Comparison of X-chromosome inactivation patterns in multiple tissues from human females

Bittel, Douglas C.; Theodoro, Mariana F.; Kibiryeva, Nataliya; Fischer, William; Talebizadeh, Zohreh; Butler, Merlin G.

doi:10.1136/jmg.2007.055244

Cited by 103 publications

(89 citation statements)

References 21 publications

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“…Skewed X inactivation was previously reported in autism female blood (Talebizadeh et al, 2005), but this report has yet to be independently replicated or examined in additional cell types. XCI skewing ratios in blood have been reported to significantly correlated with those from brain (Bittel et al, 2007), but XCI ratios in autism brain have not been previously determined.…”

Section: Introductionmentioning

confidence: 99%

MECP2 promoter methylation and X chromosome inactivation in autism

et al. 2008

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Epigenetic mechanisms have been proposed to play a role in the etiology of autism. This hypothesis is supported by the discovery of increased MECP2 promoter methylation associated with decreased MeCP2 protein expression in autism male brain. To further understand the influence of female X chromosome inactivation (XCI) and neighboring methylation patterns on aberrant MECP2 promoter methylation in autism, multiple methylation analyses were peformed on brain and blood samples from individuals with autism. Bisulfite sequencing analyses of a region 0.6 kb upstream of MECP2 in brain DNA samples revealed an abrupt transition from a highly methylated region in both sexes to a region unmethylated in males and subject to XCI in females. Chromatin immunoprecipitation analysis demonstrated that the CCTC-binding factor (CTCF) bound to this transition region in neuronal cells, consistent with a chromatin boundary at the methylation transition. Male autism brain DNA samples displayed a slight increase in methylation in this transition region, suggesting a possible aberrant spreading of methylation into the MECP2 promoter in autism males across this boundary element. In addition, autistic female brain DNA samples showed evidence for aberrant MECP2 promoter methylation as an increase in the number of bisulfite sequenced clones with undefined XCI status for MECP2 but not androgen receptor (AR). To further investigate the specificity of MECP2 methylation alterations in autism, blood DNA samples from females and mothers of males with autism were also examined for XCI skewing at AR, but no significant increase in XCI skewing was observed compared to controls. These results suggest that the aberrant MECP2 methylation in autism brain DNA samples is due to locus-specific rather than global X chromosome methylation changes.

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Section: Introductionmentioning

confidence: 99%

MECP2 promoter methylation and X chromosome inactivation in autism

et al. 2008

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“…This variation, however, was not found to play a significant role in another study [19]. Considering that XCI patterns vary among tissues [17,20,21,22], it cannot be ruled out that these controversial results could be due to the fact that XCI analysis was performed using only leukocyte DNA.…”

Section: Introductionmentioning

confidence: 75%

Could the Leukocyte X Chromosome Inactivation Pattern Be Extrapolated to Hair Bulbs?

Kaupert¹,

Billerbeck²,

Brito³

et al. 2010

Horm Res Paediatr

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Background: The androgen receptor gene is located on the X chromosome with a polymorphic tract of CAG repeats that is inversely correlated to the receptor’s transactivation activity. A short CAG tract is associated with hyperandrogenic disorders. In women, one of the X chromosomes is inactivated and the X chromosome inactivation (XCI) pattern varies among tissues. Previous studies of hyperandrogenic disorders only evaluated XCI in leukocytes. Objective: To evaluate whether the XCI pattern in leukocytes could be extrapolated to those in hair bulbs. Material: A total of 58 healthy women were used for this study. DNA was extracted from leukocytes (n = 58 women) and pubic (n = 53 women) and scalp hair (n = 21 women). Methods:Hpa II digested and undigested DNA samples underwent fluorescence PCR GeneScan® analysis. Results: A significant and positive correlation of XCI was found between leukocytes and hair bulbs. However, individual comparisons showed that 13 and 19% of the women presented a different leukocyte XCI pattern in pubic hair and scalp hair, respectively. Conclusion: The XCI pattern was similar in leukocytes and hair bulbs of normal women indicating that leukocyte DNA is useful for XCI analysis. However, the XCI pattern could vary among tissues from the same subject, indicating that care should be taken when extrapolating individual leukocyte XCI patterns to other tissue.

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“…When no secondary skewing due to cell selection is prevalent, blood or buccal swab samples can be used to relatively accurately predict the skewing ratio in many tissues of the individual [140,141]. Thereby they can provide diagnostic information for the prevalence of active X--linked disease alleles also for inaccessible tissues like the brain.…”

Section: Females Are Mosaicsmentioning

confidence: 99%

Developmental regulation of X-chromosome inactivation

Payer

2016

Seminars in Cell & Developmental Biology

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With the emergence of sex--determination by sex chromosomes, which differ in composition and number between males and females, appeared the need to equalize X--chromosomal gene dosage between the sexes. Mammals have devised the strategy of X--chromosome inactivation (XCI), in which one of the two X--chromosomes is rendered transcriptionally silent in females. In the mouse, the best--studied model organism with respect to XCI, this inactivation process occurs in different forms, imprinted and random, interspersed by periods of X--chromosome reactivation (XCR), which is needed to switch between the different modes of XCI. In this review, I describe the recent advances with respect to the developmental control of XCI and XCR and in particular their link to differentiation and pluripotency. Furthermore, I review the mechanisms, which influence the timing and choice, with which one of the two X--chromosomes is chosen for inactivation during random XCI. This has an impact on how females are mosaics with regard to which X--chromosome is active in different cells, which has implications on the severity of diseases caused by X--linked mutations.

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Comparison of X-chromosome inactivation patterns in multiple tissues from human females

Cited by 103 publications

References 21 publications

MECP2 promoter methylation and X chromosome inactivation in autism

MECP2 promoter methylation and X chromosome inactivation in autism

Could the Leukocyte X Chromosome Inactivation Pattern Be Extrapolated to Hair Bulbs?

Developmental regulation of X-chromosome inactivation

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