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. 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;