The Thomas Lab
Research
Molecular Mechanisms of Human CNS Disorders - Overview
My research program utilizes genome-wide approaches to investigate the molecular bases of neurological disorders, including schizophrenia and Huntington’s disease, as well as the mechanisms of drugs used to treat these disorders. We use functional genomics methodologies to identify genes that are abnormally expressed in human post-mortem samples from diseased subjects, animal models of disease and in response to drug treatment and to determine epigenetic contributions to the regulation of gene expression. Our goals are to achieve a better understanding of gene regulation and its dysfunction in neuropsychiatric and neurodegenerative disorders in order to provide a basis for new therapeutic approaches and disease prevention. The main research interests of my lab can be segregated into two areas as summarized below.
Molecular Bases for Psychiatric Disorders
Our studies use transcriptomics analysis of human post-mortem brain tissue to identify molecular factors that are associated with various aspects of psychiatric disorders. We have utilized these data to elucidate important new facets of disease pathogenesis and progression. Genome-wide RNA expression profiles from post-mortem prefrontal cortical samples have been generated from subjects with schizophrenia at different stages of illness. We found that the early stages of disease (4 years or less from initial diagnosis) are associated with the greatest derangement in gene expression and that these genes are associated with diverse systems and pathways. The identification of genes associated with the early versus later stages of schizophrenia will be important for understanding disease progression and might lead to the development of agents that modify the course of disease. Using additional statistical approaches, we have also revealed extensive gene expression connectivity and have identified modules of co-expressed genes in different cohorts of subjects with schizophrenia, taking into consideration covariables, such as age, stage of disease and drug treatment. From these analyses, we have found striking differences in age-related gene expression profiles in subjects with schizophrenia compared to normal individuals. In particular, we found that genes associated with nervous system development are differentially affected by age in subjects with schizophrenia, providing new information regarding the potential time-frame of developmental triggers that may be pathogenic in this disorder.
In addition, we have explored chromatin-mediated effects that may be responsible for altered expression profiles. Using chromatin immunoprecipitation on post-mortem prefrontal cortex from normal subjects and those with schizophrenia and bipolar disorder, we find that histone H3 acetylation is correlated with the expression levels of several schizophrenia candidate genes, including GAD1 and RGS4. Further, we find that histone H3 is hypoacetylated at specific lysine residues primarily in young subjects with schizophrenia compared to age-matched controls, implicating epigenetic deficits as a potential pathogenic mechanism in this disease. Current research includes investigating and validating epigenetic-based gene transcriptional dysfunction in mouse models for schizophrenia. Epidemiological studies have demonstrated that maternal immune system activation during pregnancy increases the risk of offspring developing schizophrenia in adulthood. This phenomenon can be mimicked in rodent models. For these studies, we are performing a maternal immune activation model using polyinosinic:polycytidylic acid (polyI:C) to explore the extent of histone acetylation disruption and ensuing gene expression deficits that occur from immune environmental triggers. We have found that prenatal immune activation leads to hypoacetylation of histones in the cortex and hippocampus of 12-week old offspring, providing the basis for further characterization of epigenetic changes in this context.
Treatment Approaches for Neurological Disorders that Target Gene Regulation
We are testing therapeutic strategies in different HD mouse models aimed at improving transcriptional output via modulation of chromatin structure by HDAC inhibitors. Our work has studied a novel class of benzamide-type HDAC inhibitors, developed by my collaborator, Joel Gottesfeld at The Scripps Research Institute. These compounds, which we have shown target specific HDAC enzymes among a large family of >18 members, do not show cytotoxic properties, a feature that has limited the therapeutic potential of classical HDAC inhibitors, including SAHA and phenylbutyrate for neurodegenerative disorders. While in vitro studies have provided insight into the beneficial effects of HDAC inhibitors, in vivo studies have allowed us to study more relevant aspects of their therapeutic potential at the behavioral, molecular and histopathological levels. Our previous studies have focused on one novel HDAC inhibitor, HDACi 4b, which we found elicits significant improvement in motor performance and other disease phenotypes in R6/2 HD transgenic mice. We have used microarray analysis to show that HDACi 4b treatment ameliorates gene expression abnormalities in these mice, and, for subsets of genes, caused complete expression normalization. These genes may be considered as biomarkers for treatment effectiveness. Ongoing studies are analyzing transcriptome datasets from brain and skeletal muscle from drug-treated HD mice, in order to identify potential mechanisms of action of HDAC inhibitors. These studies have suggested protein processing pathways may contribute to the beneficial effects of drug treatment.
Our recent studies show that HDACi 4b selective targets HDAC1 and HDAC3 enzymes, suggesting that these isotypes are particularly important targets for HD. We are currently testing a library of novel, HDAC1/3-targeting HDAC inhibitors at different dose regimens in various HD model systems, in order to identify improved compounds for therapeutic application. These studies are being performed in collaboration with Repligen Corporation (Waltham, MA), who will support the advancement of a lead compound into human clinical trials for HD.
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