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Conference Paper: Crosstalk between histone modifications and DNA methylation in patients with intellectual disability due to JARID1C mutations

TitleCrosstalk between histone modifications and DNA methylation in patients with intellectual disability due to JARID1C mutations
Authors
KeywordsPsychiatric Genetics
Neurogenetics and Neurodegeneration
KW106 - MENTAL RETARDATION
KW109 - METHYLATION
KW123 - NEUROGENETICS
Issue Date2010
Citation
The 60th Annual Meeting of the American Society of Human Genetics (ASHG 2010), Washington, DC., 2-6 November 2010. How to Cite?
AbstractBACKGROUND: Genes that function in epigenetic regulation play an important role in normal neurodevelopment. However, the molecular mechanisms by which multiple hierarchical epigenetic marks drive normal development are not well understood and the critical genomic targets are largely unknown. Therefore, disorders caused by mutations in genes that apply or remove epigenetic marks at specific genomic targets provide a unique opportunity to study the pathophysiology of epigenetic dysregulation in human disease. The X-linked gene, JARID1C, encodes a H3K4 demethylase. Mutations in this gene cause intellectual disability (ID). We hypothesized that JARID1C mutations would dysregulate DNA methylation at specific genomic targets. METHOD: A genome-wide approach was used to analyze sodium bisulfite modified genomic DNA from white blood cells of patients with known JARID1C mutations (n=13). The Illumina Methylation 27 Microarray with probes for 27,578 CpG sites covering >14,000 genes was used. DNA methylation profiles of patients were compared to sex- and age- matched controls. Differentially methylated CpG sites were identified using the Mann-Whitney test (absolute methylation difference >17% and p-value cut-off <0.05) with correction for multiple testing. RESULTS: Differential methylation analysis identified 17 genes with loss of CpG methylation. For 5 genes demonstrating the most significant loss of methylation in patients, the array findings were validated by pyrosequencing. Bioinformatic analyses showed that the DNA methylation alterations co-localized with the expected types of histone modifications in the target genes. CHIP-qPCR and expression array analyses, using lymphoblastoid cell lines from the same patients, are in progress. CONCLUSION: Our study has identified a specific pattern of DNA methylation alterations in patients with JARID1C mutations. These data demonstrate the functional specificity of these epigenetic regulators and also the cross-talk that occurs between histone modifications and DNA methylation in chromatin-mediated transcriptional regulation.
DescriptionPoster presentation. Program no. 2554/W
Persistent Identifierhttp://hdl.handle.net/10722/129882

 

DC FieldValueLanguage
dc.contributor.authorChung, Ben_US
dc.contributor.authorGrafodatskaya, Den_US
dc.contributor.authorButcher, DTen_US
dc.contributor.authorScherer, SWen_US
dc.contributor.authorAbidi, FEen_US
dc.contributor.authorSchwartz, CEen_US
dc.contributor.authorWeksberg, Ren_US
dc.date.accessioned2010-12-23T08:43:48Z-
dc.date.available2010-12-23T08:43:48Z-
dc.date.issued2010en_US
dc.identifier.citationThe 60th Annual Meeting of the American Society of Human Genetics (ASHG 2010), Washington, DC., 2-6 November 2010.en_US
dc.identifier.urihttp://hdl.handle.net/10722/129882-
dc.descriptionPoster presentation. Program no. 2554/W-
dc.description.abstractBACKGROUND: Genes that function in epigenetic regulation play an important role in normal neurodevelopment. However, the molecular mechanisms by which multiple hierarchical epigenetic marks drive normal development are not well understood and the critical genomic targets are largely unknown. Therefore, disorders caused by mutations in genes that apply or remove epigenetic marks at specific genomic targets provide a unique opportunity to study the pathophysiology of epigenetic dysregulation in human disease. The X-linked gene, JARID1C, encodes a H3K4 demethylase. Mutations in this gene cause intellectual disability (ID). We hypothesized that JARID1C mutations would dysregulate DNA methylation at specific genomic targets. METHOD: A genome-wide approach was used to analyze sodium bisulfite modified genomic DNA from white blood cells of patients with known JARID1C mutations (n=13). The Illumina Methylation 27 Microarray with probes for 27,578 CpG sites covering >14,000 genes was used. DNA methylation profiles of patients were compared to sex- and age- matched controls. Differentially methylated CpG sites were identified using the Mann-Whitney test (absolute methylation difference >17% and p-value cut-off <0.05) with correction for multiple testing. RESULTS: Differential methylation analysis identified 17 genes with loss of CpG methylation. For 5 genes demonstrating the most significant loss of methylation in patients, the array findings were validated by pyrosequencing. Bioinformatic analyses showed that the DNA methylation alterations co-localized with the expected types of histone modifications in the target genes. CHIP-qPCR and expression array analyses, using lymphoblastoid cell lines from the same patients, are in progress. CONCLUSION: Our study has identified a specific pattern of DNA methylation alterations in patients with JARID1C mutations. These data demonstrate the functional specificity of these epigenetic regulators and also the cross-talk that occurs between histone modifications and DNA methylation in chromatin-mediated transcriptional regulation.-
dc.languageengen_US
dc.relation.ispartofAnnual Meeting of the American Society of Human Genetics, ASHG 2010-
dc.subjectPsychiatric Genetics-
dc.subjectNeurogenetics and Neurodegeneration-
dc.subjectKW106 - MENTAL RETARDATION-
dc.subjectKW109 - METHYLATION-
dc.subjectKW123 - NEUROGENETICS-
dc.titleCrosstalk between histone modifications and DNA methylation in patients with intellectual disability due to JARID1C mutationsen_US
dc.typeConference_Paperen_US
dc.identifier.emailChung, B: bhychung@HKUCC-COM.hku.hken_US
dc.identifier.hkuros178639en_US
dc.description.otherThe 60th Annual Meeting of the American Society of Human Genetics (ASHG 2010), Washington, DC., 2-6 November 2010.-

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