Early nurture epigenetically tunes the oxytocin receptor.

Mammalian sociality is regulated in part by the neuropeptide oxytocin. In prairie voles, subtle variation in early life experience changes oxytocin receptor-mediated social behaviors. We report that low levels of early care in voles leads to de novo DNA methylation at specific regulatory sites in the oxytocin receptor gene (Oxtr), impacting gene expression and protein distribution in the nucleus accumbens. DNA methylation state of the blood predicts expression in the brain indicating the utility of the blood as a biomarker for the transcription state of the brain. These experience-sensitive CpG sites are conserved in humans, are related to gene expression in the brain, and have been associated with psychiatric disorders and individual differences in neural response to social stimuli. These results identify a mechanism by which early care regulates later displays of typical prairie vole social behavior and suggest the potential for nurture driven epigenetic tuning of OXTR in humans.

Smooth muscle cell-specific deletion of Col15a1 unexpectedly leads to impaired development of advanced atherosclerotic lesions.

Atherosclerotic plaque rupture with subsequent embolic events is a major cause of sudden death from myocardial infarction or stroke. Although smooth muscle cells (SMCs) produce and respond to collagens in vitro, there is no direct evidence in vivo that SMCs are a crucial source of collagens and that this impacts lesion development or fibrous cap formation. We sought to determine how conditional SMC-specific knockout of collagen type XV (COL15A1) in SMC lineage tracing mice affects advanced lesion formation given that 1) we have previously identified a Col15a1 sequence variant associated with age-related atherosclerosis, 2) COL15A1 is a matrix organizer enhancing tissue structural integrity, and 3) small interfering RNA-mediated Col15a1 knockdown increased migration and decreased proliferation of cultured human SMCs. We hypothesized that SMC-derived COL15A1 is critical in advanced lesions, specifically in fibrous cap formation. Surprisingly, we demonstrated that SMC-specific Col15a1 knockout mice fed a Western diet for 18 wk failed to form advanced lesions. SMC-specific Col15a1 knockout resulted in lesions reduced in size by 78%, with marked reductions in numbers and proliferating SMCs, and lacked a SMC and extracellular matrix-rich lesion or fibrous cap. In vivo RNA-seq analyses on SMC Col15a1 knockout and wild-type lesions suggested that a mechanism for these effects is through global repression of multiple proatherogenic inflammatory pathways involved in lesion development. These results provide the first direct evidence that a SMC-derived collagen, COL15A1, is critical during lesion pathogenesis, but, contrary to expectations, its loss resulted in marked attenuation rather than exacerbation of lesion pathogenesis.NEW & NOTEWORTHY We report the first direct in vivo evidence that a smooth muscle cell (SMC)-produced collagen, collagen type XV (COL15A1), is critical for atherosclerotic lesion development. SMC Col15a1 knockout markedly attenuated advanced lesion formation, likely through reducing SMC proliferation and impairing multiple proatherogenic inflammatory processes.

Plasma oxytocin explains individual differences in neural substrates of social perception.

The neuropeptide oxytocin plays a critical role in social cognition and behavior. A number of studies using intranasal administration have demonstrated that oxytocin improves social perception. However, little is known about the relationship between individual differences in endogenous levels of oxytocin and social cognition. In the current study, we assessed the relationship between endogenous oxytocin and brain activity during an animacy perception paradigm. Thirty-seven male participants underwent scanning and provided a blood sample for oxytocin analysis. In line with previous research, perception of animacy was associated with activations in superior temporal sulcus, inferior frontal gyrus, and medial prefrontal cortex (mPFC). Notably, participants' levels of plasma oxytocin robustly predicted activation in areas critical for social cognitive processes, such that higher oxytocin levels were related to increased activity in dorsal mPFC, ventral mPFC, dorsolateral PFC, superior temporal gyrus, and temporoparietal junction (TPJ), suggesting differential processing of social stimuli. Together these results show that stable variations in endogenous oxytocin levels explain individual differences in social perception.

Epigenetic regulation of COL15A1 in smooth muscle cell replicative aging and atherosclerosis.

Smooth muscle cell (SMC) proliferation is a hallmark of vascular injury and disease. Global hypomethylation occurs during SMC proliferation in culture and in vivo during neointimal formation. Regardless of the programmed or stochastic nature of hypomethylation, identifying these changes is important in understanding vascular disease, as maintenance of a cells' epigenetic profile is essential for maintaining cellular phenotype. Global hypomethylation of proliferating aortic SMCs and concomitant decrease of DNMT1 expression were identified in culture during passage. An epigenome screen identified regions of the genome that were hypomethylated during proliferation and a region containing Collagen, type XV, alpha 1 (COL15A1) was selected by 'genomic convergence' for characterization. COL15A1 transcript and protein levels increased with passage-dependent decreases in DNA methylation and the transcript was sensitive to treatment with 5-Aza-2'-deoxycytidine, suggesting DNA methylation-mediated gene expression. Phenotypically, knockdown of COL15A1 increased SMC migration and decreased proliferation and Col15a1 expression was induced in an atherosclerotic lesion and localized to the atherosclerotic cap. A sequence variant in COL15A1 that is significantly associated with atherosclerosis (rs4142986, P = 0.017, OR = 1.434) was methylated and methylation of the risk allele correlated with decreased gene expression and increased atherosclerosis in human aorta. In summary, hypomethylation of COL15A1 occurs during SMC proliferation and the consequent increased gene expression may impact SMC phenotype and atherosclerosis formation. Hypomethylated genes, such as COL15A1, provide evidence for concomitant epigenetic regulation and genetic susceptibility, and define a class of causal targets that sit at the intersection of genetic and epigenetic predisposition in the etiology of complex disease.

The C terminus of c-Src inhibits breast tumor cell growth by a kinase-independent mechanism.

Overexpression or increased activity of cellular Src (c-Src) is frequently detected in human breast cancer, implicating involvement of c-Src in the etiology of breast carcinomas. Curiously, overexpression of c-Src in tissue culture cells results in a weakly or non-transforming phenotype, indicating that it alone is not sufficient for oncogenesis. However, the protein has been demonstrated to potentiate mitogenic signals from transmembrane receptors. This report investigates the requirement for c-Src in breast cancer as a transducer and integrator of anchorage-dependent and -independent growth signals by utilizing the Src family pharmacological inhibitors, PP1 and PP2, or stable overexpression of the catalytically inactive c-Src mutant (K- c-Src). Both methods of inhibiting endogenous c-Src diminished formation of soft agar colonies and tumors in nude mice. The majority of the dominant-negative activity of K- c-Src was mapped to the Src homology 2 (SH2) domain and C-terminal half of the molecule, but not to the Unique domain, Src homology 3 (SH3) domain, or the N-terminal half of K- c-Src. Further analysis of the C terminus revealed that its ability to inhibit growth localized to the N-terminal lobe (N-lobe) of the catalytic region. These results underscore the requirement for c-Src to maintain the oncogenic phenotype of breast cancer cells and suggest that c-Src may be manipulated to inhibit cell growth by the direct disruption of its catalytic activity or the introduction of either the SH2 domain or the N-lobe of K- c-Src.