scholarly journals Single-cell analyses of X Chromosome inactivation dynamics and pluripotency during differentiation

2016 ◽  
Vol 26 (10) ◽  
pp. 1342-1354 ◽  
Author(s):  
Geng Chen ◽  
John Paul Schell ◽  
Julio Aguila Benitez ◽  
Sophie Petropoulos ◽  
Marlene Yilmaz ◽  
...  
Keyword(s):  
Single Cell ◽  
X Chromosome ◽  
X Chromosome Inactivation ◽  
Chromosome Inactivation

scholarly journals Integrated analysis of Xist upregulation and X-chromosome inactivation with single-cell and single-allele resolution

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Guido Pacini ◽  
Ilona Dunkel ◽  
Norbert Mages ◽  
Verena Mutzel ◽  
Bernd Timmermann ◽  
...  
Keyword(s):  
Gene Silencing ◽  
Single Cell ◽  
X Chromosome ◽  
Embryonic Stem ◽  
X Chromosome Inactivation ◽  
Chromosome Inactivation ◽  
Cellular Heterogeneity ◽  
Integrated Analysis ◽  
X Chromosomes ◽  
Multiple Levels

AbstractTo ensure dosage compensation between the sexes, one randomly chosen X chromosome is silenced in each female cell in the process of X-chromosome inactivation (XCI). XCI is initiated during early development through upregulation of the long non-coding RNA Xist, which mediates chromosome-wide gene silencing. Cell differentiation, Xist upregulation and gene silencing are thought to be coupled at multiple levels to ensure inactivation of exactly one out of two X chromosomes. Here we perform an integrated analysis of all three processes through allele-specific single-cell RNA-sequencing. Specifically, we assess the onset of random XCI in differentiating mouse embryonic stem cells, and develop dedicated analysis approaches. By exploiting the inter-cellular heterogeneity of XCI onset, we identify putative Xist regulators. Moreover, we show that transient Xist upregulation from both X chromosomes results in biallelic gene silencing right before transitioning to the monoallelic state, confirming a prediction of the stochastic model of XCI. Finally, we show that genetic variation modulates the XCI process at multiple levels, providing a potential explanation for the long-known X-controlling element (Xce) effect, which leads to preferential inactivation of a specific X chromosome in inter-strain crosses. We thus draw a detailed picture of the different levels of regulation that govern the initiation of XCI. The experimental and computational strategies we have developed here will allow us to profile random XCI in more physiological contexts, including primary human cells in vivo.

Studying X chromosome inactivation in the single-cell genomic era

2018 ◽  
Vol 46 (3) ◽  
pp. 577-586 ◽  
Author(s):  
Andrew Keniry ◽  
Marnie E. Blewitt
Keyword(s):  
Single Cell ◽  
X Chromosome ◽  
Single Cells ◽  
Transcriptional Silencing ◽  
X Chromosome Inactivation ◽  
Chromosome Inactivation ◽  
The Novel ◽  
Ideal Model ◽  
Single Cell Genomics ◽  
Silent State

Single-cell genomics is set to revolutionise our understanding of how epigenetic silencing works; by studying specific epigenetic marks or chromatin conformations in single cells, it is possible to ask whether they cause transcriptional silencing or are instead a consequence of the silent state. Here, we review what single-cell genomics has revealed about X chromosome inactivation, perhaps the best characterised mammalian epigenetic process, highlighting the novel findings and important differences between mouse and human X inactivation uncovered through these studies. We consider what fundamental questions these techniques are set to answer in coming years and propose that X chromosome inactivation is an ideal model to study gene silencing by single-cell genomics as technical limitations are minimised through the co-analysis of hundreds of genes.

scholarly journals X-chromosome dosage compensation dynamics in human early embryos

2020 ◽  
Author(s):  
Kevin Huang ◽  
Qiao Zeng ◽  
Yun Feng ◽  
Youjin Hu ◽  
Qin An ◽  
...  
Keyword(s):  
Single Cell ◽  
X Chromosome ◽  
Dosage Compensation ◽  
Cell Mass ◽  
X Chromosome Inactivation ◽  
Chromosome Inactivation ◽  
Preimplantation Embryos ◽  
Human Embryos ◽  
Dosage Balance ◽  
Sister Cells

AbstractIn mammals, female cells are obliged to inactivate one of two X chromosomes to achieve dosage parity with the single X chromosome in male cells, and it is also thought that the single active X chromosome is increased 2-fold to achieve dosage balance with two sets of autosomes (X:A ratio = 1, or Ohno’s hypothesis). However, the ontogeny of X-chromosome inactivation and augmentation of the single active X remains unclear during human embryogenesis. Here, we perform single-cell RNA-seq analysis to examine the timing of X:A balancing and X-inactivation (XCI) in pre- and peri-implantation human embryos up to fourteen days in culture. We find that X-chromosome gene expression in both male and female preimplantation embryos is approximately balanced with autosomes (X:A ratio = 1) after embryonic genome activation (EGA) and persists through fourteen days in vitro. Cross-species analysis of preimplantation embryo also show balanced X:A ratio within the first few days of development. By single-cell mRNA SNP profiling, we find XCI beginning in day 6-7 blastocyst embryos, but does not affect X:A dosage balance. XCI is most evident in trophoectoderm (TE) cells, but can also be observed in a small number of inner cell mass (ICM)-derived cells including primitive endoderm (PE) and epiblast (EPI) cells. Analysis between individual XaXa and XaXi sister cells from the same embryo reveals random XCI and persistently balanced X:A ratio, including sister cells transitioning between XaXa and XaXi states. We therefore conclude that the male X-chromosome undergoes X chromosome augmentation prior to the simultaneous X-chromosome inactivation and augmentation in females. Together, our data demonstrate an evolutionally conserved model of X chromosome dosage compensation in humans and other mammalian species.

X-linked CNV and skewed X-chromosome inactivation

2020 ◽  
pp. 19-21
Author(s):  
Е.А. Фонова ◽  
Е.Н. Толмачева ◽  
А.А. Кашеварова ◽  
М.Е. Лопаткина ◽  
К.А. Павлова ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Intellectual Disability ◽  
X Chromosome ◽  
Copy Number ◽  
Copy Number Variations ◽  
X Chromosome Inactivation ◽  
Chromosome Inactivation ◽  
Chromosome X ◽  
Skewed X Chromosome Inactivation

Смещение инактивации Х-хромосомы может быть следствием и маркером нарушения клеточной пролиферации при вариациях числа копий ДНК на Х-хромосоме. Х-сцепленные CNV выявляются как у женщин с невынашиванием беременности и смещением инактивации Х-хромосомы (с частотой 33,3%), так и у пациентов с умственной отсталостью и смещением инактивацией у их матерей (с частотой 40%). A skewed X-chromosome inactivation can be a consequence and a marker of impaired cell proliferation in the presence of copy number variations (CNV) on the X chromosome. X-linked CNVs are detected in women with miscarriages and a skewed X-chromosome inactivation (with a frequency of 33.3%), as well as in patients with intellectual disability and skewed X-chromosome inactivation in their mothers (with a frequency of 40%).

scholarly journals X-Linked Emery–Dreifuss Muscular Dystrophy: Study Of X-Chromosome Inactivation and Its Relation with Clinical Phenotypes in Female Carriers

Genes ◽  
2019 ◽  
Vol 10 (11) ◽  
pp. 919 ◽  
Author(s):  
Viggiano ◽  
Madej-Pilarczyk ◽  
Carboni ◽  
Picillo ◽  
Ergoli ◽  
...  
Keyword(s):  
Muscular Dystrophy ◽  
X Chromosome ◽  
Clinical Symptoms ◽  
Fibrous Tissue ◽  
X Chromosome Inactivation ◽  
Chromosome Inactivation ◽  
Cardiac Conduction ◽  
Asymptomatic Carriers ◽  
Cardiac Symptoms ◽  
Female Carriers

X-linked Emery–Dreifuss muscular dystrophy (EDMD1) affects approximately 1:100,000 male births. Female carriers are usually asymptomatic but, in some cases, they may present clinical symptoms after age 50 at cardiac level, especially in the form of conduction tissue anomalies. The aim of this study was to evaluate the relation between heart involvement in symptomatic EDMD1 carriers and the X-chromosome inactivation (XCI) pattern. The XCI pattern was determined on the lymphocytes of 30 symptomatic and asymptomatic EDMD1 female carriers—25 familial and 5 sporadic cases—seeking genetic advice using the androgen receptor (AR) methylation-based assay. Carriers were subdivided according to whether they were above or below 50 years of age. A variance analysis was performed to compare the XCI pattern between symptomatic and asymptomatic carriers. The results show that 20% of EDMD1 carriers had cardiac symptoms, and that 50% of these were ≥50 years of age. The XCI pattern was similar in both symptomatic and asymptomatic carriers. Conclusions: Arrhythmias in EDMD1 carriers poorly correlate on lymphocytes to a skewed XCI, probably due to (a) the different embryological origin of cardiac conduction tissue compared to lymphocytes or (b) the preferential loss of atrial cells replaced by fibrous tissue.

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