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Sex-specific transcriptional and proteomic signatures in schizophrenia.

ABSTRACT: It has remained unclear why schizophrenia typically manifests after adolescence and which neurobiological mechanisms are underlying the cascade leading to the actual onset of the illness. Here we show that the use of induced pluripotent stem cell-derived neurons of monozygotic twins from pairs discordant for schizophrenia enhances disease-specific signal by minimizing genetic heterogeneity. In proteomic and pathway analyses, clinical illness is associated especially with altered glycosaminoglycan, GABAergic synapse, sialylation, and purine metabolism pathways. Although only 12% of all 19,462 genes are expressed differentially between healthy males and females, up to 61% of the illness-related genes are sex specific. These results on sex-specific genes are replicated in another dataset. This implies that the pathophysiology differs between males and females, and may explain why symptoms appear after adolescence when the expression of many sex-specific genes change, and suggests the need for sex-specific treatments.

SUBMITTER: Tiihonen J

PROVIDER: S-EPMC6718673 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Sex-specific transcriptional and proteomic signatures in schizophrenia.

Tiihonen Jari J Koskuvi Marja M Storvik Markus M Hyötyläinen Ida I Gao Yanyan Y Puttonen Katja A KA Giniatullina Raisa R Poguzhelskaya Ekaterina E Ojansuu Ilkka I Vaurio Olli O Cannon Tyrone D TD Lönnqvist Jouko J Therman Sebastian S Suvisaari Jaana J Kaprio Jaakko J Cheng Lesley L Hill Andrew F AF Lähteenvuo Markku M Tohka Jussi J Giniatullin Rashid R Lehtonen Šárka Š Koistinaho Jari J

Nature communications 20190902 1

It has remained unclear why schizophrenia typically manifests after adolescence and which neurobiological mechanisms are underlying the cascade leading to the actual onset of the illness. Here we show that the use of induced pluripotent stem cell-derived neurons of monozygotic twins from pairs discordant for schizophrenia enhances disease-specific signal by minimizing genetic heterogeneity. In proteomic and pathway analyses, clinical illness is associated especially with altered glycosaminoglyca ...[more]

PMID: 31477693

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Project description:BackgroundConverging evidence suggests that stress alters behavioural responses in a sex-specific manner; however, the underlying molecular mechanisms of stress remain largely unknown.MethodsWe adapted unpredictable maternal separation (UMS) and adult restraint stress (RS) paradigms to mimic stress in rats in early life or adulthood, respectively. The sexual dimorphism of the prefrontal cortex was noted, and we performed RNA sequencing (RNA-Seq) to identify specific genes or pathways responsible for sexually dimorphic responses to stress. We then performed quantitative reverse transcription polymerase chain reaction (qRT-PCR) to verify the results of RNA-Seq.ResultsFemale rats exposed to either UMS or RS showed no negative effects on anxiety-like behaviours, whereas the emotional functions of the PFC were impaired markedly in stressed male rats. Leveraging differentially expressed genes (DEG) analyses, we identified sex-specific transcriptional profiles associated with stress. There were many overlapping DEGs between UMS and RS transcriptional data sets, where 1406 DEGs were associated with both biological sex and stress, while only 117 DEGs were related to stress. Notably, Uba52 and Rpl34-ps1 were the first-ranked hub gene in 1406 and 117 DEGs respectively, and Uba52 was higher than Rp134-ps1, suggesting that stress may have led to a more pronounced effect on the set of 1406 DEGs. Pathway analysis revealed that 1406 DEGs were primarily enriched in ribosomal pathway. These results were confirmed by qRT-PCR.LimitationsSex-specific transcriptional profiles associated with stress were identified in this study, but more in-depth experiments, such as single-cell sequencing and manipulation of male and female gene networks in vivo, are needed to verify our findings.ConclusionOur findings show sex-specific behavioural responses to stress and highlight sexual dimorphism at the transcriptional level, shedding light on developing sex-specific therapeutic strategies for stress-related psychiatric disorders.

Project description:Despite their diminutive size, islets of Langerhans play a large role in maintaining systemic energy balance in the body. New technologies have enabled us to go from studying the whole pancreas to isolated whole islets, to partial islet sections, and now to islet substructures isolated from within the islet. Using a microfluidic nanodroplet-based proteomics platform coupled with laser capture microdissection and field asymmetric waveform ion mobility spectrometry, we present an in-depth investigation of protein profiles specific to features within the islet. These features include the islet-acinar interface vascular tissue, inner islet vasculature, isolated endocrine cells, whole islet with vasculature, and acinar tissue from around the islet. Compared to interface vasculature, unique protein signatures observed in the inner vasculature indicate increased innervation and intra-islet neuron-like crosstalk. We also demonstrate the utility of these data for identifying localized structure-specific drug–target interactions using existing protein/drug binding databases. Graphical Abstract Highlights • We differentiated intra-islet substructures by their proteome profiles in situ.• We demonstrated significant functional differences between vasculature types.• Novel differences in innervation and colocalization of nerves were observed.• We demonstrated a depth of coverage useful for predictive binding discovery assays.• We identified pathways with these techniques that could aid drug characterizations. In Brief Improved sample handling techniques have enabled us to go from studying the whole pancreas, to isolated whole islets, to islet sections, and now to islet substructures isolated from within islet sections. Using a microfluidic nanodroplet-based proteomics platform coupled with laser capture microdissection and field asymmetric waveform ion mobility spectrometry, we present an in-depth investigation of protein profiles from intra-islet features. The protein coverage and expression profiles obtained are sufficient to fully distinguish each of these features while presenting their own unique proteome signatures.

Project description:Investigating sex as a biological variable is key to determine obesity manifestation and treatment response. Individual neuroimaging modalities have uncovered mechanisms related to obesity and altered ingestive behaviours. However, few, if any, studies have integrated data from multi-modal brain imaging to predict sex-specific brain signatures related to obesity. We used a data-driven approach to investigate how multi-modal MRI and clinical features predict a sex-specific signature of participants with high body mass index (overweight/obese) compared to non-obese body mass index in a sex-specific manner. A total of 78 high body mass index (55 female) and 105 non-obese body mass index (63 female) participants were enrolled in a cross-sectional study. All participants classified as high body mass index had a body mass index greater than 25 kg/m2 and non-obese body mass index had a body mass index between 19 and 20 kg/m2. Multi-modal neuroimaging (morphometry, functional resting-state MRI and diffusion-weighted scan), along with a battery of behavioural and clinical questionnaires were acquired, including measures of mood, early life adversity and altered ingestive behaviours. A Data Integration Analysis for Biomarker discovery using Latent Components was conducted to determine whether clinical features, brain morphometry, functional connectivity and anatomical connectivity could accurately differentiate participants stratified by obesity and sex. The derived models differentiated high body mass index against non-obese body mass index participants, and males with high body mass index against females with high body mass index obtaining balanced accuracies of 77 and 75%, respectively. Sex-specific differences within the cortico-basal-ganglia-thalamic-cortico loop, the choroid plexus-CSF system, salience, sensorimotor and default-mode networks were identified, and were associated with early life adversity, mental health quality and greater somatosensation. Results showed multi-modal brain signatures suggesting sex-specific cortical mechanisms underlying obesity, which fosters clinical implications for tailored obesity interventions based on sex.

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Sex-specific transcriptional and proteomic signatures in schizophrenia.

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Sex-specific transcriptional and proteomic signatures in schizophrenia.

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