Multilocus loss of DNA methylation in individuals with mutations in the histone H3 Lysine 4 Demethylase KDM5C

BMC Medical Genomics

Rosanna Weksberg⁷  Charles E Schwartz³  Stephen W Scherer⁵  Shoshana Wodak⁸  Jill Hamilton⁷  Carolyn A Bondy¹  James Stavropoulos²  Cindy Skinner³  Fatima E Abidi³  Rageen Rajendram⁶  Chunhua Zhao⁶  Youliang Lou⁶  Yi-An Chen⁶  Sana Choufani⁴  Sarah J Goodman⁴  Andrei L Turinsky⁸  Darci T Butcher⁶  Barian HY Chung⁴  Daria Grafodatskaya⁶ 

[1] Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA;Department of Pediatric Laboratory Medicine, Hospital for Sick Children, Toronto, ON, Canada;J.C. Self Research Institute, Greenwood Genetic Center, Greenwood, SC, USA;Centre of Reproduction, Growth & Development, Department of Pediatrics & Adolescent Medicine, The University of Hong Kong, Hong Kong, Hong Kong;The Centre for Applied Genomics, Hospital for Sick Children, Toronto, ON, Canada;Genetics and Genome Biology Program, Hospital for Sick Children, Toronto, ON, Canada;Department of Pediatrics, University of Toronto, Toronto, ON, Canada;Program in Molecular Structure and Function, Hospital for Sick Children, Toronto, ON, Canada

关键词: Intellectual disability;    H3K4 methylation;    DNA methylation;    KDM5C;   

Others  :  1121208
DOI  :  10.1186/1755-8794-6-1

 received in 2012-10-02, accepted in 2013-01-14,  发布年份 2013

【 摘 要 】

Background

A number of neurodevelopmental syndromes are caused by mutations in genes encoding proteins that normally function in epigenetic regulation. Identification of epigenetic alterations occurring in these disorders could shed light on molecular pathways relevant to neurodevelopment.

Results

Using a genome-wide approach, we identified genes with significant loss of DNA methylation in blood of males with intellectual disability and mutations in the X-linked KDM5C gene, encoding a histone H3 lysine 4 demethylase, in comparison to age/sex matched controls. Loss of DNA methylation in such individuals is consistent with known interactions between DNA methylation and H3 lysine 4 methylation. Further, loss of DNA methylation at the promoters of the three top candidate genes FBXL5, SCMH1, CACYBP was not observed in more than 900 population controls. We also found that DNA methylation at these three genes in blood correlated with dosage of KDM5C and its Y-linked homologue KDM5D. In addition, parallel sex-specific DNA methylation profiles in brain samples from control males and females were observed at FBXL5 and CACYBP.

Conclusions

We have, for the first time, identified epigenetic alterations in patient samples carrying a mutation in a gene involved in the regulation of histone modifications. These data support the concept that DNA methylation and H3 lysine 4 methylation are functionally interdependent. The data provide new insights into the molecular pathogenesis of intellectual disability. Further, our data suggest that some DNA methylation marks identified in blood can serve as biomarkers of epigenetic status in the brain.

【 授权许可】

   
2013 Grafodatskaya et al.; licensee BioMed Central Ltd.

【 图 表 】

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