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Patterns of DNA Methylation across the Leptin Core Promoter in Four Diverse Asian and North American Populations
Citation
Mosher, MJ and Melton, PE and Stapleton, P and Schanfield, MS and Crawford, MH, Patterns of DNA Methylation across the Leptin Core Promoter in Four Diverse Asian and North American Populations, Human Biology, 88, (2) pp. 121-135. ISSN 0018-7143 (2016) [Refereed Article]
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Copyright Statement
© 2017 Wayne State University Press
DOI: doi:10.13110/humanbiology.88.2.0121
Abstract
DNA methylation is the most widely studied of epigenetic mechanisms, with environmental effects
recorded through patterned attachments of methyl groups along the DNA that are capable of modifying gene expression without altering the DNA sequencing. The degree to which these patterns of DNA
methylation are heritable, the expected range of normality across populations, and the phenotypic
relevance of pattern variation remain unclear. Genes regulating metabolic pathways appear to be
vulnerable to ongoing nutritional programming over the life course, as dietary nutrients are significant
environmental determinants of DNA methylation, supplying both the methyl groups and energy to
generate the methylation process.
Here we examine methylation patterns along a region of the metabolic gene leptin (LEP). LEP’s
putative functions include regulation of energy homeostasis, with its signals affecting energy intake
and expenditure, adipogenesis and energy storage, lipid and glucose metabolism, bone metabolism,
and reproductive endocrine function. A pattern of differential methylation across CpG sites of the LEP
core promoter has been previously identified; however, any consistency of pattern or its phenotypic
significance is not fully elucidated among populations. Using DNA extracted from unfractionated white
blood cells of peripheral blood samples, our pilot study, divided into two parts, examined the significance
of variation in DNA methylation patterns along the leptin core promoter in four populations (phase 1)
and used biomarkers reflecting leptin’s functional process in two of those populations, western Buryat
of Siberia and the Mennonite of central Kansas, to investigate the relevance of the ethnic variation
identified in the DNA methylation (phase 2).
LEP’s core promoter region contains both the binding site for C/EBPα (CCAAT/enhancer binding
protein alpha), which tempers the final step in adipocyte maturity and capacity to synthesize leptin, and
the TATA motif controlling leptin synthesis. Previous studies report that increased methylation in this
region is correlated to decreased gene expression, suggesting tissue-specific methylation variation at
this region (Melzner et al. 2002). We hypothesized that evidence of nutritional epigenetic programming
would be identified through variation in patterns of DNA methylation and that functional relevance of
that variation among populations would be identified through biomarkers that reflect leptin’s metabolic
signals: serum leptin levels, lipoproteins of the lipid transport system, and anthropometric measures.
In phase 1, our combined analyses of 313 individuals documented a distinct and consistent overall
pattern of differential DNA methylation across seven CpG sites of LEP core promoter in all ethnicities
and both sexes. This pattern replicates those identified in previous studies, suggesting a conserved core
promoter region across populations. Phase 2 analyses of two of the four populations (n = 239), correlating methylation at the C/EBPα transcription binding site (TBS) with metabolic and anthropometric
biomarkers reflecting LEP roles, showed that stature, which reflects bone growth and remodeling, was
significantly and inversely correlated with the percentage of DNA methylation at this site in both sexes.
We suggest that variation in DNA methylation along the LEP core promoter plays a substantial role in
energy signals affecting both adipogenesis and bone metabolism.
Item Details
Item Type: | Refereed Article |
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Keywords: | DNA methylation; energy; leptin; stature. |
Research Division: | Biological Sciences |
Research Group: | Genetics |
Research Field: | Anthropological genetics |
Objective Division: | Expanding Knowledge |
Objective Group: | Expanding knowledge |
Objective Field: | Expanding knowledge in the biological sciences |
UTAS Author: | Melton, PE (Dr Phillip Melton) |
ID Code: | 141430 |
Year Published: | 2016 |
Web of Science® Times Cited: | 8 |
Deposited By: | Menzies Institute for Medical Research |
Deposited On: | 2020-10-20 |
Last Modified: | 2021-07-29 |
Downloads: | 4 View Download Statistics |
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