Abstract
Methylation changes observed in Prader-Willi syndrome (PWS) may impact global methylation as well as regional methylation status of imprinted genes on chromosome 15 (in cis) or other imprinted obesity-related genes on other chromosomes (in trans) leading to differential effects on gene expression impacting obesity phenotype unique to (PWS). Characterize the global methylation profiles and methylation status for select imprinted genes associated with obesity phenotype in a well-characterized imprinted, obesity-related syndrome (PWS) relative to a cohort of obese and non-obese individuals. Global methylation was assayed using two methodologies: 1) enriched LINE-1 repeat sequences by EpigenDx and 2) ELISA-based immunoassay method sensitive to genomic 5-methylcytosine by Epigentek. Target gene methylation patterns at selected candidate obesity gene loci were determined using methylation-specific PCR. Study participants were recruited as part of an ongoing research program on obesity-related genomics and Prader-Willi syndrome. Individuals with non-syndromic obesity (N=26), leanness (N=26) and PWS (N=39). A detailed characterization of the imprinting status of select target genes within the critical PWS 15q11-q13 genomic region showed enhanced cis but not trans methylation of imprinted genes. No significant differences in global methylation were found between non-syndromic obese, PWS or non-obese controls. None. Percentage methylation and the methylation index. The methylation abnormality in PWS due to errors of genomic imprinting effects both upstream and downstream effectors in the 15q11-q13 region showing enhanced cis but not trans methylation of imprinted genes. Obesity in our subject cohorts did not appear to impact global methylation levels using the described methodology.
Highlights
Obesity characterized by a body mass index (BMI) over 30 is a pervasive global health problem that is increasing in frequency and severity [1]
No significant differences in global methylation were found between nonsyndromic obese, Prader-Willi syndrome (PWS) or non-obese controls
Methylation status was assessed via LINE-1 elements within the genome at selected sites by EpigenDx and with the use of methylation detection by 5-methylcytosine based immunoassay methods of the CpG islands undertaken by Epigentek
Summary
Obesity characterized by a body mass index (BMI) over 30 is a pervasive global health problem that is increasing in frequency and severity [1]. Obesity is one of the cardinal features in Prader-Willi syndrome (PWS), a neurodevelopmental disorder due to errors in genomic imprinting usually as a result of a paternally derived deletion of the chromosome 15q11-q13 region [6,7,8,9]. Genomic imprinting is an important gene regulatory process emerging as a contributor to obesity and several disease-associated disorders. Most imprinted genes have CpG-rich differentially methylated regions (DMR) typically arranged in clusters or domains on different chromosomes and under control of an imprinting center. Methylation status at these centers and nearby elements regulates gene expression often important for cellular growth, development and viability [10]. Parental origin impacts methylation status with the paternal or maternal genomes exerting counteracting influences on gene expression and often involved with embryonic development and growth [11]
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