Differences in fat and muscle mass associated with a functional human polymorphism in a post‐transcriptional BMP2 gene regulatory element

Abstract

A classic morphogen, bone morphogenetic protein 2 (BMP2) regulates the differentiation of pluripotent mesenchymal cells. High BMP2 levels promote osteogenesis or chondrogenesis and low levels promote adipogenesis. BMP2 inhibits myogenesis. Thus, BMP2 synthesis is tightly controlled. Several hundred nucleotides within the 3′ untranslated regions of BMP2 genes are conserved from mammals to fishes indicating that the region is under stringent selective pressure. Our analyses indicate that this region controls BMP2 synthesis by post-transcriptional mechanisms. A common A to C single nucleotide polymorphism (SNP) in the BMP2 gene (rs15705, +A1123C) disrupts a putative post-transcriptional regulatory motif within the human ultra-conserved sequence. In vitro studies indicate that RNAs bearing the A or C alleles have different protein binding characteristics in extracts from mesenchymal cells. Reporter genes with the C allele of the ultra-conserved sequence were differentially expressed in mesenchymal cells. Finally, we analyzed MRI data from the upper arm of 517 healthy individuals aged 18–41 years. Individuals with the C/C genotype were associated with lower baseline subcutaneous fat volumes (P = 0.0030) and an increased gain in skeletal muscle volume (P = 0.0060) following resistance training in a cohort of young males. The rs15705 SNP explained 2–4% of inter-individual variability in the measured parameters. The rs15705 variant is one of the first genetic markers that maybe exploited to facilitate early diagnosis, treatment, and/or prevention of diseases associated with poor fitness. Furthermore, understanding the mechanisms by which regulatory polymorphisms influence BMP2 synthesis will reveal novel pharmaceutical targets for these disabling conditions.

Heterogeneity in resistance training-induced muscle strength and mass responses in men and women of different ages

“…In previous studies with healthy human subjects, e.g., several genetic variations (Riechman et al 2004;Devaney et al 2009;Walsh et al 2012;Van Deveire et al 2012), differences in skeletal muscle gene Raue et al 2012;Phillips et al 2013) and microRNA expression (Davidsen et al 2011), phosphorylation status of signaling proteins (Mayhew et al 2011;Mitchell et al 2013), androgen receptor concentrations (Ahtiainen et al 2011;Mitchell et al 2013), and satellite cell count (Petrella et al 2008) have been suggested to segregate high and low responders to RTinduced muscle hypertrophy. The physiological aspects of individual variation in phenotype responses to RT are apparently very complex phenomena and more studies specifically focused on high and low responders are required to reveal unambiguously the mechanisms of individual differences in RT-induced adaptations.…”

Systematic Analysis of AU-Rich Element Expression in Cancer Reveals Common Functional Clusters Regulated by Key RNA-Binding Proteins

“…A growing body of evidence has linked aberrantly elevated and prolonged expression of ARE-encoding mRNAs to cancer, including those participating in angiogenesis, chemotaxis, and invasion. Examples of such genes include EGF, estrogen receptor (ER), COX-2, VEGF, matrix metalloproteinase (MMP) 1, the chemokine receptor CXCR4, and urokinase-type plasminogen activator (uPA) and its receptor (4)(5)(6)(7)(8)(9). The ARE-mRNAs are regulated by trans-acting RNA-binding proteins notably tristetraprolin (TTP/ZFP36) and human antigen R (HuR/ELAVL1).…”

Repressive BMP2 gene regulatory elements near the BMP2 promoter

“…Repressors can block every intracellular signaling transduction step [32; 33]. Negative post-transcriptional regulatory mechanisms also may influence BMP2 expression [34; 35]. A growing body of evidence indicates that relief of repression at multiple regulatory levels is an important means of controlling BMP2 gene expression.…”