Abstract
BackgroundMelanin-concentrating hormone receptor 1 (MCHR1) plays a significant role in regulation of energy balance, food intake, physical activity and body weight in humans and rodents. Several association studies for human obesity showed contrary results concerning the SNPs rs133072 (G/A) and rs133073 (T/C), which localize to the first exon of MCHR1. The variations constitute two main haplotypes (GT, AC). Both SNPs affect CpG dinucleotides, whereby each haplotype contains a potential methylation site at one of the two SNP positions. In addition, 15 CpGs in close vicinity of these SNPs constitute a weak CpG island. Here, we studied whether DNA methylation in this sequence context may contribute to population- and age-specific effects of MCHR1 alleles in obesity.Principal FindingsWe analyzed DNA methylation of a 315 bp region of MCHR1 encompassing rs133072 and rs133073 and the CpG island in blood samples of 49 individuals by bisulfite sequencing. The AC haplotype shows a significantly higher methylation level than the GT haplotype. This allele-specific methylation is age-dependent. In young individuals (20–30 years) the difference in DNA methylation between haplotypes is significant; whereas in individuals older than 60 years it is not detectable. Interestingly, the GT allele shows a decrease in methylation status with increasing BMI, whereas the methylation of the AC allele is not associated with this phenotype. Heterozygous lymphoblastoid cell lines show the same pattern of allele-specific DNA methylation. The cell line, which exhibits the highest difference in methylation levels between both haplotypes, also shows allele-specific transcription of MCHR1, which can be abolished by treatment with the DNA methylase inhibitor 5-aza-2′-deoxycytidine.ConclusionsWe show that DNA methylation at MCHR1 is allele-specific, age-dependent, BMI-associated and affects transcription. Conceivably, this epigenetic regulation contributes to the age- and/or population specific effects reported for MCHR1 in several human obesity studies.
Highlights
DNA methylation is an essential epigenetic modification of the genome, and is involved in many cellular processes like transcription, X chromosome inactivation, genomic imprinting and chromosome stability [1,2]
We show that DNA methylation at Melanin-concentrating hormone receptor 1 (MCHR1) is allele-specific, age-dependent, BMI-associated and affects transcription
This epigenetic regulation contributes to the age- and/or population specific effects reported for MCHR1 in several human obesity studies
Summary
DNA methylation is an essential epigenetic modification of the genome, and is involved in many cellular processes like transcription, X chromosome inactivation, genomic imprinting and chromosome stability [1,2]. Some genomic regions show less depletion of CpGs. some genomic regions show less depletion of CpGs Such CpG islands frequently overlap with the transcriptional start sites (TSS) of genes [1,7,8]. DNA methylation around the TSS can repress gene expression in two ways, either directly by inhibition of binding of transcription factors or indirectly by recruiting methyl-CpG-binding proteins and associated repressive chromatin remodelling activities [1,2]. Several association studies for human obesity showed contrary results concerning the SNPs rs133072 (G/A) and rs133073 (T/C), which localize to the first exon of MCHR1. The variations constitute two main haplotypes (GT, AC) Both SNPs affect CpG dinucleotides, whereby each haplotype contains a potential methylation site at one of the two SNP positions. We studied whether DNA methylation in this sequence context may contribute to population- and age-specific effects of MCHR1 alleles in obesity
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