ATRX marks the inactive X chromosome (Xi) in somatic cells and during imprinted X chromosome inactivation in trophoblast stem cells

Women represent 80% of people affected by autoimmune diseases. Although, many studies have demonstrated a role for sex hormone receptor signaling, particularly estrogens, in the direct regulation of innate and adaptive components of the immune system, recent data suggest that female sex hormones are not the only cause of the female predisposition to autoimmunity. Besides sex steroid hormones, growing evidence points towards the role of X-linked genetic factors. In female mammals, one of the two X chromosomes is randomly inactivated during embryonic development, resulting in a cellular mosaicism, where about one-half of the cells in a given tissue express either the maternal X chromosome or the paternal one. X chromosome inactivation (XCI) is however not complete and 15 to 23% of genes from the inactive X chromosome (Xi) escape XCI, thereby contributing to the emergence of a female-specific heterogeneous population of cells with bi-allelic expression of some X-linked genes. Although the direct contribution of this genetic mechanism in the female susceptibility to autoimmunity still remains to be established, the cellular mosaicism resulting from XCI escape is likely to create a unique functional plasticity within female immune cells. Here, we review recent findings identifying key immune related genes that escape XCI and the relationship between gene dosage imbalance and functional responsiveness in female cells.

Download Full-text

X-linked clonality testing: interpretation and limitations

Blood ◽

10.1182/blood-2006-09-018655 ◽

2007 ◽

Vol 110 (5) ◽

pp. 1411-1419 ◽

Cited By ~ 45

Author(s):

George L. Chen ◽

Josef T. Prchal

Keyword(s):

X Chromosome ◽

Methylation Status ◽

X Chromosome Inactivation ◽

Protein Isoforms ◽

Chromosome Inactivation ◽

Detection Methods ◽

Parental Origin ◽

Genetic Changes ◽

Clonal Population ◽

Inactive X Chromosome

Abstract Clonality often defines the diseased state in hematology. Clonal cells are genetically homogenous and derived from the same precursor; their detection is based on genotype or phenotype. Genotypic clonality relies on somatic mutations to mark the clonal population. Phenotypic clonality identifies the clonal population by the expression pattern of surrogate genes that track the clonal process. The most commonly used phenotypic clonality methods are based on the X-chromosome inactivation principle. Clonality detection based on X-chromosome inactivation patterns (XCIP) requires discrimination of the active from the inactive X chromosome and differentiation of each X chromosome's parental origin. Detection methods are based on detection of X-chromosome sequence polymorphisms identified by protein isoforms, transcribed mRNA, and methylation status. Errors in interpreting clonality tests arise from stochastic, genetic, and cell selection pressures on the mechanism of X inactivation. Progressive X-chromosome skewing has recently been suggested by XCIP clonality studies in aging hematopoietic cells. This has led to new insights into the pathophysiology of X-linked and autoimmune disorders. Other research applications include combining XCIP clonality testing with genetic clonality testing to identify clonal populations with yet-to-be-discovered genetic changes.

Download Full-text

Inducible XIST-dependent X-chromosome inactivation in human somatic cells is reversible

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.0610946104 ◽

2007 ◽

Vol 104 (24) ◽

pp. 10104-10109 ◽

Cited By ~ 45

Author(s):

J. C. Chow ◽

L. L. Hall ◽

S. E. L. Baldry ◽

N. P. Thorogood ◽

J. B. Lawrence ◽

...

Keyword(s):

X Chromosome ◽

Somatic Cells ◽

X Chromosome Inactivation ◽

Chromosome Inactivation

Download Full-text

Aberrant Patterns of X Chromosome Inactivation in a New Line of Human Embryonic Stem Cells Established in Physiological Oxygen Concentrations

Stem Cell Reviews and Reports ◽

10.1007/s12015-014-9505-4 ◽

2014 ◽

Vol 10 (4) ◽

pp. 472-479 ◽

Cited By ~ 6

Author(s):

Juliana Andrea de Oliveira Georges ◽

Naja Vergani ◽

Simone Aparecida Siqueira Fonseca ◽

Ana Maria Fraga ◽

Joana Carvalho Moreira de Mello ◽

...

Keyword(s):

Stem Cells ◽

Embryonic Stem Cells ◽

X Chromosome ◽

Human Embryonic Stem Cells ◽

Embryonic Stem ◽

X Chromosome Inactivation ◽

Chromosome Inactivation ◽

Oxygen Concentrations

Download Full-text

Histone H3 Lysine 36 Trimethylation Is Established over theXistPromoter by AntisenseTsixTranscription and Contributes to RepressingXistExpression

Molecular and Cellular Biology ◽

10.1128/mcb.00561-15 ◽

2015 ◽

Vol 35 (22) ◽

pp. 3909-3920 ◽

Cited By ~ 15

Author(s):

Tatsuya Ohhata ◽

Mika Matsumoto ◽

Martin Leeb ◽

Shinwa Shibata ◽

Satoshi Sakai ◽

...

Keyword(s):

Stem Cells ◽

Embryonic Stem Cells ◽

X Chromosome ◽

Antisense Rna ◽

Histone H3 ◽

Embryonic Stem ◽

X Chromosome Inactivation ◽

Chromosome Inactivation ◽

X Chromosomes ◽

Histone H3.3

One of the two X chromosomes in female mammals is inactivated by the noncodingXistRNA. In mice, X chromosome inactivation (XCI) is regulated by the antisense RNATsix, which repressesXiston the active X chromosome. In the absence ofTsix, PRC2-mediated histone H3 lysine 27 trimethylation (H3K27me3) is established over theXistpromoter. Simultaneous disruption ofTsixand PRC2 leads to derepression ofXistand in turn silencing of the single X chromosome in male embryonic stem cells. Here, we identified histone H3 lysine 36 trimethylation (H3K36me3) as a modification that is recruited byTsixcotranscriptionally and extends over theXistpromoter. Reduction of H3K36me3 by expression of a mutated histone H3.3 with a substitution of methionine for lysine at position 36 causes a significant derepression ofXist. Moreover, depletion of the H3K36 methylaseSetd2leads to upregulation ofXist, suggesting H3K36me3 as a modification that contributes to the mechanism ofTsixfunction in regulating XCI. Furthermore, we found that reduction of H3K36me3 does not facilitate an increase in H3K27me3 over theXistpromoter, indicating that additional mechanisms exist by whichTsixblocks PRC2 recruitment to theXistpromoter.

Download Full-text

X chromosome inactivation in human pluripotent stem cells as a model for human development: back to the drawing board?

Human Reproduction Update ◽

10.1093/humupd/dmx015 ◽

2017 ◽

Vol 23 (5) ◽

pp. 520-532 ◽

Cited By ~ 15

Author(s):

Mieke Geens ◽

Susana M. Chuva De Sousa Lopes

Keyword(s):

Stem Cells ◽

Human Development ◽

X Chromosome ◽

Pluripotent Stem Cells ◽

X Chromosome Inactivation ◽

Human Pluripotent Stem Cells ◽

Chromosome Inactivation ◽

Drawing Board

Download Full-text

Polycomb complexes in X chromosome inactivation

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2017.0021 ◽

2017 ◽

Vol 372 (1733) ◽

pp. 20170021 ◽

Cited By ~ 35

Author(s):

Neil Brockdorff

Keyword(s):

X Chromosome ◽

Rna Binding ◽

Rna Binding Proteins ◽

X Chromosome Inactivation ◽

Chromosome Inactivation ◽

Histone H2a ◽

Post Translational Modifications ◽

Link Type ◽

Polycomb Proteins ◽

Inactive X Chromosome

Identifying the critical RNA binding proteins (RBPs) that elicit Xist mediated silencing has been a key goal in X inactivation research. Early studies implicated the Polycomb proteins, a family of factors linked to one of two major multiprotein complexes, PRC1 and PRC2 (Wang 2001 Nat. Genet. 28 , 371–375 ( doi:10.1038/ng574 ); Silva 2003 Dev. Cell 4 , 481–495 ( doi:10.1016/S1534-5807(03)00068-6 ); de Napoles 2004 Dev. Cell 7 , 663–676 ( doi:10.1016/j.devcel.2004.10.005 ); Plath 2003 Science 300 , 131–135 ( doi:10.1126/science.1084274 )). PRC1 and PRC2 complexes catalyse specific histone post-translational modifications (PTMs), ubiquitylation of histone H2A at position lysine 119 (H2AK119u1) and methylation of histone H3 at position lysine 27 (H3K27me3), respectively, and accordingly, these modifications are highly enriched over the length of the inactive X chromosome (Xi). A key study proposed that PRC2 subunits bind directly to Xist RNA A-repeat element, a region located at the 5′ end of the transcript known to be required for Xist mediated silencing (Zhao 2008 Science 322 , 750–756 ( doi:10.1126/science.1163045 )). Subsequent recruitment of PRC1 was assumed to occur via recognition of PRC2 mediated H3K27me3 by the CBX subunit of PRC1, as has been shown to be the case at other Polycomb target loci (Cao 2002 Science 298 , 1039–1043 ( doi:10.1126/science.1076997 )). More recently, several reports have questioned aspects of the prevailing view, both in relation to the mechanism for Polycomb recruitment by Xist RNA and the contribution of the Polycomb pathway to Xist mediated silencing. In this article I provide an overview of our recent progress towards resolving these discrepancies. This article is part of the themed issue ‘X-chromosome inactivation: a tribute to Mary Lyon’.

Download Full-text