Major depressive disorder (MDD) currently remains one of the leading causes of global disability. Despite the rise in treatment options, remission rates in MDD patients are very low. Thus, there is critical need to identify the biological substrates that precipitate in MDD in order to develop effective therapy. It is widely known that MDD involves short- and long-term maladaptive processes to external stimuli, impairing the ability of individuals to appropriately interact with the environment. So far, there is no coherent hypothesis that can fully explain this phenomenon. Increasing evidence suggests that fine-tuning of transcriptional regulation by gene-environment interaction is central to the etiology of MDD. In this regard, a paradigm shifting phenomenon has recently been introduced with the unique concept of post-transcriptional gene regulation through epitranscriptomic mechanism (most prominently being N6-methyladenosine [m6A]) which is not only involved in the regulation of transcript abundance but has the profound ability to impact maturity, stability, localization, and most importantly, availability of ?select? gene transcripts to protein translation despite varying transcription rates in a highly ?dynamic? and ?reversible? fashion. This mechanism facilitates quick response to external stimuli, fine-tunes protein accessibility, and executes localized control, which is critical to stimulus-adaptive gene expression. Their roles have recently been shown in synaptic plasticity as well as in the stress coping behavior of mice. Our own preliminary data demonstrate that not only is m6A mRNA methylation machinery differentially expressed in various brain areas, but their expression and functions in manipulating m6A methylation and subsequent expression of specific transcripts are aberrant in the MDD brain. This has led us to propose an overarching hypothesis that m6A methylation-based epitranscriptomic modification of mRNAs may act as a dynamic regulator of a subset of genes in a brain region specific manner, which, by affecting specific molecular pathways in a coordinated fashion, will participate in MDD pathogenesis. To test this, in dlPFC and hippocampus from healthy controls and well-matched MDD subjects, we propose the following aims: 1) Examine whether MDD is associated with differential regulation of m6A methylation machinery and distinctive m6A methylation profile at the epitranscriptomic level in brain region specific manner; 2) Define MDD associated role of YTH family of reader proteins in epitranscriptomic turnover of protein coding genes; 3) Examine the impact of m6A mRNA methylation on dendritic availability of local epitranscriptomic pool and their contribution to MDD pathogenesis. By using highly innovative molecular approaches, by precisely identifying the fate of the transcripts in translatable and non-translatable pools mediated through specific m6A reader proteins, by examining the role of m6A methylation at the synapse, and by analyzing data using novel bioinformatics tools, our study is highly innovative; it has the potential to discover unique epitranscriptome-based gene regulation as a mechanism in MDD etiopathogenesis and identify novel targets for therapeutic intervention.
Major depression is a debilitating disorder affecting millions of people worldwide with limited success in treatment or remission. Despite a wealth of neurobiological studies over the last few decades, our understanding of the cellular and molecular processes associated with major depression is rudimentary, precluding the development of effective treatments. In this application, we are proposing an innovative line of research to examine unique epitranscriptomic regulation of genes, representing dynamic and reversible RNA modifications at post-transcriptional level, in human postmortem brain that can be used as novel ??molecular tools?? to understand the etiopathogenesis of depressive behavior with a high potential to generate new molecular-based therapies to treat this severe mental disorder.