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Dosage compensation

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


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Journal ArticleDOI
03 Aug 1978-Nature
TL;DR: The method which facilitates determination of the sex of the embryonic material being assayed has led to the demonstration that early male and female mouse blastocysts differ twofold in HGPRT activity, a finding indicative of uncompensated X- chromosome dosage dependent gene activity before X-chromosome inactivation.
Abstract: ALTHOUGH neither X chromosome of preimplantation female mammalian embryos exhibits the two cytological signs of inactivation and dosage compensation—heteropyknosis and late replication1,2—it has not been known whether both X chromosomes actually function during this period. Biochemical evidence based on increasing hypoxanthine-guanine phosphoribosyltransferase (HGPRT) activity during the mouse morula stage indicates that at least one X chromosome is functional3,4. This is corroborated by the observation that mouse embryos lacking an X chromosome do not survive beyond the early cleavage stages5. The principal approach to determining whether both X chromosomes are functional before inactivation has been to look at the distributions of the activities of known X-linked enzymes in individual embryos6,7. A bimodal distribution would be expected if dosage compensation had not yet occurred and female embryos with two X chromosomes made twice as much enzyme as male embryos with only one. However, identities of the embryos being assayed are not known, and conclusions based on activity distributions are necessarily inferential. We have circumvented this difficulty by using a method which facilitates determination of the sex of the embryonic material being assayed. This has led to the demonstration that early male and female mouse blastocysts differ twofold in HGPRT activity, a finding indicative of uncompensated X-chromosome dosage dependent gene activity before X-chromosome inactivation.

209 citations

Journal ArticleDOI
TL;DR: It is proposed that the MSL complex recognizes most X-linked genes, but only in the context of chromatin factors or modifications indicative of active transcription, which is likely to be an important function common to many chromatin organizing and modifying activities.
Abstract: X-chromosome dosage compensation in Drosophila requires the male-specific lethal (MSL) complex, which up-regulates gene expression from the single male X chromosome. Here, we define X-chromosome-specific MSL binding at high resolution in two male cell lines and in late-stage embryos. We find that the MSL complex is highly enriched over most expressed genes, with binding biased toward the 3 end of transcription units. The binding patterns are largely similar in the distinct cell types, with ∼600 genes clearly bound in all three cases. Genes identified as clearly bound in one cell type and not in another indicate that attraction of MSL complex correlates with expression state. Thus, sequence alone is not sufficient to explain MSL targeting. We propose that the MSL complex recognizes most X-linked genes, but only in the context of chromatin factors or modifications indicative of active transcription. Distinguishing expressed genes from the bulk of the genome is likely to be an important function common to many chromatin organizing and modifying activities.

209 citations

Journal ArticleDOI
TL;DR: The characterization of a widely transcribed X- linked homologue of Uty, called Utx, is reported, which maps to the proximal region of the mouse X chromosome and which detects a human X-linked homologue at Xp11.2.
Abstract: We recently have identified a ubiquitously transcribed mouse Y chromosome gene, Uty, which encodes a tetratricopeptide repeat (TPR) protein. A peptide derived from the UTY protein confers H-Y antigenicity on male cells. Here we report the characterization of a widely transcribed X-linked homologue of Uty, called Utx, which maps to the proximal region of the mouse X chromosome and which detects a human X-linked homologue at Xp11.2. Given that Uty is ubiquitously transcribed, we assayed for Utx expression from the inactive X chromosome (Xi) in mice and found that Utx escapes X chromosome inactivation. Only Smcx and the pseudoautosomal Sts gene on the mouse X chromosome have been reported previously to escape inactivation. The human UTX gene was also found to be expressed from Xi. We discuss the significance of these data for our understanding of dosage compensation of X-Y homologous genes in humans and mice.

208 citations

Journal ArticleDOI
TL;DR: It is proposed that XCI status should be routinely checked in subcultures of female hESCs, with cultures displaying XCI markers better suited for use in regenerative medicine.
Abstract: X chromosome inactivation (XCI) is an essential mechanism for dosage compensation of X-linked genes in female cells. We report that subcultures from lines of female human embryonic stem cells (hESCs) exhibit variation (0–100%) for XCI markers, including XIST RNA expression and enrichment of histone H3 lysine 27 trimethylation (H3K27me3) on the inactive X chromosome (Xi). Surprisingly, regardless of the presence or absence of XCI markers in different cultures, all female hESCs we examined (H7, H9, and HSF6 cells) exhibit a monoallelic expression pattern for a majority of X-linked genes. Our results suggest that these established female hESCs have already completed XCI during the process of derivation and/or propagation, and the XCI pattern of lines we investigated is already not random. Moreover, XIST gene expression in subsets of cultured female hESCs is unstable and subject to stable epigenetic silencing by DNA methylation. In the absence of XIST expression, ≈12% of X-linked promoter CpG islands become hypomethylated and a portion of X-linked alleles on the Xi are reactivated. Because alterations in dosage compensation of X-linked genes could impair somatic cell function, we propose that XCI status should be routinely checked in subcultures of female hESCs, with cultures displaying XCI markers better suited for use in regenerative medicine.

207 citations

Journal ArticleDOI
29 Jul 2010-Nature
TL;DR: It is concluded that the avian Z and mammalian X chromosomes followed convergent evolutionary trajectories, despite their evolving with opposite (female versus male) systems of heterogamety.
Abstract: Birds and mammals have distinct sex chromosomes. In birds, males have a pair of Z chromosomes and females a Z and a W. In mammals, males are XY and females XX. It has long been assumed that sex-chromosome evolution has involved dramatic modification of the sex-specific (W and Y) chromosomes but only modest changes to the Z and X chromosomes shared by the sexes. Not so, according to a new study reporting the sequence of the chicken Z chromosome and comparing it with the finished sequence of human X. The Z and X chromosomes have changed dramatically from the autosomal (non-sex) chromosomes that gave rise to them. And they seem to have followed convergent evolutionary trajectories, including the acquisition and amplification of testis-expressed gene families, despite having arisen independently from different portions of the ancestral genome. Birds and mammals have distinct sex chromosomes: in birds, males are ZZ and females ZW; in mammals, males are XY and females XX. By sequencing the chicken Z chromosome and comparing it with the human X chromosome, these authors overturn the currently held view that these chromosomes have diverged little from their autosomal progenitors. The Z and X chromosomes seem to have followed convergent evolutionary trajectories, despite evolving with opposite systems of heterogamety. In birds, as in mammals, one pair of chromosomes differs between the sexes. In birds, males are ZZ and females ZW. In mammals, males are XY and females XX. Like the mammalian XY pair, the avian ZW pair is believed to have evolved from autosomes, with most change occurring in the chromosomes found in only one sex—the W and Y chromosomes1,2,3,4,5. By contrast, the sex chromosomes found in both sexes—the Z and X chromosomes—are assumed to have diverged little from their autosomal progenitors2. Here we report findings that challenge this assumption for both the chicken Z chromosome and the human X chromosome. The chicken Z chromosome, which we sequenced essentially to completion, is less gene-dense than chicken autosomes but contains a massive tandem array containing hundreds of duplicated genes expressed in testes. A comprehensive comparison of the chicken Z chromosome with the finished sequence of the human X chromosome demonstrates that each evolved independently from different portions of the ancestral genome. Despite this independence, the chicken Z and human X chromosomes share features that distinguish them from autosomes: the acquisition and amplification of testis-expressed genes, and a low gene density resulting from an expansion of intergenic regions. These features were not present on the autosomes from which the Z and X chromosomes originated but were instead acquired during the evolution of Z and X as sex chromosomes. We conclude that the avian Z and mammalian X chromosomes followed convergent evolutionary trajectories, despite their evolving with opposite (female versus male) systems of heterogamety. More broadly, in birds and mammals, sex chromosome evolution involved not only gene loss in sex-specific chromosomes, but also marked expansion and gene acquisition in sex chromosomes common to males and females.

206 citations


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Performance
Metrics
No. of papers in the topic in previous years
YearPapers
202330
202272
202183
202051
201980
201870