The causes and consequences of random and non‐random X chromosome inactivation in humans

Brown, Carolyn J.; Robinson, Wendy P.

doi:10.1034/j.1399-0004.2000.580504.x

Cited by 127 publications

(111 citation statements)

References 126 publications

(135 reference statements)

Supporting

Mentioning

108

Contrasting

Order By: Relevance

“…4G). The hypotrophic cells were clustered in a mosaic pattern, consistent with the origins of these clusters from single cells that have undergone X inactivation of the chromosome not containing the transgene (8). We then examined cardiomyocytes isolated from the hearts of Lef-1⌬20 transgenics.…”

Section: Resultsmentioning

confidence: 99%

The β-Catenin/T-Cell Factor/Lymphocyte Enhancer Factor Signaling Pathway Is Required for Normal and Stress-Induced Cardiac Hypertrophy

Chen

Shevtsov

Hsich

et al. 2006

Molecular and Cellular Biology

123

View full text Add to dashboard Cite

In cells capable of entering the cell cycle, including cancer cells, ␤-catenin has been termed a master switch, driving proliferation over differentiation. However, its role as a transcriptional activator in terminally differentiated cells is relatively unknown. Herein we utilize conditional, cardiac-specific deletion of the ␤-catenin gene and cardiac-specific expression of a dominant inhibitory mutant of Lef-1 (Lef-1⌬20), one of the members of the T-cell factor/lymphocyte enhancer factor (Tcf/Lef) family of transcription factors that functions as a coactivator with ␤-catenin, to demonstrate that ␤-catenin/Tcf/Lef-dependent gene expression regulates both physiologic and pathological growth (hypertrophy) of the heart. Indeed, the profound nature of the growth impairment of the heart in the Lef-1⌬20 mouse, which leads to very early development of heart failure and premature death, suggests ␤-catenin/Tcf/Lef targets are dominant regulators of cardiomyocyte growth. Thus, our studies, employing complementary models in vivo, implicate ␤-catenin/Tcf/Lef signaling as an essential growth-regulatory pathway in terminally differentiated cells.

show abstract

Section: Resultsmentioning

confidence: 99%

The β-Catenin/T-Cell Factor/Lymphocyte Enhancer Factor Signaling Pathway Is Required for Normal and Stress-Induced Cardiac Hypertrophy

Chen

Shevtsov

Hsich

et al. 2006

Molecular and Cellular Biology

123

View full text Add to dashboard Cite

show abstract

“…Increased XCI skewing has been observed in several human diseases with relevance to autism, such as Rett syndrome (Huppke et al, 2006;Knudsen et al, 2006) and X-linked mental retardation (MR) (Plenge et al, 2002). Increased skewing can result from multiple mechanisms including X-linked mutations and reduction in the pool of cells at the time of XCI in early embryogenesis (Brown et al, 2000). 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.…”

Section: Introductionmentioning

confidence: 96%

MECP2 promoter methylation and X chromosome inactivation in autism

et al. 2008

View full text Add to dashboard Cite

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.

show abstract

“…Preferential XCI is an infrequent event in humans, which can be associated with conditions such as extensive X chromosome structural rearrangements, X-linked lethal traits and reduction of the number of embryonic precursor cells in the inner mass at the time of XCI commitment. 4,5 In extra-embryonic tissues of marsupials and mice, the X P is always inactivated. 3 In humans, conflicting data have been reported; of four recent studies, using the methylation assay of androgen receptor (AR), one reported X P preferential inactivation, 6 and three showed both random and preferential XCI.…”

Section: Introductionmentioning

confidence: 99%

Biparental expression of ESX1L gene in placentas from normal and intrauterine growth-restricted pregnancies

et al. 2003

View full text Add to dashboard Cite

Equivalent levels of X-linked gene products between males and females are reached by means of X chromosome inactivation (XCI). In the human and murine embryonic tissues, both the paternally and maternally derived X chromosomes (X P and X M ) may be inactivated. In murine extra-embryonic tissues, X P is imprinted and always silenced; humans, unlike mice, can inactivate the X M in extra-embryonic lineages without an adverse outcome. This difference is probably due to the presence of imprinted placental genes on the murine X chromosome, but not on the human homologue, essential for placental development and function. An example is the paternally imprinted Esx1 gene; mice with a null maternally derived Esx1 allele show intrauterine growth restriction (IUGR) because of placental insufficiency. We investigated the imprinting status of the human orthologous Esx1 gene (ESX1L) in placental samples of four normal full-term and 13 IUGR female fetuses, in which we determined the XCI pattern. Our findings demonstrated that IUGR as well as normal placentas display XCI heterogeneity, thus indicating that the IUGR phenotype is not correlated with a preferential pattern of XCI in placentas. Moreover, ESX1L is equally expressed in IUGR and normal placentas, and shows the same methylation pattern in the presence of both random and skewed XCI. These findings provide evidence that ESX1L is not imprinted in human third-trimester placentas and there is no parent-of-origin effect of chromosome X associated with placental insufficiency.

show abstract

The causes and consequences of random and non‐random X chromosome inactivation in humans

Cited by 127 publications

References 126 publications

The β-Catenin/T-Cell Factor/Lymphocyte Enhancer Factor Signaling Pathway Is Required for Normal and Stress-Induced Cardiac Hypertrophy

The β-Catenin/T-Cell Factor/Lymphocyte Enhancer Factor Signaling Pathway Is Required for Normal and Stress-Induced Cardiac Hypertrophy

MECP2 promoter methylation and X chromosome inactivation in autism

Biparental expression of ESX1L gene in placentas from normal and intrauterine growth-restricted pregnancies

Contact Info

Product

Resources

About