The m6A-methylome in major depression: A bioinformatic analysis of publicly available datasets

One of the most common RNA modifications found in the mammalian brain is N6-methyladenosine (m6A) and this modification has been implicated in fine-tuning neuronal gene expression by regulating RNA metabolism with consequent impact on brain function and behaviour. The presence, absence, and overall influence of m6A on any given transcript is governed by so-called m6A machinery genes and include m6A ‘writers’, ‘erasers’ and ‘readers.’ Changes in the functional expression of m6A machinery genes in the pathophysiology of major depression (MD) and its consequence on m6A mediated regulation of gene expression has not been explored. To this end, we exploited and analysed 23 publicly available microarray, bulk, and single-nucleus RNA sequencing datasets on post-mortem brain tissue from MD patients and healthy controls (1410 samples). Our analysis points to cell-specific dysregulation in the expression of m6A ‘writer’ METTL16 and ‘readers’ YTHDC1 and YTHDC2 in the prefrontal cortex (PFC). We also determined significant differential expression of various m6A ‘readers’ and ‘writers’ on multiple transcript biotypes including messenger RNAs, ribosomal RNAs and small-nuclear RNAs. In the dorsolateral PFC, we also identified sex- but not sub-region-specific roles of m6A in regulating gene expression. Taken together, our in-silico analyses provide an insight into the putative role of m6A-dysregulation in the pathophysiology of MD which requires biochemical validation, exploration of causality in future work, and also raises the prospect that specific m6A-machinery enzymes may be viable therapeutic targets for the treatment of MD.