Sex-specific role for the long non-coding RNA linc00473 in depression

Depression is a common disorder that affects women at twice the rate of men. Here we report that long non-coding RNAs (lncRNAs), a recently discovered class of regulatory transcripts, represent about one-third of the differentially expressed genes in the brains of depressed humans, and display complex region- and sex-specific patterns of regulation. We identified the primate-specific, neuronal-enriched gene, linc00473, as downregulated in prefrontal cortex of depressed females but not males. Using viral-mediated gene transfer to express linc00473 in mouse prefrontal cortex neurons, we mirrored the human sex-specific phenotype by inducing stress resilience solely in female mice. This sex-specific phenotype was accompanied by changes in synaptic function and gene expression selectively in female mice and, along with studies of human neuron-like cells in culture, implicates linc00473 as a CREB effector. Together, our studies identify linc00473 as a female-specific driver of stress resilience that is aberrant in female depression. Overall design: RNA profiled in mPFC of female mice expressing linc00473 or GFP only in mPFC, either at baseline or after CVS (chronic variable stress). RNA-seq of NPCs derived from male or female healthy human subjects after knockdown of linc00473; Chromatin isolation by RNA purification (ChIRP) followed by DNA-sequencing (DNA-seq) to identify direct partners for linc00473 in human cells;