RNA stability controlled by m6A methylation contributes to X-to-autosome dosage compensation in mammals
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PROVIDER: EGAS00001007112 | EGA |
REPOSITORIES: EGA
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Project description:In therian mammals, X-chromosomal genes are expressed only from a single active X chromosome, both in males (XY) as well as females (XX). To compensate for this reduction in dosage compared to the evolutionary ancestral state on two autosomes, it has been proposed that genes from the active X chromosome exhibit dosage compensation (“Ohno’s hypothesis”). However, the existence and mechanism of X-to-autosome dosage compensation are still under debate. Here, we show that dosage compensation is achieved via differential N6-methyladenosine (m6A) RNA modification. X-chromosomal transcripts are reduced in m6A modifications and more stable compared to the autosomal counterparts. Acute depletion of m6A using a small molecule inhibitor differentially affects autosomal and X-chromosomal transcripts across sexes, cell types, tissues and species, resulting in perturbed dosage compensation. We propose that higher stability of X-chromosomal transcripts is directed by lower levels of m6A, indicating that mammalian dosage compensation occurs via epitranscriptomic RNA regulation.
2023-02-14 | GSE203642 | GEO
Project description:In therian mammals, X-chromosomal genes are expressed only from a single active X chromosome, both in males (XY) as well as females (XX). To compensate for this reduction in dosage compared to the evolutionary ancestral state on two autosomes, it has been proposed that genes from the active X chromosome exhibit dosage compensation (“Ohno’s hypothesis”). However, the existence and mechanism of X-to-autosome dosage compensation are still under debate. Here, we show that dosage compensation is achieved via differential N6-methyladenosine (m6A) RNA modification. X-chromosomal transcripts are reduced in m6A modifications and more stable compared to the autosomal counterparts. Acute depletion of m6A using a small molecule inhibitor differentially affects autosomal and X-chromosomal transcripts across sexes, cell types, tissues and species, resulting in perturbed dosage compensation. We propose that higher stability of X-chromosomal transcripts is directed by lower levels of m6A, indicating that mammalian dosage compensation occurs via epitranscriptomic RNA regulation.
2023-02-14 | GSE203637 | GEO
Project description:In therian mammals, X-chromosomal genes are expressed only from a single active X chromosome, both in males (XY) as well as females (XX). To compensate for this reduction in dosage compared to the evolutionary ancestral state on two autosomes, it has been proposed that genes from the active X chromosome exhibit dosage compensation (“Ohno’s hypothesis”). However, the existence and mechanism of X-to-autosome dosage compensation are still under debate. Here, we show that dosage compensation is achieved via differential N6-methyladenosine (m6A) RNA modification. X-chromosomal transcripts are reduced in m6A modifications and more stable compared to the autosomal counterparts. Acute depletion of m6A using a small molecule inhibitor differentially affects autosomal and X-chromosomal transcripts across sexes, cell types, tissues and species, resulting in perturbed dosage compensation. We propose that higher stability of X-chromosomal transcripts is directed by lower levels of m6A, indicating that mammalian dosage compensation occurs via epitranscriptomic RNA regulation.
2023-02-14 | GSE203652 | GEO
Project description:In therian mammals, X-chromosomal genes are expressed only from a single active X chromosome, both in males (XY) as well as females (XX). To compensate for this reduction in dosage compared to the evolutionary ancestral state on two autosomes, it has been proposed that genes from the active X chromosome exhibit dosage compensation (“Ohno’s hypothesis”). However, the existence and mechanism of X-to-autosome dosage compensation are still under debate. Here, we show that dosage compensation is achieved via differential N6-methyladenosine (m6A) RNA modification. X-chromosomal transcripts are reduced in m6A modifications and more stable compared to the autosomal counterparts. Acute depletion of m6A using a small molecule inhibitor differentially affects autosomal and X-chromosomal transcripts across sexes, cell types, tissues and species, resulting in perturbed dosage compensation. We propose that higher stability of X-chromosomal transcripts is directed by lower levels of m6A, indicating that mammalian dosage compensation occurs via epitranscriptomic RNA regulation.
2023-02-14 | GSE203648 | GEO
Project description:In mammals, X-chromosomal genes are expressed from a single copy since males (XY) possess a single X chromosome, while females (XX) undergo X inactivation. To compensate for this reduction in dosage compared to two active copies of autosomes, it has been proposed that genes from the active X chromosome exhibit dosage compensation. However, the existence and mechanism of X-to-autosome dosage compensation are still under debate. Here, we show that X-chromosomal transcripts are reduced in m6A modifications and more stable compared to their autosomal counterparts. Acute depletion of m6A selectively stabilises autosomal transcripts, resulting in perturbed dosage compensation in mouse embryonic stem cells. We propose that higher stability of X-chromosomal transcripts is directed by lower levels of m6A, indicating that mammalian dosage compensation is partly regulated by epitranscriptomic RNA modifications.
| EGAD00001010194 | EGA
Project description:Condensins are evolutionarily conserved protein complexes that are required for chromosome segregation during cell division and genome organization during interphase. In C. elegans, a specialized condensin, which forms the core of the dosage compensation complex (DCC), binds to and represses X chromosome transcription. Here, we analyzed DCC localization and the effect of DCC depletion on histone modifications, transcription factor binding, and gene expression using ChIP-seq and mRNA-seq. Across the X, DCC accumulates at accessible gene regulatory sites in active chromatin and not heterochromatin. DCC is required for reducing the levels of activating histone modifications, including H3K4me3 and H3K27ac, but not repressive modification H3K9me3. In X-to-autosome fusion chromosomes, DCC spreading into the autosomal sequences locally reduces gene expression, thus establishing a direct link between DCC binding and repression. Together, our results indicate that DCC-mediated transcription repression is associated with a reduction in the activity of X chromosomal gene regulatory elements.
2019-01-08 | GSE122639 | GEO
Project description:X-chromosome dosage compensation ensures balanced gene dosage between the X chromosome and autosomes and between the sexes, involving divergent mechanisms among mammals. We elucidated a distinct mechanism for X-chromosome inactivation (XCI) in cynomolgus monkeys, a model for human development. The trophectoderm and cytotrophoblast acquire XCI around implantation through an active intermediate bearing repressive modifications and compacted structure, whereas the amnion, epiblast, and hypoblast maintain such an intermediate protractedly, attaining XCI by a week after implantation. Males achieve X-chromosome up-regulation (XCU) progressively, whereas females show XCU coincidentally with XCI, both establishing the X:autosome dosage compensation by 1 week after implantation. Conversely, primordial germ cells undergo X-chromosome reactivation by reversing the XCI pathway early during their development. Our findings establish a foundation for clarifying the dosage compensation mechanisms in primates, including humans.
2021-11-19 | GSE151149 | GEO
Project description:Chromosomal and segmental aneuploidies are usually lethal or common features of cancer cells and variety of disease, but little is known about how copy number relates to gene expression. Drosophila males have a single X chromosome and two sets of autosomes, but X chromosome and autosome transcripts are equally abundant. This 2-fold increase in X chromosome gene expression requires a dosage compensation complex (MSL) that acetylates histone 4 at lysine 16 (H4AcK16). To determine the contribution of general buffering and MSL to X chromosome dosage compensation, we analyzed genome-wide copy number, expression and histone modification pattern in male Drosophila S2 cells with and without MSL. Keywords: Gene Regulation Study, genomic analyses
2010-01-11 | GSE16344 | GEO
Project description:In C. elegans, a condensin-like protein complex associates specifically with both X chromosomes of XX animals to execute dosage compensation. Dosage Compensation Complex (DCC) reduces the level of transcripts arising from each of the two X chromosomes. Recruitment to X is specified in part by discrete DNA sequence motifs, but following recruitment, the DCC is targeted to the promoters of individual active genes by an unknown mechanism. Here, we investigated three outstanding questions regarding the molecular mechanism of DCC recruitment and spreading along X. By examining the genome-wide binding patterns of several DCC subunits in different stages of C. elegans development, and in strains harboring X:Autosome chromosomal fusions, we provide evidence that: (1) DCC binding is dynamically specified according to gene activity during development (2) The condensin-like subunits of the DCC spread from recruitment sites to active promoters more readily than the non-conserved SDC subunits, which are involved in initial X-targeting and (3) the mechanism of DCC spreading is independent of X-chromosome DNA sequence, and will proceed onto any active promoter near a recruitment site. Our results contribute to understanding how chromatin complexes can be targeted to achieve domain-scale transcriptional regulation during development. ChIP-chip analysis of SDC-2, DPY-26 and MIX-1 were done in C elegans N2 embryos. DPY-27 and RNA Polymerase II ChIP-chip were performed in N2 L4s. DPY-27 ChIP-chip in X-autosome fusions were done, X chromosome fused to either V (YPT47), II (YPT41) or I (11dh). RNA abundance analysis in N2, YPT41 and YPT47 embryos are included.
2009-11-15 | E-GEOD-16621 | biostudies-arrayexpress
Project description:Here we exploit the essential process of X-chromosome dosage compensation to elucidate basic mechanisms that control the assembly, genome-wide binding, and function of gene regulatory complexes that act over large chromosomal territories. We demonstrate that a subunit of C. elegans MLL/COMPASS, a gene-activation complex, acts within the dosage compensation complex (DCC), a condensin complex, to target the DCC to both X chromosomes of hermaphrodites and thereby reduce chromosome-wide gene expression. The DCC binds to two categories of sites on X: rex sites that recruit the DCC in an autonomous, sequence- dependent manner, and dox sites that reside primarily in promoters of expressed genes and bind the DCC robustly only when attached to X. We find that DCC mutants that abolish rex-site binding do not eliminate dox-site binding, but instead reduce it to the level observed at autosomal binding sites in wild-type animals. Changes in DCC binding to these non-rex sites occur throughout development and correlate with transcriptional activity of adjacent genes. Moreover, autosomal DCC binding is enhanced by rex-site binding in cis in X-autosome fusion chromosomes. Thus, dox and autosomal sites exhibit similar binding properties. Our data support a model for DCC binding in which low-level DCC binding at dox and autosomal sites is dictated by intrinsic properties correlated with high transcriptional activity. Sex-specific DCC recruitment to rex sites then greatly elevates DCC binding to dox sites in cis, which lack intrinsically high DCC affinity on their own. We also show here that the C. elegans DCC achieves dosage compensation through its effects on transcription. The processed data files available here were used in Figure 6 of the paper which references this data. ChIP-chip experiments using antibodies against DPY-27 in wild type mixed embryos and fed L1 larvae.
2011-03-01 | E-GEOD-25877 | biostudies-arrayexpress