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Sex-Specific Role for the Long Non-coding RNA LINC00473 in Depression
Open accessAbstract
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.
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“Using whole-genome sequencing, a recent study found that lncRNAs accounted for 30% of the differences between patients with depression and control populations.311”
From Epigenetic regulation in major depression and other stress-related disorders: molecular mechanisms, clinical relevance and therapeutic potential (2023) · cites this paper as [311]
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Cites
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Yuan, M., Yang, B., Rothschild, G., Mann, J. J., Sanford, L. D., Tang, X., Huang, C., Wang, C., & Zhang, W. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01519-z · Cited by 246
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Neurobiological basis of stress resilience
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Self-citationDevelopmental dynamics of RNA translation in the human brain
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Large-Scale Transcriptomics Studies Provide Insight Into Sex Differences in Depression
Seney, M. L., Glausier, J. R., & Sibille, E. L. (2021) · Biological Psychiatry · doi:10.1016/j.biopsych.2020.12.025 · Cited by 100
Metadata
- Authors
- Issler, O., van der Zee, Y. Y., Ramakrishnan, A., Wang, J., Tan, C., Loh, Y.-H. E., Purushothaman, I., Walker, D. M., Lorsch, Z. S., Hamilton, P. J., Peña, C. J., Flaherty, E., Hartley, B. J., Torres-Berrío, A., Parise, E. M., Kronman, H., Duffy, J. E., Estill, M. S., Calipari, E. S., Labonté, B., Neve, R. L., Tamminga, C. A., Brennand, K. J., Dong, Y., Shen, L., & Nestler, E. J.
- Affiliations
- Icahn School of Medicine at Mount Sinai (US)
- Maastricht University (NL)
- University of Pittsburgh (US)
- The University of Texas Southwestern Medical Center (US)
- Massachusetts General Hospital (US)
- Corresponding author
- Nestler, Eric J.
- ORCID
- Issler, Orna
- van der Zee, Yentl Y.
- Ramakrishnan, Aarthi
- Wang, Junshi
- Tan, Chunfeng
- Loh, Yong-Hwee E.
- Walker, Deena M.
- Lorsch, Zachary S.
- Hamilton, Peter J.
- Peña, Catherine J.
- Flaherty, Erin
- Parise, Eric M.
- Kronman, Hope
- Estill, Molly S.
- Calipari, Erin S.
- Neve, Rachael L.
- Tamminga, Carol A.
- Brennand, Kristen J.
- Dong, Yan
- Shen, Li
- Nestler, Eric J.
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2020-06
- Volume
- 106
- Issue
- 6
- Pages
- 912-926.e5
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC7305959
- OpenAlex
- W3017236879
- Cited by
- 156
- References
- 105
- Citations by year
- 2026: 15 · 2025: 24 · 2024: 25 · 2023: 32 · 2022: 25 · 2021: 27 · 2020: 8
- FWCI
- 13.79
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- Research Publications (Maastricht University) (publishedVersion, other-oa)
- PubMed Central (acceptedVersion)
- Research Publications (Maastricht University) (submittedVersion, other-oa)
- Funders
- Hope for Depression Research Foundation
- National Institute of Mental Health
- Topics
- Health Sciences › Medicine › Pharmacology (medical) › Treatment of Major Depression
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer-related molecular mechanisms research
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Keywords
- LINC00473, long non-coding RNA, depression, sex differences, stress resilience, prefrontal cortex, depression in women, CREB, synaptic function, neuronal gene expression
- MeSH terms
- RNA-Seq, Adult, Aged, Aged, 80 and over, Animals, Behavior, Animal, Depression, Major Depressive Disorder, Depressive Disorder, Major, Female, Humans, Male, Mice, Transgenic, Middle Aged, Neurons, Sex Factors, Stress, Psychological, Down-Regulation, Prefrontal Cortex, Mice, Resilience, Psychological, Young Adult, RNA, Long Noncoding
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