Escape from X inactivation of Smcx is preceded by silencing during mouse development

Lingenfelter, Patricia A.; Adler, David A.; Poslinski, Diane; Thomas, Sushma; Elliott, Rosemary W.; Chapman, Verne M.; Distèche, Christine M.

doi:10.1038/ng0398-212

Cited by 96 publications

(87 citation statements)

References 12 publications

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“…First, we explored whether the Xi chromosome superstructure is conserved among mammals by applying Hi-C to cells from mouse and rhesus macaque (SI Appendix, Table S1). For mouse, we studied the female Patski cell line (17). Because the cell line was derived from an interspecies hybrid cross (Mus musculus × Mus spretus), it has a high heterozygosity rate (1 in ∼64 bases) that facilitates assignment of a large fraction of alignable reads (49%) to particular chromosome homologs.…”

Section: Resultsmentioning

confidence: 99%

Deletion of DXZ4 on the human inactive X chromosome alters higher-order genome architecture

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Dudchenko

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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During interphase, the inactive X chromosome (Xi) is largely transcriptionally silent and adopts an unusual 3D configuration known as the "Barr body." Despite the importance of X chromosome inactivation, little is known about this 3D conformation. We recently showed that in humans the Xi chromosome exhibits three structural features, two of which are not shared by other chromosomes. First, like the chromosomes of many species, Xi forms compartments. Second, Xi is partitioned into two huge intervals, called "superdomains," such that pairs of loci in the same superdomain tend to colocalize. The boundary between the superdomains lies near DXZ4, a macrosatellite repeat whose Xi allele extensively binds the protein CCCTC-binding factor. Third, Xi exhibits extremely large loops, up to 77 megabases long, called "superloops." DXZ4 lies at the anchor of several superloops. Here, we combine 3D mapping, microscopy, and genome editing to study the structure of Xi, focusing on the role of DXZ4. We show that superloops and superdomains are conserved across eutherian mammals. By analyzing ligation events involving three or more loci, we demonstrate that DXZ4 and other superloop anchors tend to colocate simultaneously. Finally, we show that deleting DXZ4 on Xi leads to the disappearance of superdomains and superloops, changes in compartmentalization patterns, and changes in the distribution of chromatin marks. Thus, DXZ4 is essential for proper Xi packaging.

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Section: Resultsmentioning

confidence: 99%

Deletion of DXZ4 on the human inactive X chromosome alters higher-order genome architecture

Darrow

Huntley

Dudchenko

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

261

313

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“…However, it has been shown that these loci actually undergo a transient silencing coincident with the inactivation of all other X-linked genes by XCI, and then become transcriptionally reactivated shortly thereafter (Lingenfelter et al, 1998). Thus, we wondered if escape of Type II and III X-linked miRNA genes from MSCI might also follow a transient period of inactivation.…”

Section: Discussionmentioning

confidence: 99%

Escape of X-linked miRNA genes from meiotic sex chromosome inactivation

et al. 2015

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Past studies have indicated that transcription of all X-linked genes is repressed by meiotic sex chromosome inactivation (MSCI) during the meiotic phase of spermatogenesis in mammals. However, more recent studies have shown an increase in steady-state levels of certain X-linked miRNAs in pachytene spermatocytes, suggesting that either synthesis of these miRNAs increases or that degradation of these miRNAs decreases dramatically in these cells. To distinguish between these possibilities, we performed RNA-FISH to detect nascent transcripts from multiple miRNA genes in various spermatogenic cell types. Our results show definitively that Type I X-linked miRNA genes are subject to MSCI, as are all or most X-linked mRNA genes, whereas Type II and III X-linked miRNA genes escape MSCI by continuing ongoing, active transcription in primary spermatocytes. We corroborated these results by co-localization of RNA-FISH signals with both a corresponding DNA-FISH signal and an immunofluorescence signal for RNA polymerase II. We also found that X-linked miRNA genes that escape MSCI locate non-randomly to the periphery of the XY body, whereas genes that are subject to MSCI remain located within the XY body in pachytene spermatocytes, suggesting that the mechanism of escape of X-linked miRNA genes from MSCI involves their relocation to a position outside of the repressive chromatin domain associated with the XY body. The fact that Type II and III X-linked miRNA genes escape MSCI suggests an immediacy of function of the encoded miRNAs specifically required during the meiotic stages of spermatogenesis.

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“…(2) This question may possibly be addressed by measuring allele-specific gene expression in single individual cells of early embryos as we described for later stage embryos. (19) A second related question is whether the X p is inherited in a preinactivated state from the sperm, in which case it would simply remain inactive, (1) or whether both X chromosomes are initially active in the zygote, implying a reactivation step in the zygote. (2) The path of X inactivation in the male germline is not well understood.…”

Section: Introductionmentioning

confidence: 99%