Female predisposition to TLR7-driven autoimmunity: gene dosage and the escape from X chromosome inactivation

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.

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X-Chromosome Inactivation during Preimplantation Development and in Pluripotent Stem Cells

Cytogenetic and Genome Research ◽

10.1159/000508610 ◽

2020 ◽

Vol 160 (6) ◽

pp. 283-294 ◽

Cited By ~ 1

Author(s):

Paola Rebuzzini ◽

Maurizio Zuccotti ◽

Silvia Garagna

Keyword(s):

Stem Cells ◽

X Chromosome ◽

Dosage Compensation ◽

Pluripotent Stem Cells ◽

Mammalian Cells ◽

Gene Dosage ◽

X Chromosome Inactivation ◽

Preimplantation Development ◽

Chromosome Inactivation ◽

Transcriptional Gene Silencing

X dosage compensation between XX female and XY male mammalian cells is achieved by a process known as X-chromosome inactivation (XCI). XCI initiates early during preimplantation development in female cells, and it is subsequently stably maintained in somatic cells. However, XCI is a reversible process that occurs in vivo in the inner cell mass of the blastocyst, in primordial germ cells or in spermatids during reprogramming. Erasure of transcriptional gene silencing can occur though a mechanism named X-chromosome reactivation (XCR). XCI and XCR have been substantially deciphered in the mouse, whereas they still remain debated in the human. In this review, we summarized the recent advances in the knowledge of X-linked gene dosage compensation during mouse and human preimplantation development and in pluripotent stem cells.

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X chromosome inactivation: new players in the initiation of gene silencing

F1000Research ◽

10.12688/f1000research.10707.1 ◽

2017 ◽

Vol 6 ◽

pp. 344 ◽

Cited By ~ 23

Author(s):

Ines Pinheiro ◽

Edith Heard

Keyword(s):

Gene Silencing ◽

X Chromosome ◽

Gene Dosage ◽

X Chromosome Inactivation ◽

Chromosome Inactivation ◽

Crucial Importance ◽

Compensation Process ◽

Repressive Chromatin ◽

Non Coding Rna ◽

Recent Developments

X chromosome inactivation (XCI) is a dosage compensation process that was adopted by female mammals to balance gene dosage between XX females and XY males. XCI starts with the upregulation of the non-coding RNA Xist, after which most X-linked genes are silenced and acquire a repressive chromatin state. Even though the chromatin marks of the inactive X have been fairly well described, the mechanisms responsible for the initiation of XCI remain largely unknown. In this review, we discuss recent developments that revealed unexpected factors playing a role in XCI and that might be of crucial importance to understand the mechanisms responsible for the very first steps of this chromosome-wide gene-silencing event.

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Mechanistic insights in X-chromosome inactivation

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2016.0356 ◽

2017 ◽

Vol 372 (1733) ◽

pp. 20160356 ◽

Cited By ~ 24

Author(s):

Zhipeng Lu ◽

Ava C. Carter ◽

Howard Y. Chang

Keyword(s):

X Chromosome ◽

New Technologies ◽

Protein Complexes ◽

Gene Dosage ◽

X Chromosome Inactivation ◽

Chromosome Inactivation ◽

Epigenetic Mechanism ◽

X Chromosomes ◽

Technological Advances ◽

Lncrna Xist

X-chromosome inactivation (XCI) is a critical epigenetic mechanism for balancing gene dosage between XY males and XX females in eutherian mammals. A long non-coding RNA (lncRNA), XIST, and its associated proteins orchestrate this multi-step process, resulting in the inheritable silencing of one of the two X-chromosomes in females. The XIST RNA is large and complex, exemplifying the unique challenges associated with the structural and functional analysis of lncRNAs. Recent technological advances in the analysis of macromolecular structure and interactions have enabled us to systematically dissect the XIST ribonucleoprotein complex, which is larger than the ribosome, and its place of action, the inactive X-chromosome. These studies shed light on key mechanisms of XCI, such as XIST coating of the X-chromosome, recruitment of DNA, RNA and histone modification enzymes, and compaction and compartmentalization of the inactive X. Here, we summarize recent studies on XCI, highlight the critical contributions of new technologies and propose a unifying model for XIST function in XCI where modular domains serve as the structural and functional units in both lncRNA–protein complexes and DNA–protein complexes in chromatin. This article is part of the themed issue ‘X-chromosome inactivation: a tribute to Mary Lyon’.

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X-Chromosome Inactivation as a System of Gene Dosage Compensation to Regulate Gene Expression

Progress in Nucleic Acid Research and Molecular Biology ◽

10.1016/s0079-6603(08)60166-x ◽

1989 ◽

pp. 119-130 ◽

Cited By ~ 33

Author(s):

Mary F. Lyon

Keyword(s):

Gene Expression ◽

X Chromosome ◽

Dosage Compensation ◽

Gene Dosage ◽

X Chromosome Inactivation ◽

Chromosome Inactivation ◽

Regulate Gene Expression ◽

Regulate Gene

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X-chromosome inactivation: dosage compensation of genes or heterochromatin?

10.36811/ijbm.2019.110010 ◽

2019 ◽

pp. 75-87

Author(s):

AI Ibraimov

Keyword(s):

X Chromosome ◽

Dosage Compensation ◽

Sex Chromosome ◽

Gene Dosage ◽

Alternative Hypothesis ◽

X Chromosome Inactivation ◽

Chromosome Inactivation ◽

X Chromosomes ◽

Inactive X Chromosome ◽

Mammalian Female

X-chromosome inactivation (XCI) is the process by which one of two X chromosomes in mammalian female cells is inactivated. The DNA of the inactive X chromosome is packaged in transcriptionally inactive heterochromatin. It is generally accepted that XCI have evolved to enable dosage compensation in mammals as a way to equalize X-linked gene expression between XX and XY individuals. However, there remain several controversial issues regarding the causes of XCI. The most important of them, why dosage compensation of genes? An alternative hypothesis is discussed that XCI is caused by dose compensation for heterochromatin, rather than genes, in the genome of female mammals due to the lack of a sex chromosome in their karyotype with a large constitutive heterochromatin block, as in Y chromosome in males. It is for this reason that heterochromatinization of the euchromatin regions of one of the X chromosomes occurs. The biological meaning of heterochromatinization is to increase the density of condensed chromatin (??) around the interphase nucleus, responsible for removing excess heat from the nucleus into the cytoplasm, since the compaction of ?? depends on the amount of heterochromatin. The consequence of this process is the inactivation of genes that were in the area of heterochromatinization of the X chromosome. Keywords: X-chromosome inactivation; Lyonization; Gene dosage compensation; Heterochromatin dosage compensation; Cell thermoregulation

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X-linked CNV and skewed X-chromosome inactivation

Nauchno-prakticheskii zhurnal «Medicinskaia genetika» ◽

10.25557/2073-7998.2020.03.19-21 ◽

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%).

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Faculty of 1000 evaluation for Cellular resolution maps of x chromosome inactivation: implications for neural development, function, and disease.

F1000 - Post-publication peer review of the biomedical literature ◽

10.3410/f.718235579.793490044 ◽

2014 ◽

Author(s):

Franck Polleux ◽

Julien Courchet

Keyword(s):

X Chromosome ◽

Neural Development ◽

X Chromosome Inactivation ◽

Chromosome Inactivation ◽

Cellular Resolution

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

Genes ◽

10.3390/genes10110919 ◽

2019 ◽

Vol 10 (11) ◽

pp. 919 ◽

Cited By ~ 1

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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