Marsupial X chromosome inactivation: past, present and future

2013 ◽  
Vol 61 (1) ◽  
pp. 13 ◽  
Author(s):  
Janine E. Deakin

Marsupial and eutherian mammals inactivate one X chromosome in female somatic cells in what is thought to be a means of compensating for the unbalanced X chromosome dosage between XX females and XY males. The hypothesis of X chromosome inactivation (XCI) was first published by Mary Lyon just over 50 years ago, with the discovery of XCI in marsupials occurring a decade later. However, we are still piecing together the evolutionary origins of this fascinating epigenetic mechanism. From the very first studies on marsupial X inactivation, it was apparent that, although there were some similarities between marsupial and eutherian XCI, there were also some striking differences. For instance, the paternally derived X was found to be preferentially silenced in marsupials, although the silencing was often incomplete, which was in contrast to the random and more tightly controlled inactivation of the X chromosome in eutherians. Many of these earlier studies used isozymes to study the activity of just a few genes in marsupials. The sequencing of several marsupial genomes and the advent of molecular cytogenetic techniques have facilitated more in-depth studies into marsupial X chromosome inactivation and allowed more detailed comparisons of the features of XCI to be made. Several important findings have come from such comparisons, among which is the absence of the XIST gene in marsupials, a non-coding RNA gene with a critical role in eutherian XCI, and the discovery of the marsupial RSX gene, which appears to perform a similar role to XIST. Here I review the history of marsupial XCI studies, the latest advances that have been made and the impact they have had towards unravelling the evolution of XCI in mammals.

2021 ◽  
Author(s):  
Yuhua Pan ◽  
Ting Lu ◽  
Ling Peng ◽  
Qi Zeng ◽  
Xiangyu Huang ◽  
...  

Abstract Objectives: The aim of this study was to identify genetic clues for the causes of familial non-syndromic oligodontia and explore the underlying mechanisms involved, while focusing on the role of human dental pulp stem cells (hDPSCs).Materials and Methods: Candidate gene sequences were obtained by PCR amplification and Sanger sequencing. Functional analysis was conducted, and the pathogenesis associated with EDA mutations in hDPSCs was investigated to explore the impact of the identified mutation on the phenotype. Capillary electrophoresis (CE) was used to detect X chromosome inactivation (XCI) in the blood of female carriers.Results: In this study, we identified an EDA mutation in a Chinese family:the missense mutation c.1013C>T (Thr338Met). Transfection of hDPSCs with a mutant EDA lentivirus decreased the expression of EDA and dentin sialophosphoprotein (DSPP) compared with transfection of control EDA lentivirus. Mechanistically, mutant EDA inhibited the activation of the NF-κB pathway. The CE results showed that symptomatic female carriers had a skewed XCI with a preferential inactivation of the X chromosome that carried the normal allele.Conclusions: In summary, we demonstrated that EDA mutations result in non-syndromic tooth agenesis in heterozygous females and that, mechanistically, EDA regulates odontogenesis through the NF-κB signalling pathway in hDPSCs.Clinical Relevance: Due to the large heterogeneity of tooth agenesis, this study provided a genetic basis for individuals who exhibit similar clinical phenotypes.


Open Biology ◽  
2019 ◽  
Vol 9 (12) ◽  
pp. 190213 ◽  
Author(s):  
Neil Brockdorff

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.


2009 ◽  
Vol 17 (5) ◽  
pp. 671-685 ◽  
Author(s):  
Janine E. Deakin ◽  
Julie Chaumeil ◽  
Timothy A. Hore ◽  
Jennifer A. Marshall Graves

F1000Research ◽  
2017 ◽  
Vol 6 ◽  
pp. 344 ◽  
Author(s):  
Ines Pinheiro ◽  
Edith Heard

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.


2021 ◽  
Vol 11 (7) ◽  
pp. 904
Author(s):  
Boudewien A Brand ◽  
Alyssa E Blesson ◽  
Constance L. Smith-Hicks

Nearly 20% of genes located on the X chromosome are associated with neurodevelopmental disorders (NDD) due to their expression and role in brain functioning. Given their location, several of these genes are either subject to or can escape X-chromosome inactivation (XCI). The degree to which genes are subject to XCI can influence the NDD phenotype between males and females. We provide a general review of X-linked NDD genes in the context of XCI and detailed discussion of the sex-based differences related to MECP2 and FMR1, two common X-linked causes of NDD that are subject to XCI. Understanding the effects of XCI on phenotypic expression of NDD genes may guide the development of stratification biomarkers in X-linked disorders.


2021 ◽  
Author(s):  
Yuhua Pan ◽  
Ting Lu ◽  
Ling Peng ◽  
Qi Zeng ◽  
Xiangyu Huang ◽  
...  

Abstract BackgroundMutations of the Ectodysplasin-A (EDA) gene are generally associated with other developmental anomalies (syndrome hypohidrotic ectodermal dysplasia) or as an isolated condition (non-syndromic tooth agenesis). The influence of EDA mutations on dentinogenesis and odontoblast differentiation have not been reported. The aim of the present study was to identify genetic clues for familial nonsyndromic oligodontia and explore the underlying mechanisms, focusing on the role of human dental pulp stem cells (hDPSCs).MethodsThe candidate genes sequences were performed by PCR amplification and Sanger sequencing. Functional analysis and pathogenesis associated with EDA mutations in hDPSCs were also investigated to explore the impact of the identified mutation on this phenotype. Capillary electrophoresis (CE) was used to detect X chromosome inactivation (XCI) on the blood of female carrier.ResultsIn this study, we identified a reported EDA mutation in a Chinese family:a missense mutation c.1013C>T (Thr338Met). Transfection of hDPSCs with mutant EDA lentivirus decreased the expression of EDA and dentin sialophosphoprotein (DSPP) compared with those transfected with control EDA lentivirus. Mechanically, the mutant EDA inhibited the activation of the NF-κB pathway. The results of CE showed that symptomatic female carrier had a skewed XCI with a preferential inactivation of the X chromosome carrying the normal allele.ConclusionIn summary, we demonstrated EDA mutation result in non-syndromic tooth agenesis in heterozygous females and mechanically EDA regulates odontogenesis through the NF-κB signaling pathway in human dental pulp stem cells.


2021 ◽  
Vol 2021 ◽  
pp. 1-10
Author(s):  
Yuhua Pan ◽  
Ting Lu ◽  
Ling Peng ◽  
Qi Zeng ◽  
Xiangyu Huang ◽  
...  

Background. Mutations of the Ectodysplasin-A (EDA) gene are generally associated with syndrome hypohidrotic ectodermal dysplasia or nonsyndromic tooth agenesis. The influence of EDA mutations on dentinogenesis and odontoblast differentiation has not been reported. The aim of this study was to identify genetic clues for the causes of familial nonsyndromic oligodontia and explore the underlying mechanisms involved, while focusing on the role of human dental pulp stem cells (hDPSCs). Materials and Methods. Candidate gene sequences were obtained by PCR amplification and Sanger sequencing. Functional analysis was conducted, and the pathogenesis associated with EDA mutations in hDPSCs was investigated to explore the impact of the identified mutation on the phenotype. Capillary electrophoresis (CE) was used to detect X-chromosome inactivation (XCI) in the blood of female carriers. Results. In this study, we identified an EDA mutation in a Chinese family: the missense mutation c.1013C>T (Thr338Met). Transfection of hDPSCs with a mutant EDA lentivirus decreased the expression of EDA and dentin sialophosphoprotein (DSPP) compared with transfection of control EDA lentivirus. Mechanistically, mutant EDA inhibited the activation of the NF-κB pathway. The CE results showed that symptomatic female carriers had a skewed XCI with a preferential inactivation of the X chromosome that carried the normal allele. Conclusions. In summary, we demonstrated that EDA mutations result in nonsyndromic tooth agenesis in heterozygous females and that, mechanistically, EDA regulates odontogenesis through the NF-κB signalling pathway in hDPSCs. Due to the large heterogeneity of tooth agenesis, this study provided a genetic basis for individuals who exhibit similar clinical phenotypes.


2014 ◽  
Vol 5 (1) ◽  
Author(s):  
Emily Maclary ◽  
Emily Buttigieg ◽  
Michael Hinten ◽  
Srimonta Gayen ◽  
Clair Harris ◽  
...  

2009 ◽  
Vol 12 (5) ◽  
pp. 502-506 ◽  
Author(s):  
Thomas Heiberg Brix ◽  
Pia Skov Hansen ◽  
Finn Noe Bennedbæk ◽  
Steen Joop Bonnema ◽  
Kirsten Ohm Kyvik ◽  
...  

AbstractAhigher frequency of skewed X chromosome inactivation (XCI) is found in patients with autoimmune thyroid disease (AITD) than in controls. Although goitre is often present in AITD, a recent study failed to show an association between XCI and clinically overt nontoxic goitre. However, the etiology of overt goitre is complex, and the mechanisms influencing thyroid volume may involve fewer factors than the mechanisms underlying overt goitre. In order to examine the impact of XCI on thyroid volume in euthyroid females, we studied whether within cohort (n= 138) and within twin pair (n= 69) differences in XCI are correlated with differences in thyroid volume. XCI was determined by PCR analysis of a polymorphic CAG repeat in the first exon of the androgen receptor gene. Thyroid volume was determined by ultrasound. Neither in the within cohort nor in the within twin pair analysis could we demonstrate a statistically significant association between XCI and thyroid volume: Regression coefficient (β) = 0.023 (95% confidence interval, –0.062–0.108),p= 0.592 and β = 0.038 (–0.080–0.156),p= 0.521, respectively. Controlling for potential confounders such as zygosity, age, TSH, smoking habits and use of oral contraceptives did not change the findings. In conclusion, in a sample of euthyroid Danish female twins, we found no evidence of a relationship between XCI pattern and thyroid volume.


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