DNA methylation in schizophrenia in different patient-derived cell types

DNA methylation of gene promoter regions represses transcription and is a mechanism via which environmental risk factors could affect cells during development in individuals at risk for schizophrenia. We investigated DNA methylation in patient-derived cells that might shed light on early development in schizophrenia. Induced pluripotent stem cells may reflect a “ground state” upon which developmental and environmental influences would be minimal. Olfactory neurosphere-derived cells are an adult-derived neuro-ectodermal stem cell modified by developmental and environmental influences. Fibroblasts provide a non-neural control for life-long developmental and environmental influences. Genome-wide profiling of DNA methylation and gene expression was done in these three cell types from the same individuals. All cell types had distinct, statistically significant schizophrenia-associated differences in DNA methylation and linked gene expression, with Gene Ontology analysis showing that the differentially affected genes clustered in networks associated with cell growth, proliferation, and movement, functions known to be affected in schizophrenia patient-derived cells. Only five gene loci were differentially methylated in all three cell types. Understanding the role of epigenetics in cell function in the brain in schizophrenia is likely to be complicated by similar cell type differences in intrinsic and environmentally induced epigenetic regulation.
Epigenetics: A genome-wide picture in patient-derived cells Schizophrenia-associated differences in the DNA methylation status of patient-derived cells suggest it could affect early brain development. Mechanisms that control gene expression without altering the genetic code, such as DNA methylation, could explain how environmental risk factors contribute to schizophrenia in genetically susceptible individuals. Alan Mackay-Sim and colleagues from Griffith University, Australia, carried out genome-wide comparisons of DNA methylation in induced pluripotent stem (iPS) cells, olfactory neurosphere-derived cells and fibroblasts from patients and controls. Differences in the DNA methylation pattern between patient and control iPS cells, which could reflect what happens in the embryo, suggest a disease-associated effect very early on in development. Only five genes were differentially methylated in all three patient-derived cell types compared to controls. None of these genes has previously been associated with schizophrenia and may represent new targets for future research.