TY - JOUR
T1 - The long noncoding RNA FEDORA is a cell type– and sex-specific regulator of depression
AU - Issler, Orna
AU - van der Zee, Yentl Y.
AU - Ramakrishnan, Aarthi
AU - Xia, Sunhui
AU - Zinsmaier, Alexander K.
AU - Tan, Chunfeng
AU - Li, Wei
AU - Browne, Caleb J.
AU - Walker, Deena M.
AU - Salery, Marine
AU - Torres-Berrío, Angélica
AU - Futamura, Rita
AU - Duffy, Julia E.
AU - Labonte, Benoit
AU - Girgenti, Matthew J.
AU - Tamminga, Carol A.
AU - Dupree, Jeffrey L.
AU - Dong, Yan
AU - Murrough, James W.
AU - Shen, Li
AU - Nestler, Eric J.
N1 - Publisher Copyright:
Copyright © 2022 The Authors.
PY - 2022/12
Y1 - 2022/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85143105159&partnerID=8YFLogxK
U2 - 10.1126/sciadv.abn9494
DO - 10.1126/sciadv.abn9494
M3 - Article
C2 - 36449610
AN - SCOPUS:85143105159
SN - 2375-2548
VL - 8
JO - Science advances
JF - Science advances
IS - 48
M1 - eabn9494
ER -