Sex-Specific Role for the Long Non-coding RNA LINC00473 in Depression

Orna Issler, Yentl Y. van der Zee, Aarthi Ramakrishnan, Junshi Wang, Chunfeng Tan, Yong-Hwee E. Loh, Immanuel Purushothaman, Deena M. Walker, Zachary S. Lorsch, Peter J. Hamilton, Catherine J. Pena, Erin Flaherty, Brigham J. Hartley, Angelica Torres-Berrio, Eric M. Parise, Hope Kronman, Julia E. Duffy, Molly S. Estill, Erin S. Calipari, Benoit LabonteRachael L. Neve, Carol A. Tamminga, Kristen J. Brennand, Yan Dong, Li Shen, Eric J. Nestler*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

37 Citations (Web of Science)

Abstract

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 (PFC) of depressed females but not males. Using viral-mediated gene transfer to express LINC00473 in adult mouse PFC 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.

Original languageEnglish
Pages (from-to)912-+
Number of pages20
JournalNeuron
Volume106
Issue number6
DOIs
Publication statusPublished - 17 Jun 2020

Keywords

  • PREFRONTAL CORTEX
  • UNIQUE FEATURES
  • SOCIAL DEFEAT
  • GENOME-WIDE
  • STRESS
  • CELLS
  • EVOLUTION
  • SUSCEPTIBILITY
  • TRANSCRIPTION
  • LOCALIZATION

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