The goal of this proposed research is to determine whether differences in the expression of epigenetic related biomarkers are present in lymphocytes of people with genetic high risk and/or prodromal symptoms of schizophrenia (HRSK subjects) as previously found in lymphocytes of chronic schizophrenia (SZ) patients. We will also assess whether the presence of these biomarkers predicts which HRSK subjects will progressively develop more psychotic symptoms over a two year period and who will convert from HRSK status to first episode schizophrenia or another diagnosable psychotic disorder. Investigators on this proposal, have been collaborating with a group of investigators in Hunan, China for several years (Wu et al., 2008;2012). The China group is currently conducting a multi-center study supported by the Chinese Ministry of Health that involves 5000 HRSK and 2000 control subjects. The research we are proposing would be an addendum to this larger study. DNA methylation and demethylation are key epigenetic components involved in orchestrating transcription of specific genes in post mitotic neurons (Guidotti et al., 2011). It has been suggested that the DNA methylation/demethylation process is perturbed in neuropsychiatric disorders such as schizophrenia (SZ), bipolar disorder (BP), and autism. We have shown that abnormalities in some of these epigenetic marks in the brain of SZ patients are also present in their lymphocytes. Lymphocytes of SZ patients have higher DNMT1 mRNA expression than non-psychotic controls (Zhubi et al 2009), higher levels of other methylating and demethylating enzymes (growth arrest and DNA damage-inducible protein [GADD45] and ten-eleven translocation protein [TET]), and lower levels of glucocorticoid receptor and GAD67 mRNA (preliminary data). If differences in these potential epigenetic biomarkers can be confirmed in lymphocytes of HRSK subjects, some of the underlying biochemical developmental pathology leading to SZ might be uncovered. This result could provide epigenetic biomarkers useful in predicting which HRSK subjects are more likely to develop full symptoms of SZ or a related psychosis. Identifying potential biomarkers would have implications for prognosis and identifying patients who would be most likely to benefit from intensive early intervention and specialized treatment. This background leads us to pursue three Specific Aims for the current proposed study:
AIM1 : Measure the expression level of DNA methylation related genes in lymphocytes of HRSK subjects at baseline compared to controls and first episode and chronic SZ patients.
AIM 2 : Determine whether epigenetic chromatin status and the expression of SZ candidate genes is regulated by the binding of proteins that are constituents of the DNA- methylation/demethylation pathways in lymphocytes of HRSK subjects at baseline compared to controls and first episode and chronic SZ patients.
AIM 3 Determine whether HRSK subjects who also have epigenetic lymphocyte abnormalities at baseline are more likely to progress to more severe psychotic-like symptoms or convert to diagnosable psychotic status during a two year follow up. This proposed research is potentially a major step toward the identification of objective biomarkers capable of predicting conversion to psychosis in HRSK subjects.
The goal of this research is to determine whether differences in the expression of epigenetic biomarkers previously found in the post-mortem brain and lymphocytes of patients meeting DSM-IV criteria for schizophrenia are also present in lymphocytes of people with genetic high risk and/or prodromal symptoms of schizophrenia. The research would be a collaborative effort between investigators in the U.S. and investigators in China. The China group is currently conducting a multicenter study supported by the Chinese Ministry of Health that involves 5000 subjects with high risk for schizophrenia and 2000 controls. The proposed research would be an addendum to this larger Chinese study. This internationally supported research could potentially be a major step toward the identification of objective biomarkers predicting individuals most likely to benefit from early intervention and specialized treatment.
|Alessandro, Guidotti; Erbo, Dong; Grayson, Dennis R (2017) Epigenetic Basis of Clozapine Action. J Drug Des Res 4:|
|Auta, James; Zhang, Huaibo; Pandey, Subhash C et al. (2017) Chronic Alcohol Exposure Differentially Alters One-Carbon Metabolism in Rat Liver and Brain. Alcohol Clin Exp Res 41:1105-1111|
|Zhubi, Adrian; Chen, Ying; Guidotti, Alessandro et al. (2017) Epigenetic regulation of RELN and GAD1 in the frontal cortex (FC) of autism spectrum disorder (ASD) subjects. Int J Dev Neurosci 62:63-72|
|Dong, Erbo; Dzitoyeva, Svetlana G; Matrisciano, Francesco et al. (2015) Brain-derived neurotrophic factor epigenetic modifications associated with schizophrenia-like phenotype induced by prenatal stress in mice. Biol Psychiatry 77:589-96|
|Guidotti, Alessandro; Dong, Erbo; Tueting, Patricia et al. (2014) Modeling the molecular epigenetic profile of psychosis in prenatally stressed mice. Prog Mol Biol Transl Sci 128:89-101|
|Guidotti, A; Auta, J; Davis, J M et al. (2014) Toward the identification of peripheral epigenetic biomarkers of schizophrenia. J Neurogenet 28:41-52|
|Auta, J; Smith, R C; Dong, E et al. (2013) DNA-methylation gene network dysregulation in peripheral blood lymphocytes of schizophrenia patients. Schizophr Res 150:312-8|
|Guidotti, A; Auta, J; Chen, Y et al. (2011) Epigenetic GABAergic targets in schizophrenia and bipolar disorder. Neuropharmacology 60:1007-16|