetyltransferase (HAT) MOF. In male cells, MOF resides in a complex (dosage compensation complex, DCC) with MSL proteins and noncoding roX RNA. Previous studies suggested that MOF's localization to the X chromosome was largely RNA-mediated. We now found that contact of the MOF chromo-related domain with roX RNA plays only a minor role in correct targeting to the X chromosome in vivo. Instead, a strong, direct interaction between a conserved MSL1 domain and a zinc finger within MOF's HAT domain is crucial. The functional consequences of this interaction were studied in vitro. Simultaneous contact of MOF with MSL1 and MSL3 led to its recruitment to chromatin, a dramatic stimulation of HAT activity and to improved substrate specificity. Activation of MOF's HAT activity upon integration into the DCC may serve to restrict the critical histone modification to the male X chromosome.

Acetylation↗
PubMed1992

The non-dosage compensated LSP1-alpha gene of Drosophila melanogaster lies immediately downstream of the dosage compensated L12 gene.

The X-linked gene LSP1-alpha of Drosophila melanogaster, expressed in the third larval instar, does not exhibit dosage compensation at its normal locus but does compensate when it is relocated to ectopic sites on the X chromosome. A transcription unit designated L12, which is active in the second larval instar and capable of encoding a putative protein of 28.5 kDa, lies immediately downstream from LSP1-alpha. We have determined that L12 is dosage compensated by measuring the steady-state level of its transcript in male and female larvae. The difference in response of these two adjacent genes should be taken into consideration when models of the mechanism of dosage compensation are formulated.

Animals↗
PubMed2005

Stable chromosomal association of MSL2 defines a dosage-compensated nuclear compartment.

Dosage compensation in Drosophila is controlled by a complex (DCC) of proteins and noncoding RNA that binds specifically to the male X chromosome and leads to fine-tuning of transcription. Here, we employ male SL2 cells to characterize DCC function and dynamics during steady state of dosage compensation. Knocking down the key regulator of dosage compensation, male-specific-lethal 2 (MSL2), leads to loss of propagation of histone H4 lysine 16 acetylation and of the twofold elevation of transcription characteristic of the compensated male X chromosome. Surprisingly, lack of dosage compensation does not impair cell viability. Targeting of MSL2 to a reporter gene suffices to initiate dosage compensation in the cell model. Using photobleaching techniques in living cells, we found the association of MSL2 with the X chromosome to be exceptionally stable, essentially excluding dynamic redistribution of the DCC during interphase. This immobility distinguishes MSL2 from most other chromosomal proteins. Our findings have profound implications for the mechanism underlying dosage compensation and furthermore provide a new, conceptual reference of stability in an otherwise highly dynamic nuclear environment.

Acetylation↗
PubMed1994

Acetylated histone H4 on the male X chromosome is associated with dosage compensation in Drosophila.

Dosage compensation in Drosophila occurs by an increase in transcription of genes on the X chromosome in males. This elevated expression requires the function of at least four loci, known collectively as the male-specific lethal (msl) genes. The proteins encoded by two of these genes, maleless (mle) and male-specific lethal-1 (msl-1), are found associated with the X chromosome in males, suggesting that they act as positive regulators of dosage compensation. A specific acetylated isoform of histone H4, H4Ac16, is also detected predominantly on the male X chromosome. We have found that MLE and MSL-1 bind to the X chromosome in an identical pattern and that the pattern of H4Ac16 on the X is largely coincident with that of MLE/MSL-1. We fail to detect H4Ac16 on the X chromosome in homozygous msl males, correlating with the lack of dosage compensation in these mutants. Conversely, in Sxl mutants, we detect H4Ac16 on the female X chromosomes, coincident with an inappropriate increase in X chromosome transcription. These data suggest that synthesis or localization of H4Ac16 is controlled by the dosage compensation regulatory hierarchy. Dosage compensation may involve H4Ac16 function, potentially through interaction with the product of the msl genes.

Acetylation↗
PubMed1999

Guilt by association: non-coding RNAs, chromosome-specific proteins and dosage compensation in Drosophila.

Dosage compensation is a striking example of the interplay between gene-specific regulation and chromosomal architecture. This process has evolved to make X-linked gene expression equivalent in males with one X chromosome and females with two. Examining species at the molecular level has shown that dosage compensation is mediated by sex-specific factors that decorate the X chromosomes to regulate chromatin structure and gene expression. In Drosophila, dosage compensation is achieved, at least in part, through site-specific histone H4 acetylation, which is modulated by a male- and X-specific protein complex. The discovery of non-coding RNAs that 'paint' dosage-compensated X chromosomes in mammals and in Drosophila suggests that RNAs play an intriguing, unexpected role in the regulation of chromatin structure and gene expression.

Animals↗
PubMed2000

Activation of transcription through histone H4 acetylation by MOF, an acetyltransferase essential for dosage compensation in Drosophila.

Dosage compensation in Drosophila involves a 2-fold increase in transcription from the single male X relative to the two female X chromosomes. Regulation at the level of the chromosome involves alterations in chromatin organization: male X chromosomes appear decondensed and are marked by acetylation of histone H4 at lysine 16. We demonstrate that MOF, a protein required for dosage compensation with significant sequence similarity to the MYST family of acetyltransferases, is a histone acetyltransferase that acetylates chromatin specifically at histone H4 lysine 16. This acetylation relieves chromatin-mediated repression of transcription in vitro and in vivo if MOF is targeted to a promoter by fusion to a DNA-binding domain. Acetylation of chromatin by MOF, therefore, appears to be causally involved in transcriptional activation during dosage compensation.

Acetylation↗
PubMed1999

Development of an insulated reporter system to search for cis-acting DNA sequences required for dosage compensation in Drosophila.

Dosage compensation (equalization of X-linked gene products) occurs in Drosophila melanogaster by a two-fold transcriptional increase of X-linked gene expression in the male. The cis-acting X-linked DNA sequences required for dosage compensation (called DCREs) remain elusive, despite numerous attempts to identify them. We have developed an insulated reporter system to minimise problems previously encountered with identifying these elements. The system consists of the constitutive autosomal armadillo promoter fused to the lacZ reporter gene (called arm-lacZ) which was flanked by SCS insulator elements to block potential repressive effects of an autosomal chromatin environment. Seven X-linked DNA fragments, totaling 62.7 kb, were each inserted between the SCS element and the armadillo promoter. If an X-linked fragment contains a DCRE, then transgenic males carrying an autosomal insert of the construct should produce twice the beta-galactosidase activity of females. However, in all cases, males and females expressed the same level of lacZ. Thus, it's likely that none of the X-linked fragments contained a DCRE, suggesting these elements may be rarer than previously thought. The insulated reporter system was also used to test the hypothesis that some genes may be dosage compensated due to repression by Sex lethal (Sxl) in females. A fragment from the runt gene containing three Sxl binding sites was inserted into the 3' untranslated region of arm-lacZ. Transgenic males carrying an autosomal insert of the construct had on average 1.31-1.46 times the level of beta-galactosidase than females, suggesting that some genes could be compensated, at least partially, by Sxl repression in females.

Animals↗
PubMed1997

mof, a putative acetyl transferase gene related to the Tip60 and MOZ human genes and to the SAS genes of yeast, is required for dosage compensation in Drosophila.

Dosage compensation is a regulatory process that insures that males and females have equal amounts of X-chromosome gene products. In Drosophila, this is achieved by a 2-fold enhancement of X-linked gene transcription in males, relative to females. The enhancement of transcription is mediated by the activity of a group of regulatory genes characterized by the male-specific lethality of their loss-of-function alleles. The products of these genes form a complex that is preferentially associated with numerous sites on the X chromosome in somatic cells of males but not of females. Binding of the dosage compensation complex is correlated with a significant increase in the presence of a specific histone isoform, histone 4 acetylated at Lys16, on this chromosome. Experimental results and sequence analysis suggest that an additional gene, males-absent on the first (mof), encodes a putative acetyl transferase that plays a direct role in the specific histone acetylation associated with dosage compensation. The predicted amino acid sequence of MOF exhibits a significant level of similarity to several other proteins, including the human HIV-1 Tat interactive protein Tip60, the human monocytic leukemia zinc finger protein MOZ and the yeast silencing proteins SAS3 and SAS2.

Acetyltransferases↗
PubMed1994

How flies make one equal two: dosage compensation in Drosophila.

Dosage compensation is the process by which the expression of X-linked genes is equalized in males and females. In Drosophila, dosage compensation occurs by coordinately upregulating the transcription rates of all the genes on the single X chromosome in males. This hypertranscription requires the functioning of four autosomal male-specific lethal (msl) genes and is under the control of the Sxl gene. Recent genetic and molecular studies have suggested that the msl proteins may associate with one another in a sex-specific heteromeric complex on the male X chromosome, where they may function to alter its chromatin structure.

Animals↗
PubMed2006

Chromosome-wide gene-specific targeting of the Drosophila dosage compensation complex.

The dosage compensation complex (DCC) of Drosophila melanogaster is capable of distinguishing the single male X from the other chromosomes in the nucleus. It selectively interacts in a discontinuous pattern with much of the X chromosome. How the DCC identifies and binds the X, including binding to the many genes that require dosage compensation, is currently unknown. To identify bound genes and attempt to isolate the targeting cues, we visualized male-specific lethal 1 (MSL1) protein binding along the X chromosome by combining chromatin immunoprecipitation with high-resolution microarrays. More than 700 binding regions for the DCC were observed, encompassing more than half the genes found on the X chromosome. In addition, several rare autosomal binding sites were identified. Essential genes are preferred targets, and genes binding high levels of DCC appear to experience the most compensation (i.e., greatest increase in expression). DCC binding clearly favors genes over intergenic regions, and binds most strongly to the 3' end of transcription units. Within the targeted genes, the DCC exhibits a strong preference for exons and coding sequences. Our results demonstrate gene-specific binding of the DCC, and identify several sequence elements that may partly direct its targeting.

Animals↗