X chromosome inactivation in bone marrow cells of adult mice carrying Searle’s X-autosome translocation: occurrence of the early-replicating inactive X chromosome

1984 ◽  
Vol 38 (1) ◽  
pp. 62-69 ◽  
Author(s):  
N. Takagi ◽  
S. Endo ◽  
O. Sugawara
Keyword(s):  
Bone Marrow ◽  
X Chromosome ◽  
Bone Marrow Cells ◽  
X Chromosome Inactivation ◽  
Chromosome Inactivation ◽  
Adult Mice ◽  
Inactive X Chromosome ◽  
Autosome Translocation ◽  
Marrow Cells

Non-random X-chromosome inactivation in mouse X-autosome translocation embryos—location of the inactivation centre

Development ◽  
1983 ◽  
Vol 78 (1) ◽  
pp. 1-22
Author(s):  
Sohaila Rastan
Keyword(s):  
Simple Model ◽  
X Chromosome ◽  
X Chromosome Inactivation ◽  
Chromosome Inactivation ◽  
Differential Staining ◽  
Female Embryo ◽  
Reciprocal Translocations ◽  
Inactive X Chromosome ◽  
Autosome Translocation ◽  
Chromosome Material

X-chromosome inactivation was investigated cytologically using the modified Kanda method which differentially stains inactive X-chromosome material at metaphase in balanced 13½-day female embryos heterozygous for four X-autosome rearrangements, reciprocal translocations T(X;4)37H, T(X;11)38H and T(X;16)16H (Searle's translocation) and the insertion translocation Is(7;X)1Ct (Cattanach's translocation). In all cases non-random inactivation was found. In the reciprocal translocation heterozygotes only one translocation product ever showed Kanda staining. In addition in a proportion of cells from T(X;4)37H, T(X;11)38H and Is(7;X)1Ct the Kanda staining revealed differential staining of X-chromosome material and attached autosomal material within the translocation product. In a study of 8½-day female embryos doubly heterozygous for Searle's translocation and Cattanach's translocation two unbalanced types of embryo were found. In one type of unbalanced female embryo of the karyotype 40(X(7)/X16;16/16) no inactivated X-chromosomal material is found. A second unbalanced type of female embryo, of the presumptive karyotype 40(X(7)/XN;16x/l6) was found in which two inactivated chromosomes were present in the majority of metaphase spreads. A simple model for the initiation of X-chromosome inactivation based on the presence of a single inactivation centre distal to the breakpoint in Searle's translocation explains these findings.

scholarly journals Escape from X Chromosome Inactivation and the Female Predominance in Autoimmune Diseases

2021 ◽  
Vol 22 (3) ◽  
pp. 1114
Author(s):  
Ali Youness ◽  
Charles-Henry Miquel ◽  
Jean-Charles Guéry
Keyword(s):  
Autoimmune Diseases ◽  
X Chromosome ◽  
Gene Dosage ◽  
X Chromosome Inactivation ◽  
Chromosome Inactivation ◽  
X Chromosomes ◽  
Female Sex Hormones ◽  
Inactive X Chromosome ◽  
Immune Related Genes ◽  
Female Specific

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.

Distribution of sister chromatid exchanges on the mouse chromosomes in vivo with reference to the replication properties of the X chromosome

1984 ◽  
Vol 26 (2) ◽  
pp. 152-157
Author(s):  
S. M. Singh ◽  
D. L. Reimer
Keyword(s):  
Bone Marrow ◽  
X Chromosome ◽  
Sister Chromatid ◽  
Bone Marrow Cells ◽  
Relative Length ◽  
Chromosome Length ◽  
Sister Chromatid Exchanges ◽  
Chromatid Exchanges ◽  
Marrow Cells

Frequency of sister chromatid exchanges (SCE) were recorded separately for different chromosomes from bone marrow cells of female mice of the two genetic strains (C3H/S and C57BL/6J). SCEs were evaluated following different doses of 5-bromo-2′deoxyuridine (BrdU) as nine hourly i.p. injections. The SCE per cell increased with increasing BrdU doses which was slightly higher in C3H/S than in the C57BL/6J. SCEs per cell were variable at every treatment – strain combination, possibly reflecting the heterogeneous nature of the bone marrow cells. In general, there is a positive correlation between SCE per chromosome and the relative chromosome length. Total SCEs on one of the large chromosomes (most likely the X chromosome), however, are significantly higher than expected on the basis of relative length alone. Most of this increase is attributable to one of the homologues of this chromosome, which is not in synchrony with the rest of the chromosomes and may represent the late-replicating X. These results when viewed in the light of replication properties of the heterochromatinized X, suggest a direct involvement of DNA replication in SCE formation and may argue against the replication point as the sole site for the SCEs.Key words: sister chromatid exchange, BrdU, recombination, replication, X chromosome.

scholarly journals X-linked clonality testing: interpretation and limitations

Blood ◽  
2007 ◽  
Vol 110 (5) ◽  
pp. 1411-1419 ◽  
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.

scholarly journals Polycomb complexes in X chromosome inactivation

2017 ◽  
Vol 372 (1733) ◽  
pp. 20170021 ◽  
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’.

scholarly journals When the Lyon(ized chromosome) roars: ongoing expression from an inactive X chromosome

2017 ◽  
Vol 372 (1733) ◽  
pp. 20160355 ◽  
Author(s):  
Laura Carrel ◽  
Carolyn J. Brown
Keyword(s):  
X Chromosome ◽  
X Chromosome Inactivation ◽  
X Inactivation ◽  
Chromosome Inactivation ◽  
Sequencing Technologies ◽  
Inactive X Chromosome ◽  
Underlying Basis ◽  
Inactivation Process ◽  
Escape From X Inactivation ◽  
Mary Lyon

A tribute to Mary Lyon was held in October 2016. Many remarked about Lyon's foresight regarding many intricacies of the X-chromosome inactivation process. One such example is that a year after her original 1961 hypothesis she proposed that genes with Y homologues should escape from X inactivation to achieve dosage compensation between males and females. Fifty-five years later we have learned many details about these escapees that we attempt to summarize in this review, with a particular focus on recent findings. We now know that escapees are not rare, particularly on the human X, and that most lack functionally equivalent Y homologues, leading to their increasingly recognized role in sexually dimorphic traits. Newer sequencing technologies have expanded profiling of primary tissues that will better enable connections to sex-biased disorders as well as provide additional insights into the X-inactivation process. Chromosome organization, nuclear location and chromatin environments distinguish escapees from other X-inactivated genes. Nevertheless, several big questions remain, including what dictates their distinct epigenetic environment, the underlying basis of species differences in escapee regulation, how different classes of escapees are distinguished, and the roles that local sequences and chromosome ultrastructure play in escapee regulation. This article is part of the themed issue ‘X-chromosome inactivation: a tribute to Mary Lyon’.

Evidence for Clonality in Circulating Endothelial Progenitor Cells in Multiple Myeloma.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2357-2357
Author(s):  
Tayfun Ozcelik ◽  
Varsha Vakil ◽  
Eric Smith ◽  
Marc Braunstein ◽  
Justin Maroney ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Endothelial Cells ◽  
Progenitor Cells ◽  
Endothelial Progenitor Cells ◽  
X Chromosome ◽  
X Chromosome Inactivation ◽  
Chromosome Inactivation ◽  
M Protein ◽  
Vascular Endothelial

Abstract A governing role for neoangiogenesis in the progression of multiple myeloma (MM) is indicated by the finding in patients of increased bone marrow microvascular density that is positively correlated with disease activity and is attenuated by treatment with thalidomide. Bone marrow angiogenesis in MM is largely driven by autocrine and paracrine effects of vascular endothelial growth factor (VEGF) via VEGF receptor-2 (KDR). Elucidation of the role of neovascularization in MM growth and dissemination is likely to result in identification of better therapeutic targets than those currently available as well as provide insight into the pathogenesis of MM. Circulating endothelial cells (CECs) contribute to angiogenesis and comprise mature ECs and endothelial progenitor cells (EPCs). The present study sought to characterize CECs and their relation to disease severity in MM. CECs, identified as CD34+/CD146+/CD105+/CD11− cells, were 6-fold higher in patients compared to controls, and correlated positively with serum M protein and β2-microglobulin (P<.001 for both). In addition, circulating EPCs displayed late colony formation/outgrowth and capillary-like network formation on Matrigel. Effective thalidomide treatment inhibited these characteristics (P<.001). Co-expression of KDR and early vascular antigen CD133 characterized EPCs in MM, and KDR mRNA elevations correlated positively with M protein levels (P<.01). To evaluate the clonality of circulating EPCs, X-chromosome inactivation patterns were quantitated in female patients by human androgen receptor gene (HUMARA) assay. Radioactive (α-[33P] -dCTP) polymerase chain reaction amplification of DNA extracted from peripheral blood mononuclear cells showed that X-chromosome inactivation status was informative in 9 of the 11 MM patients. Distribution of the X-inactivation profiles according to age did not show a shift towards the skewed range in older patients or controls. DNA obtained from confluent EPCs outgrown from 4 informative patients showed an extremely skewed pattern of X-chromosome inactivation, with allele ratios of 90/10% in one patient and 97/3% in another patient, whereas a random pattern of X-chromosome inactivation was observed in two other patients displaying clonal restriction (allele ratios of 55/45% and 54/46%). Collectively, these data underscore the angiogenic aspect of MM and suggest that angioblast-like EPCs are a pathogenic biomarker and a rational treatment target in MM. Furthermore, the clonality of EPCs in MM suggests that the pathogenesis of MM may be tightly related to vascular endothelial cells both at the functional/angiogenic and at the genetic and ontogenic levels.

A New ALAS2 Mutation Inducing a Male Lethal X-Linked Sideroblastic Anemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2199-2199 ◽  
Author(s):  
Christian Rose ◽  
Claire Oudin ◽  
Martine Fournier ◽  
Alexandre Bouquet ◽  
Luca Inchiappa ◽  
...  
Keyword(s):  
Bone Marrow ◽  
X Chromosome ◽  
Blood Cells ◽  
X Chromosome Inactivation ◽  
Specific Form ◽  
Chromosome Inactivation ◽  
Sideroblastic Anemia ◽  
Aminolevulinate Synthase ◽  
Ring Sideroblasts ◽  
Skewed X Chromosome Inactivation

Abstract X-linked Sideroblastic Anemia (XLSA, MIM# 300751) is due to mutations in the erythroid-specific form of 5-aminolevulinate synthase (ALAS2) gene. Main features of this condition are microcytic anemia, iron deposits in the mitochondria of erythroid precursors (ring sideroblasts) and an X linked pattern of inheritance. However, up to one third of described cases have been reported in females mainly due to a highly skewed X-chromosome inactivation (Ducamp, Kannengiesser et al. 2011). We report for the first time in a large four generations pedigree a new mutation in ALAS2 gene inducing a Male Lethal X-linked Syndrome ascertained through an adult heterozygous female with a mild form of congenital sideroblastic anemia (CSA). The propositus of this non consanguineous family (Fig 1; individual III;9) was a female from European ancestry. She exhibited a unexplained congenital, non regenerative, macrocytic (MCV 107fL, moderate anemia (Hb 10.4 g/dL), (first assessment at 6 years old). RBC transfusions were required only twice during pregnancy. The diagnosis of CSA was made at 23 years old when the bone marrow aspiration performed, showed 38% of ring sideroblasts. Erythrocyte protoporphyrin concentration was measured in the female proband carrying an ALAS2 mutation. The protoporphyrin concentration was within the normal range of values: 1.6 µmoles/L of red blood cells (less than 1.9 µmoles/L of red blood cells), as previously observed in XLSA cases. The level of serum ferritin was 224ng/ml (N:11-306) and transferrin saturation was 90%. A heterozygote ALAS2 deleterious missense mutation c.622G>T,p.Val208Phe affecting a conserved amino acid was found. A constitutive skewed X-chromosome inactivation was demonstrated as previously reported in affected females with XLSA. However erythroid bone marrow precursor did not exhibited different pattern repartition in term of apoptosis or dyserythropoisesis. Her daughter and her mother exhibited the same mutation but did not have skewed X-chromosome inactivation and were unaffected with a normal blood count. A close inspection of the pedigree confirms a large female predominance (22 females/ 7 males) over four generations (/F/M ratio 3.1). No affected male were identified in the pedigree. Moreover a high level of miscarriage was found only in female carrying the ALAS2 mutation, as shown in the pedigree (Fig. 1). Adding the number of miscarriage (18 over the four generations) to the number of males alive the ratio of M/F over 4 generation is close of 1: 1.04 (24/23). These data highly suggest an X-linked dominant disorder with pre natal male lethality. Our pedigree confirms the non redundant role of the erythroid-specific form of delta-aminolevulinate synthase in foetal hematopoïesis; Moreover our propositus case showed that in case of X-linked Sideroblastic Anemia (XLSA) affected female, a research of excess of miscarriage in the pedigree should be considered and should evocate a male lethal XLSA. This should have an impact in term of genetic counselling. Disclosures: No relevant conflicts of interest to declare.

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