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Recognition of CpG island chromatin by KDM2A requires direct and specific interaction with linker DNA.

ABSTRACT: Up to 70% of human genes are associated with regions of nonmethylated DNA called CpG islands (S. Saxonov, P. Berg, and D. L. Brutlag, Proc. Natl. Acad. Sci. U. S. A. 103:1412-1417, 2006). Usually associated with the 5' end of genes, CpG islands are thought to impact gene expression. We previously demonstrated that the histone demethylase KDM2A is specifically recruited to CpG islands to define a unique chromatin architecture and highlight gene regulatory regions in large and complex mammalian genomes. This targeting relies on a zinc finger CXXC DNA binding domain (ZF-CXXC), but how this demethylase interfaces with CpG island chromatin in vivo remains unknown. Here we demonstrate, using defined chromatin templates in vitro and chromatin profiling in vivo, that nucleosomes are a major barrier to KDM2A binding and that CpG islands are directly interpreted by the ZF-CXXC domain through specific interaction with linker DNA. Furthermore, KDM2A appears to be constrained to CpG islands not only by their nonmethylated state but also by a combination of methylated DNA and nucleosome occlusion elsewhere in the genome. Our observations suggest that both DNA sequence and chromatin structure are defining factors in interpreting CpG island chromatin and translation of the CpG signal. More generally, these features of CpG island recognition suggest that chromatin structure and accessibility play a major role in defining how transcription factors recognize DNA and regulatory elements genome-wide.

SUBMITTER: Zhou JC

PROVIDER: S-EPMC3255781 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature

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Recognition of CpG island chromatin by KDM2A requires direct and specific interaction with linker DNA.

Zhou Jin C JC Blackledge Neil P NP Farcas Anca M AM Klose Robert J RJ

Molecular and cellular biology 20111114 2

Up to 70% of human genes are associated with regions of nonmethylated DNA called CpG islands (S. Saxonov, P. Berg, and D. L. Brutlag, Proc. Natl. Acad. Sci. U. S. A. 103:1412-1417, 2006). Usually associated with the 5' end of genes, CpG islands are thought to impact gene expression. We previously demonstrated that the histone demethylase KDM2A is specifically recruited to CpG islands to define a unique chromatin architecture and highlight gene regulatory regions in large and complex mammalian ge ...[more]

PMID: 22083960

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Project description:Background & aimsSubgroups of colorectal carcinomas (CRCs) characterized by DNA methylation anomalies are termed CpG island methylator phenotype (CIMP)1, CIMP2, or CIMP-negative. The pathogenesis of CIMP1 colorectal carcinomas, and their effects on patients' prognoses and responses to treatment, differ from those of other CRCs. We sought to identify genetic somatic alterations associated with CIMP1 CRCs.MethodsWe examined genomic DNA samples from 100 primary CRCs, 10 adenomas, and adjacent normal-appearing mucosae from patients undergoing surgery or colonoscopy at 3 tertiary medical centers. We performed exome sequencing of 16 colorectal tumors and their adjacent normal tissues. Extensive comparison with known somatic alterations in CRCs allowed segregation of CIMP1-exclusive alterations. The prevalence of mutations in selected genes was determined from an independent cohort.ResultsWe found that genes that regulate chromatin were mutated in CIMP1 CRCs; the highest rates of mutation were observed in CHD7 and CHD8, which encode members of the chromodomain helicase/adenosine triphosphate-dependent chromatin remodeling family. Somatic mutations in these 2 genes were detected in 5 of 9 CIMP1 CRCs. A prevalence screen showed that nonsilencing mutations in CHD7 and CHD8 occurred significantly more frequently in CIMP1 tumors (18 of 42 [43%]) than in CIMP2 (3 of 34 [9%]; P < .01) or CIMP-negative tumors (2 of 34 [6%]; P < .001). CIMP1 markers had increased binding by CHD7, compared with all genes. Genes altered in patients with CHARGE syndrome (congenital malformations involving the central nervous system, eye, ear, nose, and mediastinal organs) who had CHD7 mutations were also altered in CRCs with mutations in CHD7.ConclusionsAberrations in chromatin remodeling could contribute to the development of CIMP1 CRCs. A better understanding of the biological determinants of CRCs can be achieved when these tumors are categorized according to their epigenetic status.

Dataset Information

Recognition of CpG island chromatin by KDM2A requires direct and specific interaction with linker DNA.

Publications

Recognition of CpG island chromatin by KDM2A requires direct and specific interaction with linker DNA.

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