Spread of X-chromosome inactivation into chromosome 15 is associated with Prader–Willi syndrome phenotype in a boy with a t(X;15)(p21.1;q11.2) translocation

Sakazume, Satoru; Ohashi, Hirofumi; Sasaki, Yuki; Harada, Naoki; Nakanishi, K.; Sato, Hidenori; Emi, Mitsuru; Endoh, Kazushi; Sohma, Ryoichi; Kido, Yasutoshi; Nagai, Toshiro; Kubota, Takeo

doi:10.1007/s00439-011-1051-4

Cited by 15 publications

(20 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Recently, it has become possible to investigate genome-wide DNA methylation patterns using a method based on a CpG island microarray with sodium-bisulfite treated DNA [48] or with methylated DNA immunoprecipitation (MeDIP) [49]. In this study, we used an assay based on a CpG island microarray with sodium-bisulfite treated DNA.…”

Section: Discussionmentioning

confidence: 99%

Comparison of Genomic and Epigenomic Expression in Monozygotic Twins Discordant for Rett Syndrome

et al. 2013

Self Cite

View full text Add to dashboard Cite

Monozygotic (identical) twins have been widely used in genetic studies to determine the relative contributions of heredity and the environment in human diseases. Discordance in disease manifestation between affected monozygotic twins has been attributed to either environmental factors or different patterns of X chromosome inactivation (XCI). However, recent studies have identified genetic and epigenetic differences between monozygotic twins, thereby challenging the accepted experimental model for distinguishing the effects of nature and nurture. Here, we report the genomic and epigenomic sequences in skin fibroblasts of a discordant monozygotic twin pair with Rett syndrome, an X-linked neurodevelopmental disorder characterized by autistic features, epileptic seizures, gait ataxia and stereotypical hand movements. The twins shared the same de novo mutation in exon 4 of the MECP2 gene (G269AfsX288), which was paternal in origin and occurred during spermatogenesis. The XCI patterns in the twins did not differ in lymphocytes, skin fibroblasts, and hair cells (which originate from ectoderm as does neuronal tissue). No reproducible differences were detected between the twins in single nucleotide polymorphisms (SNPs), insertion-deletion polymorphisms (indels), or copy number variations. Differences in DNA methylation between the twins were detected in fibroblasts in the upstream regions of genes involved in brain function and skeletal tissues such as Mohawk Homeobox (MKX), Brain-type Creatine Kinase (CKB), and FYN Tyrosine Kinase Protooncogene (FYN). The level of methylation in these upstream regions was inversely correlated with the level of gene expression. Thus, differences in DNA methylation patterns likely underlie the discordance in Rett phenotypes between the twins.

show abstract

Section: Discussionmentioning

confidence: 99%

Comparison of Genomic and Epigenomic Expression in Monozygotic Twins Discordant for Rett Syndrome

et al. 2013

Self Cite

View full text Add to dashboard Cite

show abstract

“…Sharp et al also found that genes could still be silenced in the autosome even though there is no spreading of late replication [Sharp et al, ], suggesting that late‐replication study is not good enough to determine the spreading of X inactivation. Recently, Sakazume et al studied the DNA methylation changes on a case with X;15 translocation using DNA immunoprecipation with microarray and observed that there was gain in DNA methylation along the translocated autosome [Sakazume et al, ]. In this report, we also investigated into the spreading of X inactivation by studying DNA methylation in a baby with an unbalanced X;15 translocation using a whole genome DNA methylation microarray.…”

Section: Introductionmentioning

confidence: 89%

Spread of X inactivation on chromosome 15 is associated with a more severe phenotype in a girl with an unbalanced t(X; 15) translocation

Yeung

Chee

Luk

et al. 2014

American J of Med Genetics Pt A

View full text Add to dashboard Cite

We report on a baby girl with multiple congenital abnormalities, including cleft palate, intrauterine growth restriction, and double outlet right ventricle (DORV) with ventricular septal defect. She had an unbalanced chromosome translocation t (X;15) resulting in monosomy 15pter → p10 and trisomy Xq13.1 → q28. All three copies of Xq encompass the XIST gene. It is known that X chromosome inactivation could spread to the autosome part of an unbalanced translocation involving chromosome X and an autosome. To confirm the spread of X chromosome inactivation on chromosome 15, we evaluate the methylation change by the HumanMethylation450 BeadChip, a whole genome DNA methylation micorarray that includes 15,259 probes spanning 717 genes on chromosome 15. Results showed there was gain in DNA methylation of more than 20% in 586 CpG sites spanning the long arm of chromosome 15. We further examined the hypermethylated CpG sites located in CpG-island promoter, because genes subjected to X chromosome inactivation will have an increase in DNA methylation level in this region. A total of 75 sites representing 24 genes were hypermethylated. Nearly all of these probes are located in region proximal to the breakpoint, from 15q11.2 to 15q21.3 (35Mb) suggesting that X inactivation was spread to the proximal region of 15q. Gain of DNA methylation, especially in the CpG-island promoter, can result in functional inactivation of genes, and therefore could potentially worsen the phenotype of our patient.

show abstract

“…Methylation spread across biparental origins was manifested in patients with Prader–Willi syndrome-like features displaying hypo-pigmentation symptoms. The maternal X-chromosome was not only inactivated by methylation, but its aberrant methylation was also furthered into the paternal chromosome 15 leading to the abnormal hypermethylation and silencing of downstream targets SNRPN and OCA2 [37]. Similarly, selective “seed” methylation occurring at the large tandem repeats becomes important for the subsequent extension of the critically methylated region that resulted in stable silencing of a locus namely FWA and thus prevented late flowering in Arabidopsis thaliana [38].…”

Section: Discussionmentioning

confidence: 99%

Epigenetic Repression of RARRES1 Is Mediated by Methylation of a Proximal Promoter and a Loss of CTCF Binding

Peng

Shen

et al. 2012

PLoS ONE

View full text Add to dashboard Cite

BackgroundThe cis-acting promoter element responsible for epigenetic silencing of retinoic acid receptor responder 1 (RARRES1) by methylation is unclear. Likewise, how aberrant methylation interplays effectors and thus affects breast neoplastic features remains largely unknown.Methodology/Principal FindingsWe first compared methylation occurring at the sequences (−664∼+420) flanking the RARRES1 promoter in primary breast carcinomas to that in adjacent benign tissues. Surprisingly, tumor cores displayed significantly elevated methylation occurring solely at the upstream region (−664∼−86), while the downstream element (−85∼+420) proximal to the transcriptional start site (+1) remained largely unchanged. Yet, hypermethylation at the former did not result in appreciable silencing effect. In contrast, the proximal sequence displayed full promoter activity and methylation of which remarkably silenced RARRES1 transcription. This phenomenon was recapitulated in breast cancer cell lines, in which methylation at the proximal region strikingly coincided with downregulation. We also discovered that CTCF occupancy was enriched at the unmethylayed promoter bound with transcription-active histone markings. Furthermore, knocking-down CTCF expression hampered RARRES1 expression, suggesting CTCF positively regulated RARRES1 transcription presumably by binding to unmethylated promoter poised at transcription-ready state. Moreover, RARRES1 restoration not only impeded cell invasion but also promoted death induced by chemotherapeutic agents, denoting its tumor suppressive effect. Its role of attenuating invasion agreed with data generated from clinical specimens revealing that RARRES1 was generally downregulated in metastatic lymph nodes compared to the tumor cores.Conclusion/SignificanceThis report delineated silencing of RARRES1 by hypermethylation is occurring at a proximal promoter element and is associated with a loss of binding to CTCF, an activator for RARRES1 expression. We also revealed the tumor suppressive roles exerted by RARRES1 in part by promoting breast epithelial cell death and by impeding cell invasion that is an important property for metastatic spread.

show abstract

Spread of X-chromosome inactivation into chromosome 15 is associated with Prader–Willi syndrome phenotype in a boy with a t(X;15)(p21.1;q11.2) translocation

Cited by 15 publications

References 34 publications

Comparison of Genomic and Epigenomic Expression in Monozygotic Twins Discordant for Rett Syndrome

Comparison of Genomic and Epigenomic Expression in Monozygotic Twins Discordant for Rett Syndrome

Spread of X inactivation on chromosome 15 is associated with a more severe phenotype in a girl with an unbalanced t(X; 15) translocation

Epigenetic Repression of RARRES1 Is Mediated by Methylation of a Proximal Promoter and a Loss of CTCF Binding

Contact Info

Product

Resources

About