An X chromosome inactivation assay based on differential methylation of a CpG island coupled to a VNTR polymorphism at the 5′ end of the Monoamine Oxidase A gene

AbstractEpigenome-wide studies report higher methylation among women than men with decreasing levels with age. Little is known about associations of sex and age with methylation of monoamine oxidase A (MAOA). Methylation of the first exonic and partial first intronic region of MAOA has been shown to strengthen associations of interactions of MAOA-uVNTR genotypes and adversity with aggression and substance misuse. Our study examined associations of sex and age with MAOA first exon and intron methylation levels in 252 women and 157 men aged 14–73 years. Participants included adolescents recruited at a substance misuse clinic, their siblings and parents, and healthy women. Women showed ~ 50% higher levels of exonic, and ~ 15% higher intronic, methylation than men. Methylation levels were similar between younger (M = 22.7 years) and older (M = 46.1 years) participants, and stable across age. Age modified few associations of methylation levels with sex. MAOA genotypes modified few associations of methylation with sex and age. Higher methylation levels among women were not explained by genotype, nor interaction of genotype and sexual abuse. Findings were similar after adjusting for lifetime diagnoses of substance dependence (women = 24.3%; men = 34.2%). Methylation levels were higher among women who experienced sexual abuse than women who did not. Results extend on prior studies by showing that women display higher levels of methylation than men within first intronic/exonic regions of MAOA, which did not decrease with age in either sex. Findings were not conditioned by genotype nor interactions of genotype and trauma, and indicate X-chromosome inactivation.

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A Functional Chromatin Domain Does Not Resist X Chromosome Inactivation: Silencing of cLys Correlates with Methylation of a Dual Promoter-Replication Origin

Molecular and Cellular Biology ◽

10.1128/mcb.22.13.4667-4676.2002 ◽

2002 ◽

Vol 22 (13) ◽

pp. 4667-4676 ◽

Cited By ~ 11

Author(s):

Suyinn Chong ◽

Joanna Kontaraki ◽

Constanze Bonifer ◽

Arthur D. Riggs

Keyword(s):

X Chromosome ◽

Copy Number ◽

Cpg Island ◽

Regulatory Elements ◽

X Chromosome Inactivation ◽

Chromosome Inactivation ◽

Chromatin Domain ◽

Specific Expression ◽

Position Effects ◽

Chicken Lysozyme

ABSTRACT To investigate the molecular mechanism(s) involved in the propagation and maintenance of X chromosome inactivation (XCI), the 21.4-kb chicken lysozyme (cLys) chromatin domain was inserted into the Hprt locus on the mouse X chromosome. The inserted fragment includes flanking matrix attachment regions (MARs), an origin of bidirectional replication (OBR), and all the cis-regulatory elements required for correct tissue-specific expression of cLys. It also contains a recently identified and widely expressed second gene, cGas41. The cLys domain is known to function as an autonomous unit resistant to chromosomal position effects, as evidenced by numerous transgenic mouse lines showing copy-number-dependent and development-specific expression of cLys in the myeloid lineage. We asked the questions whether this functional chromatin domain was resistant to XCI and whether the X inactivation signal could spread across an extended region of avian DNA. A generally useful method was devised to generate pure populations of macrophages with the transgene either on the active (Xa) or the inactive (Xi) chromosome. We found that (i) cLys and cGas41 are expressed normally from the Xa; (ii) the cLys chromatin domain, even when bracketed by MARs, is not resistant to XCI; (iii) transcription factors are excluded from lysozyme enhancers on the Xi; and (iv) inactivation correlates with methylation of a CpG island that is both an OBR and a promoter of the cGas41 gene.

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Use of a HpaII-polymerase chain reaction assay to study DNA methylation in the Pgk-1 CpG island of mouse embryos at the time of X-chromosome inactivation.

Molecular and Cellular Biology ◽

10.1128/mcb.10.9.4987 ◽

1990 ◽

Vol 10 (9) ◽

pp. 4987-4989 ◽

Cited By ~ 106

Author(s):

J Singer-Sam ◽

M Grant ◽

J M LeBon ◽

K Okuyama ◽

V Chapman ◽

...

Keyword(s):

Dna Methylation ◽

X Chromosome ◽

Inner Cell Mass ◽

Cpg Island ◽

Cell Mass ◽

X Chromosome Inactivation ◽

Mouse Embryos ◽

Chromosome Inactivation ◽

Individual Mouse ◽

Polymerase Chain

A HpaII-PCR assay was used to study DNA methylation in individual mouse embryos. It was found that HpaII site H-7 in the CpG island of the X-chromosome-linked Pgk-1 gene is less than or equal to 10% methylated in oocytes and male embryos but becomes 40% methylated in female embryos at 6.5 days; about the time of X-chromosome inactivation of the inner cell mass.

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Preferential X-chromosome inactivation, DNA methylation and imprinting

Development ◽

10.1242/dev.108.supplement.55 ◽

1990 ◽

Vol 108 (Supplement) ◽

pp. 55-62

Author(s):

Marilyn Monk ◽

Mark Grant

Keyword(s):

Dna Methylation ◽

Early Development ◽

X Chromosome ◽

Expression Patterns ◽

Genetic Material ◽

X Chromosome Inactivation ◽

Differential Methylation ◽

X Inactivation ◽

Chromosome Inactivation ◽

Embryonic Tissues

Non-random X-chromosome inactivation in mammals was one of the first observed examples of differential expression dependent on the gamete of origin of the genetic material. The paternally-inherited X chromosome is preferentially inactive in all cells of female marsupials and in the extra-embryonic tissues of developing female rodents. Some form of parental imprinting during male and female gametogenesis must provide a recognition signal that determines the nonrandomness of X-inactivation but its nature is thus far unknown. In the mouse, the imprint distinguishing the X chromosomes in the extra-embryonic tissues must be erased early in development since X-inactivation is random in the embryonic cells. Random X-chromosome inactivation leads to cellular mosaicism in expression and differential methylation of active and inactive X-linked genes. Transgene imprinting shares many features with X-inactivation, including differential DNA methylation. In this paper we consider when methylation differences in early development affecting X-chromosome activity and imprinting are established. There are processes of methylation and demethylation occurring in early development, as well as changes in the activity of the DNA methylase itself. Methylation of a specific CpG site associated with activity of the X-linked PGK-1 gene has been studied. This site is already methylated on the inactive X chromosome by 6.5 days' gestation, close to the time of X-inactivation. However, differential methylation of this site is not the primary imprint marking the paternal X chromosome for preferential inactivation in the extra-embryonic membranes. A consideration of factors influencing both X-chromosome inactivation and imprinting suggests that a process of communication and comparison between nonidentical alleles might by the basis for the differential modification and expression patterns observed.

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Use of a HpaII-polymerase chain reaction assay to study DNA methylation in the Pgk-1 CpG island of mouse embryos at the time of X-chromosome inactivation

Molecular and Cellular Biology ◽

10.1128/mcb.10.9.4987-4989.1990 ◽

1990 ◽

Vol 10 (9) ◽

pp. 4987-4989

Author(s):

J Singer-Sam ◽

M Grant ◽

J M LeBon ◽

K Okuyama ◽

V Chapman ◽

...

Keyword(s):

Dna Methylation ◽

X Chromosome ◽

Inner Cell Mass ◽

Cpg Island ◽

Cell Mass ◽

X Chromosome Inactivation ◽

Mouse Embryos ◽

Chromosome Inactivation ◽

Individual Mouse ◽

Polymerase Chain

A HpaII-PCR assay was used to study DNA methylation in individual mouse embryos. It was found that HpaII site H-7 in the CpG island of the X-chromosome-linked Pgk-1 gene is less than or equal to 10% methylated in oocytes and male embryos but becomes 40% methylated in female embryos at 6.5 days; about the time of X-chromosome inactivation of the inner cell mass.

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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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