The Long Noncoding RNA FEDORA is a Cell-Type- and Sex-Specific Regulator of Depression

Abstract

Women suffer from depression at twice the rate of men, but the underlying molecular mechanisms are poorly understood. Here, we identify dramatic baseline sex differences in expression of long noncoding RNAs (lncRNAs) in human postmortem brain tissue that are profoundly lost in depression. One such lncRNA, RP11-298D21.1 (which we termed FEDORA), is enriched in oligodendrocytes and neurons and upregulated in several cortical regions of depressed females but not males. We found that virally-expressing FEDORA selectively either in neurons or in oligodendrocytes of prefrontal cortex promoted depression-like behavioral abnormalities in female mice only, changes associated with cell-type-specific regulation of synaptic properties, myelin thickness, and gene expression. We also found that blood FEDORA levels have diagnostic significance for depressed women. These findings demonstrate the important role played by lncRNAs, and FEDORA in particular, in shaping the sex-specific landscape of the brain and contributing to sex differences in depression.

RNA regulation in brain function and disease 2022 (NeuroRNA): A conference report

“…A previous study highlighted that a substantial part of the differentially expressed genes in the brains of depressed humans (~1/3) belong to lncRNA-encoding genes and that these transcripts display region- and sex-specific patterns of the regulation (Issler et al, 2020 ). Her current project focused on one particular lncRNA called FEDORA, which was found to be positively correlated with depression susceptibility in women (Issler et al, 2021 ). Last but not the least, a new insight into circRNA Cdr1as association with brain homeostasis over daily light–dark (LD) cycles was introduced by Andranik Ivanov (Berlin Institute of Health, Berlin, Germany).…”