Dosage compensation

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

Complete reactivation of X chromosomes from human chorionic villi with a switch to early DNA replication.

Abstract: Mammalian sex-dosage compensation is mediated by maintaining activity of only one X chromosome. The asynchronous DNA synthesis characterizing the silent human X chromosome is thought to be reversible only during ontogeny of oocytes. We have previously shown that the glucose-6-phosphate dehydrogenase (G6PD) locus (G6PD) on the allocyclic X chromosome in chorionic villi is partially expressed. We now show that in hybrids derived from a clone of chorionic villi cells (heterozygous for G6PD A) and mouse A9 cells, the loci for G6PD, hypoxanthine phosphoribosyltransferase (HPRT) and phosphoglycerate kinase are expressed on both human X chromosomes; the human X chromosomes carrying either G6PD A or B replicate synchronously with each other and with murine chromosomes. The X chromosome with G6PD A was identified as the original late-replicating X, because methylation in the body of the HPRT gene on this chromosome remained characteristic of the inactive X chromosome. These results indicate that X-chromosome inactivation is completely reversible in cells of trophoblast origin; induction of full transcriptional activity is accompanied by acquisition of isocyclic replication, showing an intimate relationship between these processes. The molecular events responsible for this reversal may be similar to those occurring during maturation of oocytes. Chorionic villi and derivative hybrids provide in vitro models for exploring early events that program the single active X chromosome.

Species-specific positive selection of the male-specific lethal complex that participates in dosage compensation in Drosophila.

Abstract: In many taxa, males and females have unequal ratios of sex chromosomes to autosomes, which has resulted in the invention of diverse mechanisms to equilibrate gene expression between the sexes (dosage compensation). Failure to compensate for sex chromosome dosage results in male lethality in Drosophila. In Drosophila, a male-specific lethal (MSL) complex of proteins and noncoding RNAs binds to hundreds of sites on the single male X chromosome and up-regulates gene expression. Here we use population genetics of two closely related Drosophila species to show that adaptive evolution has occurred in all five protein-coding genes of the MSL complex. This positive selection is asymmetric between closely related species, with a very strong signature apparent in Drosophila melanogaster but not in Drosophila simulans. In particular, the MSL1 and MSL2 proteins have undergone dramatic positive selection in D. melanogaster, in domains previously shown to be responsible for their specific targeting to the X chromosome. This signature of positive selection at an essential protein-DNA interface of the complex is unexpected and suggests that X chromosomal MSL-binding DNA segments may themselves be changing rapidly. This highly asymmetric, rapid evolution of the MSL genes further suggests that misregulated dosage compensation may represent one of the underlying causes of male hybrid inviability in Drosophila, wherein the fate of hybrid males depends on which species' X chromosome is inherited.

Contribution of epigenetic landscapes and transcription factors to X-chromosome reactivation in the inner cell mass.

Abstract: X-chromosome inactivation is established during early development. In mice, transcriptional repression of the paternal X-chromosome (Xp) and enrichment in epigenetic marks such as H3K27me3 is achieved by the early blastocyst stage. X-chromosome inactivation is then reversed in the inner cell mass. The mechanisms underlying Xp reactivation remain enigmatic. Using in vivo single-cell approaches (allele-specific RNAseq, nascent RNA-fluorescent in situ hybridization and immunofluorescence), we show here that different genes are reactivated at different stages, with more slowly reactivated genes tending to be enriched in H3meK27. We further show that in UTX H3K27 histone demethylase mutant embryos, these genes are even more slowly reactivated, suggesting that these genes carry an epigenetic memory that may be actively lost. On the other hand, expression of rapidly reactivated genes may be driven by transcription factors. Thus, some X-linked genes have minimal epigenetic memory in the inner cell mass, whereas others may require active erasure of chromatin marks.

X chromosome choice occurs independently of asynchronous replication timing.

Abstract: In mammals, dosage compensation is achieved by X chromosome inactivation in female cells. Xist is required and sufficient for X inactivation, and Xist gene deletions result in completely skewed X inactivation. In this work, we analyzed skewing of X inactivation in mice with an Xist deletion encompassing sequence 5 KB upstream of the promoter through exon 3. We found that this mutation results in primary nonrandom X inactivation in which the wild-type X chromosome is always chosen for inactivation. To understand the molecular mechanisms that affect choice, we analyzed the role of replication timing in X inactivation choice. We found that the two Xist alleles and all regions tested on the X chromosome replicate asynchronously before the start of X inactivation. However, analysis of replication timing in cell lines with skewed X inactivation showed no preference for one of the two Xist alleles to replicate early in S-phase before the onset of X inactivation, indicating that asynchronous replication timing does not play a role in skewing of X inactivation.

Imprinted X inactivation and reprogramming in the preimplantation mouse embryo

Abstract: X chromosome inactivation is a developmentally regulated process that causes one of the two X chromosomes in normal female mammals to become transcriptionally silenced, thus equalizing the expression of X-linked genes between the sexes. Such dosage compensation depends upon dynamic genetic and epigenetic events occurring very early in development. X inactivation is controlled by an X inactivation centre that is associated with the expression of non-coding RNAs required for the silencing. Also associated with the inactive X are repressive histone modifications and polycomb protein-mediated states, which are progressively acquired during the inactivation process. In mouse, two forms of X inactivation have been described. Random X inactivation happens in the derivatives of the inner cell mass (ICM) giving rise to embryos where the maternally inherited X(Xm) is inactive in some cells and the paternally derived X (Xp) is inactive in others. Random X inactivation occurs around the time of implantation. Imprinted X inactivation, the preferential inactivation of the Xp chromosome, occurs earlier and, although there has been some debate as to the precise timing of initiation of this event, is apparent in all cells early in preimplantation development, then is subsequently confined to the cells of the extraembryonic lineages. A picture is emerging whereby initial epigenetic asymmetry between the two parental X chromosomes is reprogrammed in a lineage specific manner resulting in a switch from imprinted to random inactivation in embryonic derivatives. Neither the underlying reason nor the full extent of these early lineage specific epigenetic changes is known, but they may be correlated with more genome-wide reprogramming events essential for normal development.