Genetic factors relating to the thyroid with emphasis on complex diseases

The nucleus of each human cell encodes approximately 30 000 genes. A large fraction of the genes in each individual exist in a form that can vary between individuals. These variable genetic forms are termed polymorphisms, and they account for much of the normal variation in body traits, such as height and hair colour. The genetic information encoded in the DNA is stored on the chromosomes and each somatic cell contains 46 chromosomes (22 autosomes and two sex chromosomes), arranged in 23 pairs, one of each derived from each parent. Since each individual inherits two copies of each chromosome (for autosomes), one from each parent, there are also two copies of each gene. The chromosomal location of a gene is termed the locus of the gene. When the gene in a certain locus exists in two or more forms, these variants of the gene are termed alleles. When an individual’s two alleles at a locus are identical, that individual is said to be homozygous at that locus, and when the two alleles are different, the individual is a heterozygote. Female somatic cells contain two X chromosomes, whereas male somatic cells contain only one X chromosome. Nevertheless, the activity of genes coded for by the X chromosome is no higher in females than in males. This is due to inactivation of most of the genes on one of the two X chromosomes. Thus, in female somatic cells only one X chromosome gene is expressed, and this process of suppression is called X-chromosome inactivation. X-chromosome inactivation occurs early in embryonic life and, thereafter, in each cell either the maternal or paternal chromosome is inactivated. This results in a tissue mosaic of paternally and maternally expressed X-chromosomal alleles, with an average of 1:1 distribution. As a result, a female who is heterozygous for an X-linked gene will show a mosaic-like distribution of cells expressing either one of the two alleles. Recently X-inactivation has been postulated to play a role in autoimmune diseases and may help explain the female preponderance of autoimmune diseases (see below).

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

International Journal of Molecular Sciences ◽

10.3390/ijms22031114 ◽

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.

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Escape from X chromosome inactivation and female bias of autoimmune diseases

Molecular Medicine ◽

10.1186/s10020-020-00256-1 ◽

2020 ◽

Vol 26 (1) ◽

Author(s):

Mohammad Javad Mousavi ◽

Mahdi Mahmoudi ◽

Somayeh Ghotloo

Keyword(s):

Autoimmune Diseases ◽

X Chromosome ◽

X Chromosome Inactivation ◽

Chromosome Inactivation ◽

X Chromosomes ◽

Female Sex Hormones ◽

Female Bias ◽

The Impact ◽

The Given ◽

Dual Expression

AbstractGenerally, autoimmune diseases are more prevalent in females than males. Various predisposing factors, including female sex hormones, X chromosome genes, and the microbiome have been implicated in the female bias of autoimmune diseases. During embryogenesis, one of the X chromosomes in the females is transcriptionally inactivated, in a process called X chromosome inactivation (XCI). This equalizes the impact of two X chromosomes in the females. However, some genes escape from XCI, providing a basis for the dual expression dosage of the given gene in the females. In the present review, the contribution of the escape genes to the female bias of autoimmune diseases will be discussed.

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Gender Specific Differences in Disease Susceptibility: The Role of Epigenetics

Biomedicines ◽

10.3390/biomedicines9060652 ◽

2021 ◽

Vol 9 (6) ◽

pp. 652

Author(s):

Lucia Migliore ◽

Vanessa Nicolì ◽

Andrea Stoccoro

Keyword(s):

Immune Responses ◽

Autoimmune Diseases ◽

X Chromosome ◽

Complex Traits ◽

Differential Susceptibility ◽

X Chromosome Inactivation ◽

Adverse Outcomes ◽

Chromosome Inactivation ◽

Gender Specific Differences ◽

Gender Specific

Many complex traits or diseases, such as infectious and autoimmune diseases, cancer, xenobiotics exposure, neurodevelopmental and neurodegenerative diseases, as well as the outcome of vaccination, show a differential susceptibility between males and females. In general, the female immune system responds more efficiently to pathogens. However, this can lead to over-reactive immune responses, which may explain the higher presence of autoimmune diseases in women, but also potentially the more adverse effects of vaccination in females compared with in males. Many clinical and epidemiological studies reported, for the SARS-CoV-2 infection, a gender-biased differential response; however, the majority of reports dealt with a comparable morbidity, with males, however, showing higher COVID-19 adverse outcomes. Although gender differences in immune responses have been studied predominantly within the context of sex hormone effects, some other mechanisms have been invoked: cellular mosaicism, skewed X chromosome inactivation, genes escaping X chromosome inactivation, and miRNAs encoded on the X chromosome. The hormonal hypothesis as well as other mechanisms will be examined and discussed in the light of the most recent epigenetic findings in the field, as the concept that epigenetics is the unifying mechanism in explaining gender-specific differences is increasingly emerging.

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Random X-chromosome inactivation in female primordial germ cells in the mouse

Development ◽

10.1242/dev.64.1.251 ◽

1981 ◽

Vol 64 (1) ◽

pp. 251-258

Author(s):

Andy McMahon ◽

Mandy Fosten ◽

Marilyn Monk

Keyword(s):

X Chromosome ◽

Germ Cells ◽

Germ Line ◽

Primordial Germ Cells ◽

Phosphoglycerate Kinase ◽

X Chromosome Inactivation ◽

Yolk Sac ◽

Chromosome Inactivation ◽

X Chromosomes

The pattern of expression of the two X chromosomes was investigated in pre-meiotic germ cells from 12½-day-old female embryos heterozygous for the variant electrophoretic forms of the X-linked enzyme phosphoglycerate kinase (PGK-1). If such germ cells carry the preferentially active Searle's translocated X chromosome (Lyon, Searle, Ford & Ohno, 1964), then only the Pgk-1 allele on this chromosome is expressed. This confirms Johnston's evidence (1979,1981) that Pgk-1 expression reflects a single active X chromosome at this time. Extracts of 12½-day germ cells from heterozygous females carrying two normal X chromosomes show both the A and the B forms of PGK; since only one X chromosome in each cell is active, different alleles must be expressed in different cells, suggesting that X-chromosome inactivation is normally random in the germ line. This result makes it unlikely that germ cells are derived from the yolk-sac endoderm where the paternally derived X chromosome is preferentially inactivated. In their pattern of X-chromosome inactivation, germ cells evidently resemble other tissues derived from the epiblast.

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Regulation of imprinted X-chromosome inactivation in mice by Tsix

Development ◽

10.1242/dev.128.8.1275 ◽

2001 ◽

Vol 128 (8) ◽

pp. 1275-1286 ◽

Cited By ~ 5

Author(s):

T. Sado ◽

Z. Wang ◽

H. Sasaki ◽

E. Li

Keyword(s):

X Chromosome ◽

X Chromosome Inactivation ◽

X Inactivation ◽

Chromosome Inactivation ◽

Maternal Allele ◽

Xist Expression ◽

Developmental Defects ◽

X Chromosomes ◽

Embryonic Tissues ◽

Early Embryonic Lethality

In mammals, X-chromosome inactivation is imprinted in the extra-embryonic lineages with paternal X chromosome being preferentially inactivated. In this study, we investigate the role of Tsix, the antisense transcript from the Xist locus, in regulation of Xist expression and X-inactivation. We show that Tsix is transcribed from two putative promoters and its transcripts are processed. Expression of Tsix is first detected in blastocysts and is imprinted with only the maternal allele transcribed. The imprinted expression of Tsix persists in the extra-embryonic tissues after implantation, but is erased in embryonic tissues. To investigate the function of Tsix in X-inactivation, we disrupted Tsix by insertion of an IRES(β)geo cassette in the second exon, which blocked transcripts from both promoters. While disruption of the paternal Tsix allele has no adverse effects on embryonic development, inheritance of a disrupted maternal allele results in ectopic Xist expression and early embryonic lethality, owing to inactivation of both X chromosomes in females and single X chromosome in males. Further, early developmental defects of female embryos with maternal transmission of Tsix mutation can be rescued by paternal inheritance of the Xist deletion. These results provide genetic evidence that Tsix plays a crucial role in maintaining Xist silencing in cis and in regulation of imprinted X-inactivation in the extra-embryonic tissues.

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Localized accumulation of Xist RNA in X chromosome inactivation

Open Biology ◽

10.1098/rsob.190213 ◽

2019 ◽

Vol 9 (12) ◽

pp. 190213 ◽

Cited By ~ 2

Author(s):

Neil Brockdorff

Keyword(s):

X Chromosome ◽

X Chromosome Inactivation ◽

Chromosome Inactivation ◽

X Chromosomes ◽

Non Coding Rna ◽

Xist Rna ◽

Analogous Manner ◽

Mammalian Embryos ◽

Non Coding Rnas ◽

In Cis

The non-coding RNA Xist regulates the process of X chromosome inactivation, in which one of the two X chromosomes present in cells of early female mammalian embryos is selectively and coordinately shut down. Remarkably Xist RNA functions in cis , affecting only the chromosome from which it is transcribed. This feature is attributable to the unique propensity of Xist RNA to accumulate over the territory of the chromosome on which it is synthesized, contrasting with the majority of RNAs that are rapidly exported out of the cell nucleus. In this review I provide an overview of the progress that has been made towards understanding localized accumulation of Xist RNA, drawing attention to evidence that some other non-coding RNAs probably function in a highly analogous manner. I describe a simple model for localized accumulation of Xist RNA and discuss key unresolved questions that need to be addressed in future studies.

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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

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Landscape of X chromosome inactivation across human tissues

Nature ◽

10.1038/nature24265 ◽

2017 ◽

Vol 550 (7675) ◽

pp. 244-248 ◽

Cited By ~ 245

Author(s):

Taru Tukiainen ◽

◽

Alexandra-Chloé Villani ◽

Angela Yen ◽

Manuel A. Rivas ◽

...

Keyword(s):

Gene Expression ◽

X Chromosome ◽

Mammalian Cells ◽

Phenotypic Diversity ◽

X Chromosome Inactivation ◽

Chromosome Inactivation ◽

Phenotypic Traits ◽

Human Tissues ◽

X Chromosomes ◽

Chromosomal Genes

Abstract X chromosome inactivation (XCI) silences transcription from one of the two X chromosomes in female mammalian cells to balance expression dosage between XX females and XY males. XCI is, however, incomplete in humans: up to one-third of X-chromosomal genes are expressed from both the active and inactive X chromosomes (Xa and Xi, respectively) in female cells, with the degree of ‘escape’ from inactivation varying between genes and individuals1,2. The extent to which XCI is shared between cells and tissues remains poorly characterized3,4, as does the degree to which incomplete XCI manifests as detectable sex differences in gene expression5 and phenotypic traits6. Here we describe a systematic survey of XCI, integrating over 5,500 transcriptomes from 449 individuals spanning 29 tissues from GTEx (v6p release) and 940 single-cell transcriptomes, combined with genomic sequence data. We show that XCI at 683 X-chromosomal genes is generally uniform across human tissues, but identify examples of heterogeneity between tissues, individuals and cells. We show that incomplete XCI affects at least 23% of X-chromosomal genes, identify seven genes that escape XCI with support from multiple lines of evidence and demonstrate that escape from XCI results in sex biases in gene expression, establishing incomplete XCI as a mechanism that is likely to introduce phenotypic diversity6,7. Overall, this updated catalogue of XCI across human tissues helps to increase our understanding of the extent and impact of the incompleteness in the maintenance of XCI.

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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.

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Do LINEs Have a Role in X-Chromosome Inactivation?

Journal of Biomedicine and Biotechnology ◽

10.1155/jbb/2006/59746 ◽

2006 ◽

Vol 2006 ◽

pp. 1-6 ◽

Cited By ~ 19

Author(s):

Mary F. Lyon

Keyword(s):

X Chromosome ◽

X Chromosome Inactivation ◽

Chromosome Inactivation ◽

Current Evidence ◽

X Chromosomes ◽

Repeat Elements ◽

Sequencing Project ◽

Human Genome Sequencing ◽

Human And Mouse

There is longstanding evidence that X-chromosome inactivation (XCI) travels less successfully in autosomal than in X-chromosomal chromatin. The interspersed repeat elements LINE1s (L1s) have been suggested as candidates for “boosters” which promote the spread of XCI in the X-chromosome. The present paper reviews the current evidence concerning the possible role of L1s in XCI. Recent evidence, accruing from the human genome sequencing project and other sources, confirms that mammalian X-chromosomes are indeed rich in L1s, except in regions where there are many genes escaping XCI. The density of L1s is the highest in the evolutionarily oldest regions. Recent work on X; autosome translocations in human and mouse suggested failure of stabilization of XCI in autosomal material, so that genes are reactivated, but resistance of autosomal genes to the original silencing is not excluded. The accumulation of L1s on the X-chromosome may have resulted from reduced recombination or late replication. Whether L1s are part of the mechanism of XCI or a result of it remains enigmatic.

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