Dosage compensation

About: Dosage compensation is a research topic. Over the lifetime, 1920 publications have been published within this topic receiving 124589 citations.

Expression in aneuploid Drosophila S2 cells.

Abstract: Extensive departures from balanced gene dose in aneuploids are highly deleterious However, we know very little about the relationship between gene copy number and expression in aneuploid cells We determined copy number and transcript abundance (expression) genome-wide in Drosophila S2 cells by DNA-Seq and RNA-Seq We found that S2 cells are aneuploid for >43 Mb of the genome, primarily in the range of one to five copies, and show a male genotype (∼ two X chromosomes and four sets of autosomes, or 2X;4A) Both X chromosomes and autosomes showed expression dosage compensation X chromosome expression was elevated in a fixed-fold manner regardless of actual gene dose In engineering terms, the system “anticipates” the perturbation caused by X dose, rather than responding to an error caused by the perturbation This feed-forward regulation resulted in precise dosage compensation only when X dose was half of the autosome dose Insufficient compensation occurred at lower X chromosome dose and excessive expression occurred at higher doses RNAi knockdown of the Male Specific Lethal complex abolished feed-forward regulation Both autosome and X chromosome genes show Male Specific Lethal–independent compensation that fits a first order dose-response curve Our data indicate that expression dosage compensation dampens the effect of altered DNA copy number genome-wide For the X chromosome, compensation includes fixed and dose-dependent components

DNA methylation stabilizes X chromosome inactivation in eutherians but not in marsupials: evidence for multistep maintenance of mammalian X dosage compensation

Abstract: In marsupials and eutherian mammals, X chromosome dosage compensation is achieved by inactivating one X chromosome in female cells; however, in marsupials, the inactive X chromosomes is always paternal, and some genes on the chromosome are partially expressed. To define the role of DNA methylation in maintenance of X chromosome inactivity, we examined loci for glucose-6-phosphate dehydrogenase and hypoxanthine phosphoribosyltransferase in a North American marsupial, the opossum Didelphis virginiana, by using genomic hybridization probes cloned from this species. We find that these marsupial genes are like their eutherian counterparts, with respect to sex differences in methylation of nuclease-insensitive (nonregulatory) chromatin. However, with respect to methylation of the nuclease-hypersensitive (regulatory) chromatin of the glucose-6-phosphate dehydrogenase locus, the opossum gene differs from those of eutherians, as the 5' cluster of CpG dinucleotides is hypomethylated in the paternal as well as the maternal gene. Despite hypomethylation of the 5' CpG cluster, the paternal allele, identified by an enzyme variant, is at best partially expressed; therefore, factors other than methylation are responsible for repression. In light of these results, it seems that the role of DNA methylation in eutherian X dosage compensation is to "lock in" the process initiated by such factors. Because of similarities between dosage compensation in marsupials and trophectoderm derivatives of eutherians, we propose that differences in timing of developmental events--rather than differences in the basic mechanisms of X inactivation--account for features of dosage compensation that differ among mammals.

Dosage Compensation in Drosophila

Abstract: Dosage compensation in Drosophila increases the transcription of genes on the single X chromosome in males to equal that of both X chromosomes in females. Site-specific histone acetylation by the male-specific lethal (MSL) complex is thought to play a fundamental role in the increased transcriptional output of the male X. Nucleation and sequence-independent spreading of the complex to active genes serves as a model for understanding the targeting and function of epigenetic chromatin-modifying complexes. Interestingly, two noncoding RNAs are key for MSL assembly and spreading to active genes along the length of the X chromosome.

The msl-2 dosage compensation gene of Drosophila encodes a putative DNA-binding protein whose expression is sex specifically regulated by Sex-lethal

Abstract: In Drosophila dosage compensation increases the rate of transcription of the male's X chromosome and depends on four autosomal male-specific lethal genes. We have cloned the msl-2 gene and shown that MSL-2 protein is co-localized with the other three MSL proteins at hundreds of sites along the male polytene X chromosome and that this binding requires the other three MSL proteins. msl-2 encodes a protein with a putative DNA-binding domain: the RING finger. MSL-2 protein is not produced in females and sequences in both the 5′ and 3′ UTRs are important for this sex-specific regulation. Furthermore, msl-2 pre-mRNA is alternatively spliced in a Sex-lethal-dependent fashion in its 5′ UTR.