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.     

Synthetic lethality strategies: Beyond BRCA1/2 mutations in pancreatic cancer

Cancer cells are often characterized by abnormalities in DNA damage response including defects in cell cycle checkpoints and/or DNA repair. Synthetic lethality between DNA damage repair (DDR) pathways has provided a paradigm for cancer therapy by targeting DDR. The successful example is that cancer cells with BRCA1/2 mutations are sensitized to poly(adenosine diphosphate [ADP]‐ribose)polymerase (PARP) inhibitors. Beyond the narrow scope of defects in the BRCA pathway, “BRCAness” provides more opportunities for synthetic lethality strategy. In human pancreatic cancer, frequent mutations were found in cell cycle and DDR genes, including P16, P73, APC, MLH1, ATM, PALB2, and MGMT. Combined DDR inhibitors and chemotherapeutic agents are under preclinical or clinical trials. Promoter region methylation was found frequently in cell cycle and DDR genes. Epigenetics joins the Knudson's “hit” theory and “BRCAness.” Aberrant epigenetic changes in cell cycle or DDR regulators may serve as a new avenue for synthetic lethality strategy in pancreatic cancer.     

DNA methylation signatures reveal that distinct combinations of transcription factors specify human immune cell epigenetic identity

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Genome‐wide DNA‐methylation profiles in human bone marrow mesenchymal stem cells on titanium surfaces

The characteristics of titanium (Ti) have been shown to influence dental implant fixation. Treatment of surfaces using the sandblasted, large‐grit, acid‐etched (SLA) method is widely used to provide effective osseointegration. However, the DNA methylation‐associated mechanism by which SLA surface treatment affects osseointegration of human bone marrow mesenchymal stem cells (hBMSCs) remains elusive. Genome‐wide methylation profiling of hBMSCs on SLA‐treated and machined smooth Ti was performed using Illumina Infinium Methylation EPIC BeadChip at day 7 of osteogenic induction. In total, 2,846 CpG sites were differentially methylated in the SLA group compared with the machined group. Of these sites, 1,651 (covering 1,066 genes) were significantly hypermethylated and 1,195 (covering 775 genes) were significantly hypomethylated. Thirty significant enrichment pathways were observed, with Wnt signaling being the most significant. mRNA expression was identified by microarray and combined with DNA‐methylation profiles. Thirty‐seven genes displayed negative association between mRNA expression and DNA‐methylation level, with the osteogenesis‐related genes insulin‐like growth factor 2 (IGF2) and carboxypeptidase X, M14 Family Member 2 (CPXM2) showing significant up‐regulation and down‐regulation, respectively. In summary, our results demonstrate differences between SLA‐treated and machined surfaces in their effects on genome‐wide DNA methylation and enrichment of osteogenic pathways in hBMSCs. We provide novel insights into genes and pathways affected by SLA treatment in hBMSCs at the molecular level.     

Biology and targeting of the Jumonji-domain histone demethylase family in childhood neoplasia: a preclinical overview

Introduction: Epigenetic mechanisms of gene regulatory control play fundamental roles in developmental morphogenesis, and, as more recently appreciated, are heavily implicated in the onset and progression of neoplastic disease, including cancer. Many epigenetic mechanisms are therapeutically targetable, providing additional incentive for understanding of their contribution to cancer and other types of neoplasia.

Areas covered: The Jumonji-domain histone demethylase (JHDM) family exemplifies many of the above traits. This review summarizes the current state of knowledge of the functions and pharmacologic targeting of JHDMs in cancer and other neoplastic processes, with an emphasis on diseases affecting the pediatric population.

Expert opinion: To date, the JHDM family has largely been studied in the context of normal development and adult cancers. In contrast, comparatively few studies have addressed JHDM biology in cancer and other neoplastic diseases of childhood, especially solid (non-hematopoietic) neoplasms. Encouragingly, the few available examples support important roles for JHDMs in pediatric neoplasia, as well as potential roles for JHDM pharmacologic inhibition in disease management. Further investigations of JHDMs in cancer and other types of neoplasia of childhood can be expected to both enlighten disease biology and inform new approaches to improve disease outcomes.     

Protein Content and Methyl Donors in Maternal Diet Interact to Influence the Proliferation Rate and Cell Fate of Neural Stem Cells in Rat Hippocampus

Maternal diet during pregnancy and early postnatal life influences the setting up of normal physiological functions in the offspring. Epigenetic mechanisms regulate cell differentiation during embryonic development and may mediate gene/environment interactions. We showed here that high methyl donors associated with normal protein content in maternal diet increased the in vitro proliferation rate of neural stem/progenitor cells isolated from rat E19 fetuses. Gene expression on whole hippocampi at weaning confirmed this effect as evidenced by the higher expression of the Nestin and Igf2 genes, suggesting a higher amount of undifferentiated precursor cells. Additionally, protein restriction reduced the expression of the insulin receptor gene, which is essential to the action of IGFII. Inhibition of DNA methylation in neural stem/progenitor cells in vitro increased the expression of the astrocyte-specific Gfap gene and decreased the expression of the neuron-specific Dcx gene, suggesting an impact on cell differentiation. Our data suggest a complex interaction between methyl donors and protein content in maternal diet that influence the expression of major growth factors and their receptors and therefore impact the proliferation and differentiation capacities of neural stem cells, either through external hormone signals or internal genomic regulation.