Human active X-specific DNA methylation events showing stability across time and tissues

Abstract

The phenomenon of X chromosome inactivation in female mammals is well characterised and remains the archetypal example of dosage compensation via monoallelic expression. The temporal series of events that culminates in inactive X-specific gene silencing by DNA methylation has revealed a 'patchwork' of gene inactivation along the chromosome, with approximately 15% of genes escaping. Such genes are therefore potentially subject to sex-specific imbalance between males and females. Aside from XIST, the non-coding RNA on the X chromosome destined to be inactivated, very little is known about the extent of loci that may be selectively silenced on the active X chromosome (Xa). Using longitudinal array-based DNA methylation profiling of two human tissues, we have identified specific and widespread active X-specific DNA methylation showing stability over time and across tissues of disparate origin. Our panel of X-chromosome loci subject to methylation on Xa reflects a potentially novel mechanism for controlling female-specific X inactivation and sex-specific dimorphisms in humans. Further work is needed to investigate these phenomena.

Allele-specific non-CG DNA methylation marks domains of active chromatin in female mouse brain

“…S4). Bcor, a gene in which mutations can lead to oculofaciocardiodental (OFCD) syndrome, was previously shown to be half as methylated in females (Xa + Xi) as in males in human blood and buccal tissue (24). This pattern runs counter to the pattern at other nonescape genes, where males show lower mCG compared with females, suggesting a unique pattern at Bcor.…”

Distinct chromatin structures at the monoamine oxidase‐A promoter correlate with allele‐specific expression in SH‐SY5Y cells

“…This is a relatively straightforward explanation for the male gender which has only one allele for MAOA. 13 To further investigate the regulation of MAOA gene expression by the uVNTR we analysed binding for 5 transcription factors: CTCF, SP1, hnRNP K, CNBP and nucleolin. Figure 4A.…”

“…This data was consistent with a role for gender in regulation of MAOA expression via epigenetic mechanisms, for example, the gender-specific changes of methylation in a longitudinal study of twins 21 and hypomethylation in the pathogenesis of panic disorder particularly in female patients. [12][13][14] However, there is still much debate about X inactivation in vivo and there may be no reason why X-inactivation of the second allele in females itself is not dependent on G × E interactions. 4,24 Indeed many studies of MAOA G × E report only on males due to compounding affects including female heterozygosity for the uVNTR.…”

“…Samples were processed using the methods described by Murgatroyd et al 16 The immunoprecipitations were performed using the following antibodies: Attempts to use qPCR to measure allele-specific expression over heterozygous VNTRs were problematic perhaps due to preferential amplification of a specific allele in early rounds of PCR and consistent, FIGURE 2 Expression of 2 MAOA isoforms: 1.5% agarose gel of MAOA uVNTR PCR amplification. [12][13][14] Alternatively, the expression of both alleles could be construed as a mosaic effect of random silencing of one allele in any particular cell and thus the population would appear to express both alleles. A, SH-SY5Y cell line cDNA: lanes from left to right: 100 bp ladder marker; basal condition; vehicle control: H 2 O 1 hour; sodium valproate treatment 1 hour; PCR negative control.…”

“…[12][13][14] To address the mechanisms which might underpin allele expression in the female we took advantage of the human neuroblastoma-derived SH-SY5Y cell line which has a female karyotype and is heterozygous for the uVNTR. However, associations of the uVNTR in females are complicated by not knowing the contribution of each allele to MAOA expression and the potential for one allele to exhibit X inactivation.…”