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The IGF1 P2 promoter is an epigenetic QTL for circulating IGF1 and human growth.

Ouni M, Gunes Y, Belot MP, Castell AL, Fradin D, Bougnères P - Clin Epigenetics (2015)

Bottom Line: Our observations introduce epigenetics among the individual determinants of child growth and serum IGF1.The P2 promoter of the IGF1 gene is the first epigenetic quantitative trait locus (QTL(epi)) reported in humans.The CG methylation of the P2 promoter takes place among the multifactorial factors explaining the variation in human stature.

View Article: PubMed Central - PubMed

Affiliation: Institut National de la Santé et de la Recherche Médicale U986, Bicêtre Hospital, Paris Sud University, 80 rue du Général Leclerc Le Kremlin-Bicêtre, Paris, 94276 France.

ABSTRACT

Background: Even if genetics play an important role, individual variation in stature remains unexplained at the molecular level. Indeed, genome-wide association study (GWAS) have revealed hundreds of variants that contribute to the variability of height but could explain only a limited part of it, and no single variant accounts for more than 0.3% of height variance. At the interface of genetics and environment, epigenetics contributes to phenotypic diversity. Quantifying the impact of epigenetic variation on quantitative traits, an emerging challenge in humans, has not been attempted for height. Since insulin-like growth factor 1 (IGF1) controls postnatal growth, we tested whether the CG methylation of the two promoters (P1 and P2) of the IGF1 gene is a potential epigenetic contributor to the individual variation in circulating IGF1 and stature in growing children.

Results: Child height was closely correlated with serum IGF1. The methylation of a cluster of six CGs located within the proximal part of the IGF1 P2 promoter showed a strong negative association with serum IGF1 and growth. The highest association was for CG-137 methylation, which contributed 13% to the variance of height and 10% to serum IGF1. CG methylation (studied in children undergoing surgery) was approximately 50% lower in liver and growth plates, indicating that the IGF1 promoters are tissue-differentially methylated regions (t-DMR). CG methylation was inversely correlated with the transcriptional activity of the P2 promoter in mononuclear blood cells and in transfection experiments, suggesting that the observed association of methylation with the studied traits reflects true biological causality.

Conclusions: Our observations introduce epigenetics among the individual determinants of child growth and serum IGF1. The P2 promoter of the IGF1 gene is the first epigenetic quantitative trait locus (QTL(epi)) reported in humans. The CG methylation of the P2 promoter takes place among the multifactorial factors explaining the variation in human stature.

No MeSH data available.


The twoIGF1gene promoters (P1 and P2) are figured in the lower part of the figure (broken arrows show the TSS of each promoter). The upper part of the figure shows the methylation level of each studied CG in the 216 children (mean ± SD). The horizontal black bar encompasses the cluster of six CGs of P2 promoter whose methylation is inversely correlated with height and serum IGF1.
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Fig1: The twoIGF1gene promoters (P1 and P2) are figured in the lower part of the figure (broken arrows show the TSS of each promoter). The upper part of the figure shows the methylation level of each studied CG in the 216 children (mean ± SD). The horizontal black bar encompasses the cluster of six CGs of P2 promoter whose methylation is inversely correlated with height and serum IGF1.

Mentions: The patterns of CG methylation within the two promoters of IGF1 are depicted in Figure 1. Methylation in the proximal part of P2 promoter showed an important individual variability (Figure 1 and Additional file 1: Table S2). Strong intra-promoter correlations (10−8 < P < 10−3) were observed between methylation of the CGs in P2 promoter, while there was no correlation within P1 or between CGs of P1 and P2. The methylation at the P2 and P1 promoters does not seem to be significantly influenced by sex or age (Additional file 1: Table S3).Figure 1


The IGF1 P2 promoter is an epigenetic QTL for circulating IGF1 and human growth.

Ouni M, Gunes Y, Belot MP, Castell AL, Fradin D, Bougnères P - Clin Epigenetics (2015)

The twoIGF1gene promoters (P1 and P2) are figured in the lower part of the figure (broken arrows show the TSS of each promoter). The upper part of the figure shows the methylation level of each studied CG in the 216 children (mean ± SD). The horizontal black bar encompasses the cluster of six CGs of P2 promoter whose methylation is inversely correlated with height and serum IGF1.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4363053&req=5

Fig1: The twoIGF1gene promoters (P1 and P2) are figured in the lower part of the figure (broken arrows show the TSS of each promoter). The upper part of the figure shows the methylation level of each studied CG in the 216 children (mean ± SD). The horizontal black bar encompasses the cluster of six CGs of P2 promoter whose methylation is inversely correlated with height and serum IGF1.
Mentions: The patterns of CG methylation within the two promoters of IGF1 are depicted in Figure 1. Methylation in the proximal part of P2 promoter showed an important individual variability (Figure 1 and Additional file 1: Table S2). Strong intra-promoter correlations (10−8 < P < 10−3) were observed between methylation of the CGs in P2 promoter, while there was no correlation within P1 or between CGs of P1 and P2. The methylation at the P2 and P1 promoters does not seem to be significantly influenced by sex or age (Additional file 1: Table S3).Figure 1

Bottom Line: Our observations introduce epigenetics among the individual determinants of child growth and serum IGF1.The P2 promoter of the IGF1 gene is the first epigenetic quantitative trait locus (QTL(epi)) reported in humans.The CG methylation of the P2 promoter takes place among the multifactorial factors explaining the variation in human stature.

View Article: PubMed Central - PubMed

Affiliation: Institut National de la Santé et de la Recherche Médicale U986, Bicêtre Hospital, Paris Sud University, 80 rue du Général Leclerc Le Kremlin-Bicêtre, Paris, 94276 France.

ABSTRACT

Background: Even if genetics play an important role, individual variation in stature remains unexplained at the molecular level. Indeed, genome-wide association study (GWAS) have revealed hundreds of variants that contribute to the variability of height but could explain only a limited part of it, and no single variant accounts for more than 0.3% of height variance. At the interface of genetics and environment, epigenetics contributes to phenotypic diversity. Quantifying the impact of epigenetic variation on quantitative traits, an emerging challenge in humans, has not been attempted for height. Since insulin-like growth factor 1 (IGF1) controls postnatal growth, we tested whether the CG methylation of the two promoters (P1 and P2) of the IGF1 gene is a potential epigenetic contributor to the individual variation in circulating IGF1 and stature in growing children.

Results: Child height was closely correlated with serum IGF1. The methylation of a cluster of six CGs located within the proximal part of the IGF1 P2 promoter showed a strong negative association with serum IGF1 and growth. The highest association was for CG-137 methylation, which contributed 13% to the variance of height and 10% to serum IGF1. CG methylation (studied in children undergoing surgery) was approximately 50% lower in liver and growth plates, indicating that the IGF1 promoters are tissue-differentially methylated regions (t-DMR). CG methylation was inversely correlated with the transcriptional activity of the P2 promoter in mononuclear blood cells and in transfection experiments, suggesting that the observed association of methylation with the studied traits reflects true biological causality.

Conclusions: Our observations introduce epigenetics among the individual determinants of child growth and serum IGF1. The P2 promoter of the IGF1 gene is the first epigenetic quantitative trait locus (QTL(epi)) reported in humans. The CG methylation of the P2 promoter takes place among the multifactorial factors explaining the variation in human stature.

No MeSH data available.