Histone modifications, DNA methylation, and schizophrenia

Abstract

Studies have demonstrated that several schizophrenia candidate genes are especially susceptible to changes in transcriptional activity as a result of histone modifications and DNA methylation. Increased expression of epigenetic enzymes which generally reduce transcription have been reported in schizophrenia postmortem brain samples. An abnormal chromatin state leading to reduced candidate gene expression can be explained by aberrant coordination of epigenetic mechanisms in schizophrenia. Dynamic epigenetic processes are difficult to study using static measures such as postmortem brain samples. Therefore, we have developed a model using cultured peripheral blood mononuclear cells (PBMCs) capable of pharmacologically probing these processes in human subjects. This approach has revealed several promising findings indicating that schizophrenia subject PBMC chromatin may be less capable of responding to agents which normally 'open' chromatin. We suggest that the ability to appropriately modify chromatin structure may be a factor in treatment response. Several pharmacological approaches for targeting epigenetic processes are reviewed.

Figure 1. Hypothetical mechanism of action for medications which target restrictive chromatin in schizophrenia

(A) Treatment Resistant Neuron. An exogenous signal (red) (e.g., neurotransmitter, medication) binds to its receptor (dark green) causing a transcription factor (TF) to translocate to the nucleus where it is prevented from serving as a platform for RNA polymerase II (POL II) by a restrictive chromatin state. Histone deacetylases, such as HDAC1, histone methyltransferases (HMT), DNA methyltransferases, such as DNMT1, and the repressor protein, HP1, cooperate both directly and indirectly through methyl-CpG domain binding proteins such as MeCP2, to induce this state. (B) Treatment Responsive Neuron. In this hypothetical model a histone deacetylase inhibitor (HDACi) prevents the deacetylation of histone proteins. This sets off a chain of events whereby the components of the restrictive chromatin state dissociate from the gene promoter region, chromatin structure is remodeled, and the promoter region in now more available for transcription factor binding. The transcription factor then serves as a platform for RNA polymerase II (POL II) binding. In this way, ‘softening’ chromatin around a gene promoter region makes expression levels more readily alterable by exogenous forces such as medications.