Integrative modeling of multi‐platform genomic data under the framework of mediation analysis

Given the availability of genomic data, there have been emerging interests in integrating multi‐platform data. Here, we propose to model genetics (single nucleotide polymorphism (SNP)), epigenetics (DNA methylation), and gene expression data as a biological process to delineate phenotypic traits under the framework of causal mediation modeling. We propose a regression model for the joint effect of SNPs, methylation, gene expression, and their nonlinear interactions on the outcome and develop a variance component score test for any arbitrary set of regression coefficients. The test statistic under the null follows a mixture of chi‐square distributions, which can be approximated using a characteristic function inversion method or a perturbation procedure. We construct tests for candidate models determined by different combinations of SNPs, DNA methylation, gene expression, and interactions and further propose an omnibus test to accommodate different models. We then study three path‐specific effects: the direct effect of SNPs on the outcome, the effect mediated through expression, and the effect through methylation. We characterize correspondences between the three path‐specific effects and coefficients in the regression model, which are influenced by causal relations among SNPs, DNA methylation, and gene expression. We illustrate the utility of our method in two genomic studies and numerical simulation studies. Copyright © 2014 John Wiley & Sons, Ltd.     

卡介苗诱导的训练免疫

训练免疫是指具有记忆性的固有免疫。本文简述了卡介苗诱导的训练免疫的作用及机制,即不仅可以抵抗结核分枝杆菌,也能帮助清除其他病原体,并且在非肌层浸润膀胱癌的治疗中发挥作用。卡介苗诱导的训练免疫通过病原体相关分子模式与模式识别受体结合启动,并引起物质代谢改变和表观遗传变化,最终引起肿瘤坏死因子及白介素等细胞因子表达上调,增强对病原体或肿瘤细胞的清除作用。     

Epigenetic dysregulation in systemic lupus erythematosus

Abstract

Systemic lupus erythematosus (SLE) is a prototypical systemic autoimmune disease that affects multiple organs and is characterized by episodic flares and elevated morbidity. The etiology of SLE is only partly known. In this context, recent attention has been paid to the importance of environmentally induced epigenetic modifications as significant contributors to the disease pathogenesis in genetically predisposed individuals. Here we review what is currently known on the role of epigenetics in SLE, and the investigations aimed at possibly targeting epigenetic mechanisms and/or related biomarkers to improve the monitoring, management and, ultimately, the prognosis of SLE.     

Promoter methylation of galanin receptors as epigenetic biomarkers for head and neck squamous cell carcinomas

Introduction: While remarkable progress has been made in standard treatments for head and neck squamous cell carcinomas (HNSCCs), the long-term survival remains at an unsatisfactory 40–50%. To improve the survival rate, biomarkers for optimal treatment selection and prognostic prediction, as well as novel, low-toxicity treatment strategies, are required. Galanin receptor (GALR) 1 and GALR2 are well-studied tumor suppressors in HNSCCs. Compared with other clinicopathological factors, the epigenetic variants of GALRs have been found to be the most powerful markers to predict the prognosis of HNSCC patients.

Areas covered: This review outlines the functions and signaling pathways of GALRs and explains the potential of GALR promoter methylation as a biomarker for HNSCC prognosis. We also summarize recent developments in promoter methylation studies in HNSCC and indicate future directions for GALR promoter methylation studies.

Expert commentary: GALR studies have highlighted two major aspects with implications in HNSCC – that G-protein coupled receptors (GPCRs) act as tumor suppressor genes and that GALR promoter methylation is significantly related to the carcinogenesis of HNSCC. The findings of GALR studies can be applied to studies on other GPCRs and further in-depth DNA methylation studies. Deeper insights into GPCR epigenetics are expected to markedly improve HNSCC treatment.     

JMJD2B/KDM4B inactivation in adipose tissues accelerates obesity and systemic metabolic abnormalities

Obesity is a serious global health issue; however, the roles of genetics and epigenetics in the onset and progression of obesity are still not completely understood. The aim of this study was to determine the role of Kdm4b, which belongs to a subfamily of histone demethylases, in adipogenesis and fat metabolism in vivo. We established conditional Kdm4b knockout mice. Inactivation of Kdm4b in adipocytes (K4bKO) induced profound obesity in mice on a high fat diet (HFD). The HFD‐fed K4bKO mice exhibited an increased volume of fat mass and higher expression levels of adipogenesis‐related genes. In contrast, the genes involved in energy expenditure and mitochondrial functions were down‐regulated. Supporting these findings, the energy expenditure of Kdm4b‐deficient cells was markedly decreased. In addition, progression of glucose intolerance and hepatic steatosis with hepatocellular damages was observed. These data indicate that Kdm4b is a critical regulator of systemic metabolism via enhancing energy expenditure in adipocytes.