Genome-wide promoter methylation profiling in a cellular model of melanoma progression reveals markers of malignancy and metastasis that predict melanoma survival.

The epigenetic changes associated with melanoma progression to advanced and metastatic stages are still poorly understood. To shed light on the CpG methylation dynamics during melanoma development, we analyzed the methylome profiles of a four-stage cell line model of melanoma progression: non-tumorigenic melanocytes (melan-a), premalignant melanocytes (4C), non-metastatic melanoma cells (4C11-), and metastatic melanoma cells (4C11+). We identified 540 hypo- and 37 hypermethylated gene promoters that together characterized a malignancy signature, and 646 hypo- and 520 hypermethylated promoters that distinguished a metastasis signature. Differentially methylated genes from these signatures were correlated with overall survival using TCGA-SKCM methylation data. Moreover, multivariate Cox analyses with LASSO regularization identified panels of 33 and 31 CpGs, respectively, from the malignancy and metastasis signatures that predicted poor survival. We found a concordant relationship between DNA methylation and transcriptional levels for genes from the malignancy (Pyroxd2 and Ptgfrn) and metastasis (Arnt2, Igfbp4 and Ptprf) signatures, which were both also correlated with melanoma prognosis. Altogether, this study reveals novel CpGs methylation markers associated with malignancy and metastasis that collectively could improve the survival prediction of melanoma patients.

Autism Spectrum Disorder: Signaling Pathways and Prospective Therapeutic Targets.

The Autism Spectrum Disorder (ASD) consists of a prevalent and heterogeneous group of neurodevelopmental diseases representing a severe burden to affected individuals and their caretakers. Despite substantial improvement towards understanding of ASD etiology and pathogenesis, as well as increased social awareness and more intensive research, no effective drugs have been successfully developed to resolve the main and most cumbersome ASD symptoms. Hence, finding better treatments, which may act as "disease-modifying" agents, and novel biomarkers for earlier ASD diagnosis and disease stage determination are needed. Diverse mutations of core components and consequent malfunctions of several cell signaling pathways have already been found in ASD by a series of experimental platforms, including genetic associations analyses and studies utilizing pre-clinical animal models and patient samples. These signaling cascades govern a broad range of neurological features such as neuronal development, neurotransmission, metabolism, and homeostasis, as well as immune regulation and inflammation. Here, we review the current knowledge on signaling pathways which are commonly disrupted in ASD and autism-related conditions. As such, we further propose ways to translate these findings into the development of genetic and biochemical clinical tests for early autism detection. Moreover, we highlight some putative druggable targets along these pathways, which, upon further research efforts, may evolve into novel therapeutic interventions for certain ASD conditions. Lastly, we also refer to the crosstalk among these major signaling cascades as well as their putative implications in therapeutics. Based on this collective information, we believe that a timely and accurate modulation of these prominent pathways may shape the neurodevelopment and neuro-immune regulation of homeostatic patterns and, hopefully, rescue some (if not all) ASD phenotypes.