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

ABSTRACT: Major depressive disorder (MDD) strikes women twice as often as men, yet the molecular mechanisms contributing to this sex difference are poorly understood. Here, we explored the regulation of long noncoding RNAs (lncRNAs) in human postpartum brain tissue and found a robust baseline sex difference in lncRNA expression levels that is profoundly lost in MDD. We highlight one such lncRNA, that is upregulated in females with MDD, therefore we named FEDORA. FEDORA arose in humans and is expressed primarily in oligodendrocytes as well as in neurons. We tested FEDORA’s causal role in MDD, by utilizing a cell-type-specific approach to express it in the prefrontal cortex (PFC) of mice of both sexes. We found that expressing FEDORA in either neurons or oligodendrocytes promoted depression-like behaviors in females only, which mirrored the human sex-specific phenotype. These behavioral changes were associated with cell-type-specific changes in electrophysiological properties, myelin thickness, and gene expression. Finally, we found that blood FEDORA levels have diagnostic and prognostic features only for women with MDD. Together, these findings suggest that lncRNAs play key roles in shaping the sex-specific landscape of the brain and contribute to sex differences in MDD.

ORGANISM(S): Mus musculus

PROVIDER: GSE188930 | GEO | 2022/10/07

REPOSITORIES: GEO

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Sex-specific Transcriptional Signatures in Human Depression

Project description:Rational: Major depressive disorder (MDD) is a leading cause of disease burden worldwide. While the incidence, symptoms and treatment of MDD all point toward major sex differences, the molecular mechanisms underlying this sexual dimorphism remain largely unknown. Methods: Here, combining differential expression and gene coexpression network analyses, we provide a comprehensive characterization of male and female transcriptional profiles associated with MDD across 6 brain regions. We overlap our human profiles with those from a mouse model of chronic variable stress and capitalize on converging pathways to define molecular and physiological mechanisms underlying the expression of stress susceptibility in males and females. Results: Our results show a major rearrangement of transcriptional patterns in MDD, with limited overlap between males and females, an effect seen in depressed humans and in stressed mice. We identify key regulators of sex-specific gene networks underlying MDD and confirm their sex-specific impact as mediators of stress susceptibility. For example, downregulation of the female-specific hub gene DUSP6 in prefrontal cortex mimics stress susceptibility in females only by increasing ERK signaling and pyramidal neuron excitability. Such DUSP6 downregulation also recapitulates the transcriptional remodeling that occurs in PFC of depressed females. Conclusions: Together, our findings reveal dramatic sexual dimorphism at the transcriptional level in MDD and highlight the importance of studying sex-specific treatments for this disorder.

2017-08-12 | GSE102556 | GEO

Pre-histopathological and sex-biased hippocampal pathology in the 5XFAD mouse model of Alzheimer's disease: a multi-omic analysis

Project description:Like many neurological disorders, Alzheimerâ€™s disease has a sex-biased epidemiological profile, affecting approximately twice as many women as men. The cause of this sex difference has yet to be elucidated. To identify molecular correlates of this sex bias, we investigated molecular pathology in females and males using the 5XFAD genetic mouse model of Alzheimerâ€™s disease. We profiled the transcriptome and proteome of the mouse hippocampus during early stages of disease development (1, 2, and 4 months) with RNA-sequencing and Liquid-chromatography mass spectrometry.

2018-10-10 | PXD006587 | Pride

Sex-specific role for SLIT1 in regulating stress susceptibility

Project description:Major depressive disorder (MDD) is a pervasive and debilitating syndrome characterized by mood disturbances, anhedonia, and alterations in cognition. While the prevalence of MDD is twice as high for women compared to men, little is known about the molecular mechanisms that drive sex differences in depression susceptibility. We discovered that Slit Guidance Ligand 1 (SLIT1), a secreted protein essential for axonal navigation and molecular guidance in cellular migration, is downregulated in the ventromedial prefrontal cortex (vmPFC) of depressed women compared to healthy controls, but not depressed men. This sex-specific downregulation of Slit1 was also observed in the vmPFC of mice exposed to chronic variable stress. To identify a causal, sex-specific role for SLIT1 in depression-related behavioral abnormalities, we performed knockdown (KD) of Slit1 expression in the vmPFC of male and female mice. When combined with stress exposure, vmPFC Slit1 KD reflected the human condition by inducing a sex-specific increase in anxiety- and depression-like behavioral abnormalities in female mice with no effect seen in male mice. Further, we found that vmPFC Slit1 KD caused a pronounced reduction in dendritic arborization and concomitant alterations to electrophysiological properties of vmPFC pyramidal neurons in females. Additionally, RNA-sequencing analysis of the vmPFC following Slit1 KD in female mice revealed an augmented transcriptional stress signature. Together, our findings establish a crucial role for SLIT1 in regulating neurophysiological and transcriptional responses to stress within the vmPFC, and provide mechanistic insight into novel signaling pathways and molecular factors influencing sex differences in depression susceptibility.

2023-09-29 | GSE158993 | GEO

Molecular and functional sex differences of noradrenergic neurons in the mouse locus coeruleus [Illumina]

Project description:Preclinical work has long focused only on male animals, even though sexual divergence in both baseline behaviors and drug responses clearly impact treatment outcomes in patients. Psychiatric disorders are notably divergent, with males showing higher prevalence of ADHD and ASD, and females GAD and MDD. This divergence is reflected in quantitative differences in subclincal behaviors. The Noradrenergic neurotransmitter system is targeted by many psychiatric drugs, but is relatively uncharacterized at a molecular level. We developed a mouse to profile these neurons, defining their both a baseline transcriptome, including druggable receptors, and their molecular response to stimulation. We also discovered a remarkable sexual divergence in their gene expression, including functionally increased expression of the EP3 receptor in females – a difference that can be used to modulate stress-induced anxiety in a sex specific manner. These findings underscore the need to conduct preclinical studies in a manner balanced for sex, and suggest that baseline differences in noradrenergic neurons could underlay sexually divergent behaviors.

2018-04-30 | GSE100004 | GEO

Molecular and functional sex differences of noradrenergic neurons in the mouse locus coeruleus [Affymetrix]

2018-04-30 | GSE100002 | GEO

Sex Differences in the Skeletal Muscle Response to a High Fat, High Sucrose Diet in Rats

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2024-03-31 | GSE228215 | GEO

Explore plasma exosomal derived lncRNA and mRNA expression in adolescent with major depressive disorder

Project description:Major Depressive Disorder (MDD) during adolescence significantly jeopardizes both mental and physical well-being. However, the etiology underlying MDD in adolescents remains unclear. Extracellular vesicles (EVs), long noncoding RNAs (lncRNAs) and microRNAs (miRNAs) played significant roles in regulating various biological processes. 10 drug-naïve adolescents with MDD patients and 10 age, sex matched healthy control were enrolled. Draw whole blood from the cubital vein from participants, plasma was centrifuged at 3500rpm 10min. An exoRNeasy Midi and Maxi Kits were used to isolate the plasma exosome and extract exosomal RNA per the manufacturer’s instruction. Microarray technology was used to detect lncRNAs and mRNAs. Bioinformatics analysis was applied to explore function of differential expression genes and screen candidate genes.

2022-11-17 | GSE217811 | GEO

Sex-specific role for the long non-coding RNA linc00473 in depression

Project description: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 of depressed females but not males. Using viral-mediated gene transfer to express linc00473 in mouse prefrontal cortex 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.

2020-04-02 | GSE138677 | GEO

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Project description:Aging and sex have a strong influence on the functional capacity of the immune system. In general, the immune response in females is stronger than that in males, but there is little information about the effect of aging on this difference. To address this question, we performed a transcriptomic analysis of peripheral blood mononuclear cells derived from nonagenarians and young controls. We found 337 and 269 genes to be differentially expressed (p<0.05, fold change >1.5 or <-1.5) in nonagenarian females and males, respectively; 177 of these were changed in both sexes. An analysis of the affected signaling pathways revealed a clear sex bias: the number of significantly changed pathways was 43 in females and 40 in males; 23 were shared. These data show that the effects of aging on the immune system are significantly different in males and females. Our study population consisted of 146 nonagenarians (103 females, 43 males) and 30 young controls (19-30 years of age, 21 females, 9 males). In our study, we analyzed the gene expression difference between nonagenarian and control women as well as between nonagenarian and control males and then compared these results.

2013-01-10 | E-GEOD-40366 | biostudies-arrayexpress

Transcriptional analysis of PBMCs reveals sex specific changes in the aging of the immune system

2015-01-22 | E-GEOD-65219 | biostudies-arrayexpress

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