The long noncoding RNA FEDORA is a cell type– and sex-specific regulator of depression

Orna Issler, Yentl Y. van der Zee, Aarthi Ramakrishnan, Sunhui Xia, Alexander K. Zinsmaier, Chunfeng Tan, Wei Li, Caleb J. Browne, Deena M. Walker, Marine Salery, Angélica Torres-Berrío, Rita Futamura, Julia E. Duffy, Benoit Labonte, Matthew J. Girgenti, Carol A. Tamminga, Jeffrey L. Dupree, Yan Dong, James W. Murrough, Li ShenEric J. Nestler

Research output: Contribution to journalArticlepeer-review

5 Scopus citations


Women suffer from depression at twice the rate of men, but the underlying molecular mechanisms are poorly understood. Here, we identify marked baseline sex differences in the expression of long noncoding RNAs (lncRNAs), a class of regulatory transcripts, in human postmortem brain tissue that are profoundly lost in depression. One such human lncRNA, RP11-298D21.1 (which we termed FEDORA), is enriched in oligodendrocytes and neurons and up-regulated in the prefrontal cortex (PFC) of depressed females only. We found that virally expressing FEDORA selectively either in neurons or in oligodendrocytes of PFC 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 implications for depressed women and are associated with clinical response to ketamine. 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.

Original languageEnglish (US)
Article numbereabn9494
JournalScience Advances
Issue number48
StatePublished - Dec 2022
Externally publishedYes

ASJC Scopus subject areas

  • General


Dive into the research topics of 'The long noncoding RNA FEDORA is a cell type– and sex-specific regulator of depression'. Together they form a unique fingerprint.

Cite this