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Xist-dependent imprinted X inactivation and the early developmental consequences of its failure

ABSTRACT: In Mammals, the difference in sex-chromosome constitution between males (XY) and females (XX) has led to the evolution of dosage compensation strategies, including silencing of an entire X chromosome in females. In mice, X chromosome inactivation (XCI) first occurs in the pre-implantation embryo. Here the non-coding Xist RNA is expressed only from the paternal allele and the paternal X (Xp) becomes inactivated. The Xp is reactivated in the inner cell mass and this is followed by random XCI in the embryo proper, while in extra-embryonic tissues the Xp remains inactive. Although random XCI initiation is thought to be fully Xist-dependent in the mouse, initiation of imprinted XCI was reported to be Xist-independent. Furthermore, the chromosome-wide dynamics of XCI in early embryos of reciprocal inter-specific crosses, which better reflect a natural situation, have never been investigated. Here we report that the expression dynamics of X-linked genes depends both on strain and parent of origin, as well as on X chromosome location, using single-cell RNA-sequencing (scRNAseq) of early mouse embryos. We also demonstrate that initiation of imprinted XCI absolutely requires Xist and that its absence leads to genome-wide transcriptional misregulation in the early blastocyst, with massive over-expression of specific genes such as Rhox5 and failure to activate the extra-embryonic pathway essential for early post-implantation development. This study provides important insights into the transcriptional and allelic dynamics of the X chromosome and the first evidence of dosage compensation failure as early as the blastocyst stage.

ORGANISM(S): Mus musculus

PROVIDER: GSE80810 | GEO | 2016/12/05

SECONDARY ACCESSION(S): PRJNA320051

REPOSITORIES: GEO

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SPEN is a molecular integrator that bridges Xist with transcriptional and epigenetic control of X-chromosome inactivation

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2021-04-19 | PXD015699 | Pride

SPEN is required for Xist upregulation during initiation of X chromosome inactivation (RNA-seq)

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2021-09-30 | GSE163320 | GEO

SPEN is required for Xist upregulation during initiation of X chromosome inactivation (ChIP-seq)

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Xist exerts gene-specific silencing during XCI maintenance and impacts lineage-specific cell differentiation and proliferation during hematopoiesis [RNA-seq]

Project description:X chromosome inactivation (XCI) is a dosage compensation phenomenon that occurs in females. Initiation of XCI depends on Xist RNA, which triggers silencing of one of the two X chromosomes, except for XCI escape genes that continue to be biallelically expressed. In the soma XCI is stably maintained with continuous Xist expression. How Xist impacts XCI maintenance remains an open question. Here we conditionally deleted Xist in hematopoietic system of mice and report differentiation and cell cycle defects in female hematopoietic stem and progenitor cells (HPSCs). By utilizing female HSPCs and mouse embryonic fibroblasts, we find that X-linked genes show variable tolerance to Xist loss. Specifically, XCI escape genes exhibit preferential transcriptional upregulation, which associates with low H3K27me3 occupancy, and high chromatin accessibility that accommodates preexisting binding of transcription factors such as Yin Yang 1 (YY1) at the basal state. We conclude that Xist is necessary for gene-specific silencing during XCI maintenance and impacts lineage-specific cell differentiation and proliferation during hematopoiesis.

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Xist exerts gene-specific silencing during XCI maintenance and impacts lineage-specific cell differentiation and proliferation during hematopoiesis [RNA-seq MEFs]

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Xist exerts gene-specific silencing during XCI maintenance and impacts lineage-specific cell differentiation and proliferation during hematopoiesis [ChIP-seq MEFs]

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Xist exerts gene-specific silencing during XCI maintenance and impacts lineage-specific cell differentiation and proliferation during hematopoiesis [ChIP-seq Lin-]

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ChIPseq on H4K20me1 on TX1072 cell line at different times of Xist induction through Doxycycline.

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2021-02-26 | GSE153146 | GEO

Female mice lacking Xist RNA show partial dosage compensation and survive to term

Project description:X chromosome inactivation (XCI) compensates for differences in X-chromosome number between male and female mammals. XCI is orchestrated by Xist RNA, whose expression in early development leads to transcriptional silencing of one X-chromosome in the female. Knockout studies have established a requirement for Xist, with inviability of female embryos that inherit an Xist deletion from the father. Here, we report that female mice lacking Xist RNA can, surprisingly, develop and survive to term. Xist-null females are born at lower frequency and are smaller at birth, but organogenesis is mostly normal. Transcriptomic analysis indicates significant overexpression of hundreds of X-linked genes across multiple tissues. Therefore, Xist-null mice can develop to term in spite of a deficiency of dosage compensation. However, the degree of X-autosomal dosage imbalance was less than anticipated (1.14- to 1.36-fold). Thus, partial dosage compensation can be achieved without Xist, supporting the idea of inherent genome balance. Nevertheless, to date, none of the mutant mice has survived beyond weaning stage. Sudden death is associated with failure of postnatal organ maturation. Our data suggest Xist-independent mechanisms of dosage compensation and demonstrate that small deviations from X-autosomal balance can have profound effects on overall fitness. RNA-sequencing of tail-tip fibroblasts (TTFs), spleen, liver and heart tissue from Xist-null and control female mice. Sequencing performed with 50nt read length on Illumina HiSeq2000 or 2500. Data consists of 3 biological replicates for TTFs (6 datasets) and 2 biological replicates for tissues (12 datasets).

2016-08-19 | E-GEOD-84665 | biostudies-arrayexpress

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