Functional Analysis of a Potassium-Chloride Co-Transporter 3 (SLC12A6) Promoter Polymorphism Leading to an Additional DNA Methylation Site

Moser, Dirk; Ekawardhani, Savira; Kumsta, Robert; Pálmason, Haukur; Bock, Christoph; Athanassiadou, Zoi; Lesch, Klaus‐Peter; Meyer, Jobst

doi:10.1038/npp.2008.77

Cited by 40 publications

(27 citation statements)

References 68 publications

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“…Owing to their high mutagenesis rate, the SNPs residing in CpG dinucleotides have been the focus of much attention in human genetics [11]. Our results further highlight the unique position of this large subgroup of SNPs in genetic-epigenetic interactions.…”

Section: Discussionsupporting

confidence: 56%

Extensive sequence-influenced DNA methylation polymorphism in the human genome

Hellman¹,

Chess

2010

Epigenetics & Chromatin

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BackgroundEpigenetic polymorphisms are a potential source of human diversity, but their frequency and relationship to genetic polymorphisms are unclear. DNA methylation, an epigenetic mark that is a covalent modification of the DNA itself, plays an important role in the regulation of gene expression. Most studies of DNA methylation in mammalian cells have focused on CpG methylation present in CpG islands (areas of concentrated CpGs often found near promoters), but there are also interesting patterns of CpG methylation found outside of CpG islands.ResultsWe compared DNA methylation patterns on both alleles between many pairs (and larger groups) of related and unrelated individuals. Direct observation and simulation experiments revealed that around 10% of common single nucleotide polymorphisms (SNPs) reside in regions with differences in the propensity for local DNA methylation between the two alleles. We further showed that for the most common form of SNP, a polymorphism at a CpG dinucleotide, the presence of the CpG at the SNP positively affected local DNA methylation in cis.ConclusionsTaken together with the known effect of DNA methylation on mutation rate, our results suggest an interesting interdependence between genetics and epigenetics underlying diversity in the human genome.

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Section: Discussionsupporting

confidence: 56%

Extensive sequence-influenced DNA methylation polymorphism in the human genome

Hellman¹,

Chess

2010

Epigenetics & Chromatin

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“…The C/G polymorphism in SNP8 is associated with a sequence change from CC to CG [5'-CCACC(C/G)CCATC-3'], which can add a CpG site for methylation. Changes in nucleotide sequences related to polymorphisms creating additional CpG sites can affect the DNA methylation and transcriptional activity (Moser et al, 2009). These findings suggest a possible function of BD-associated intronic SNPs of EGR2 regulating gene expression via alterations in DNA methylation, which requires further examination.…”

Section: Discussionmentioning

confidence: 99%

Genetic association of theEGR2gene with bipolar disorder in Korea

et al. 2012

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The early growth response gene 2 (EGR2) is located at chromosome 10q21, one of the susceptibility loci in bipolar disorder (BD). EGR2 is involved in cognitive function, myelination, and signal transduction related to neuregulin-ErbB receptor, Bcl-2 family proteins, and brain-derived neurotrophic factor. This study investigated the genetic association of the EGR2 gene with BD and schizophrenia (SPR) in Korea. In 946 subjects (350 healthy controls, 352 patients with BD, and 244 with SPR), nine single nucleotide polymorphisms (SNPs) in the EGR2 gene region were genotyped. Five SNPs showed nominally significant allelic associations with BD (rs2295814, rs61865882, rs10995315, rs2297488, and rs2297489), and the positive associations of all except rs2297488 remained significant after multiple testing correction. Linkage disequilibrium structure analysis revealed two haplotype blocks. Among the common identified haplotypes (frequency > 5%), 'T-G-A-C-T (block 1)' and 'A-A-G-C (block 2)' haplotypes were over-represented, while 'C-G-G-T-T (block 1)' haplotype was under-represented in BD. In contrast, no significant associations were found with SPR. Although an extended analysis with a larger sample size or independent replication is required, these findings suggest a genetic association of EGR2 with BD. Combined with a plausible biological function of EGR2, the EGR2 gene is a possible susceptibility gene in BD.

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“…Most of the CpG-SNPs functionally characterized are located in the 59-untranslated region or promoter regions, [48][49][50][51] while PEAR1 rs12041331 is located in a noncoding intronic region, yet with specific enhancer features. Independently of methylation at day 14.…”

Section: Discussionmentioning

confidence: 99%

Allele-specific DNA methylation reinforces PEAR1 enhancer activity

Izzi

Pistoni

Cludts

et al. 2016

Blood

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Key Points• Rs12041331 is the first functional CpG-SNP related to platelet function whose regulatory mechanism depends on DNA methylation. • Rs12041331 marks allelespecific methylation at the CpG island encompassing the first untranslated exon during megakaryopoiesis.Genetic variation in the PEAR1 locus is linked to platelet reactivity and cardiovascular disease. The major G allele of rs12041331, an intronic cytosine guanine dinucleotide-single-nucleotide polymorphism (CpG-SNP), is associated with higher PEAR1 expression in platelets and endothelial cells than the minor A allele. The molecular mechanism underlying this difference remains elusive. We have characterized the histone modification profiles of the intronic region surrounding rs12041331 and identified H3K4Me1 enhancer-specific enrichment for the region that covers the CpG-SNP. Interestingly, methylation studies revealed that the CpG site is fully methylated in leukocytes of GG carriers. Nuclear protein extracts from megakaryocytes, endothelial cells, vs control HEK-293 cells show a 3-fold higher affinity for the methylated G allele compared with nonmethylated G or A alleles in a gel electrophoretic mobility shift assay. To understand the positive relationship between methylation and gene expression, we studied DNA methylation at 4 different loci of PEAR1 during in vitro megakaryopoiesis. During differentiation, the CpG-SNP remained fully methylated, while we observed rapid methylation increases at the CpG-island overlapping the first 59-untranslated region exon, paralleling the increased PEAR1 expression. In the same region, A-allele carriers of rs12041331 showed significantly lower DNA methylation at CGI1 compared with GG homozygote. This CpG-island contains binding sites for the methylation-sensitive transcription factor CTCF, whose binding is known to play a role in enhancer activation and/or repression. In conclusion, we report the molecular characterization of the first platelet function-related CpG-SNP, a genetic predisposition that reinforces PEAR1 enhancer activity through allele-specific DNA methylation. (Blood. 2016;128(7):1003-1012

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Functional Analysis of a Potassium-Chloride Co-Transporter 3 (SLC12A6) Promoter Polymorphism Leading to an Additional DNA Methylation Site

Cited by 40 publications

References 68 publications

Extensive sequence-influenced DNA methylation polymorphism in the human genome

Extensive sequence-influenced DNA methylation polymorphism in the human genome

Genetic association of theEGR2gene with bipolar disorder in Korea

Allele-specific DNA methylation reinforces PEAR1 enhancer activity

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