Widespread transcriptional disruption of the microRNA biogenesis machinery in brain and peripheral tissues of individuals with schizophrenia

Abstract In schizophrenia, altered transcription in brain and peripheral tissues may be due to altered expression of the microRNA biogenesis machinery genes. In this study, we explore the expression of these genes both at the cerebral and peripheral levels. We used shinyGEO application to analyze gene expression from ten Gene Expression Omnibus datasets, in order to perform differential expression analyses for eight genes encoding the microRNA biogenesis machinery. First, we compared expression of the candidate genes between control subjects and individuals with schizophrenia in postmortem cerebral samples from seven different brain regions. Then, we compared the expression of the candidate genes between control subjects and individuals with schizophrenia in three peripheral tissues. In brain and peripheral tissues of individuals with schizophrenia, we report distinct altered expression patterns of the microRNA biogenesis machinery genes. In the dorsolateral prefrontal cortex, associative striatum and cerebellum of individuals with schizophrenia, we observed an overexpression pattern of some candidate genes suggesting a heightened miRNA production in these brain regions. Additionally, mixed transcriptional abnormalities were identified in the hippocampus. Moreover, in the blood and olfactory epithelium of individuals with schizophrenia, we observed distinct aberrant transcription patterns of the candidate genes. Remarkably, in individuals with schizophrenia, we report DICER1 overexpression in the dorsolateral prefrontal cortex, hippocampus and cerebellum as well as a congruent DICER1 upregulation in the blood compartment suggesting that it may represent a peripheral marker. Transcriptional disruption of the miRNA biogenesis machinery may contribute to schizophrenia pathogenesis both in brain and peripheral tissues.

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Transcriptome-scale spatial gene expression in the human dorsolateral prefrontal cortex

10.1101/2020.02.28.969931 ◽

2020 ◽

Cited By ~ 10

Author(s):

Kristen R. Maynard ◽

Leonardo Collado-Torres ◽

Lukas M. Weber ◽

Cedric Uytingco ◽

Brianna K. Barry ◽

...

Keyword(s):

Gene Expression ◽

Prefrontal Cortex ◽

Web Application ◽

Dorsolateral Prefrontal Cortex ◽

Large Scale ◽

Brain Regions ◽

Autism Spectrum ◽

Sequencing Data ◽

Dorsolateral Prefrontal ◽

Transcriptomics Data

AbstractWe used the 10x Genomics Visium platform to define the spatial topography of gene expression in the six-layered human dorsolateral prefrontal cortex (DLPFC). We identified extensive layer-enriched expression signatures, and refined associations to previous laminar markers. We overlaid our laminar expression signatures onto large-scale single nuclei RNA sequencing data, enhancing spatial annotation of expression-driven clusters. By integrating neuropsychiatric disorder gene sets, we showed differential layer-enriched expression of genes associated with schizophrenia and autism spectrum disorder, highlighting the clinical relevance of spatially-defined expression. We then developed a data-driven framework to define unsupervised clusters in spatial transcriptomics data, which can be applied to other tissues or brain regions where morphological architecture is not as well-defined as cortical laminae. We lastly created a web application for the scientific community to explore these raw and summarized data to augment ongoing neuroscience and spatial transcriptomics research (http://research.libd.org/spatialLIBD).

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Regional heterogeneity in gene expression, regulation and coherence in hippocampus and dorsolateral prefrontal cortex across development and in schizophrenia

10.1101/426213 ◽

2018 ◽

Cited By ~ 3

Author(s):

L Collado-Torres ◽

EE Burke ◽

A Peterson ◽

JH Shin ◽

RE Straub ◽

...

Keyword(s):

Gene Expression ◽

Prefrontal Cortex ◽

Brain Region ◽

Dorsolateral Prefrontal Cortex ◽

Large Scale ◽

Brain Regions ◽

Second Phase ◽

Regional Heterogeneity ◽

Surrogate Variable Analysis ◽

Dorsolateral Prefrontal

AbstractRecent large-scale genomics efforts have better characterized the molecular correlates of schizophrenia in postmortem human neocortex, but not hippocampus which is a brain region prominently implicated in its pathogenesis. Here in the second phase of the BrainSeq Consortium (Phase II), we have generated RiboZero RNA-seq data for 900 samples across both the dorsolateral prefrontal cortex (DLPFC) and the hippocampus (HIPPO) for 551 individuals (286 affected by schizophrenia disorder: SCZD). We identify substantial regional differences in gene expression, in both pre- and post-natal life, and find widespread differences in how genes are regulated across development. By extending quality surrogate variable analysis (qSVA) to multiple brain regions, we identified 48 and 245 differentially expressed genes (DEG) by SCZD diagnosis (FDR<5%) in HIPPO and DLPFC, respectively, with surprisingly minimal overlap in DEG between the two brain regions. We further identified 205,618 brain region-dependent eQTLs (FDR<1%) and found that 124 GWAS risk loci contain eQTLs in at least one of the regions. We also identify potential molecular correlates of in vivo evidence of altered prefrontal-hippocampal functional coherence in schizophrenia. These results underscore the complexity and regional heterogeneity of the transcriptional correlates of schizophrenia, and suggest future schizophrenia therapeutics may need to target molecular pathologies localized to specific brain regions.

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Molecular pathology associated with altered synaptic transcriptome in the dorsolateral prefrontal cortex of depressed subjects

Translational Psychiatry ◽

10.1038/s41398-020-01159-9 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Yuta Yoshino ◽

Bhaskar Roy ◽

Nilesh Kumar ◽

M. Shahid Mukhtar ◽

Yogesh Dwivedi

Keyword(s):

Gene Expression ◽

Cell Death ◽

Prefrontal Cortex ◽

Dorsolateral Prefrontal Cortex ◽

Gene Network ◽

Nervous System Development ◽

Network Analyses ◽

Dorsolateral Prefrontal ◽

Total Fraction ◽

Transcriptomic Changes

AbstractDisrupted synaptic plasticity is the hallmark of major depressive disorder (MDD), with accompanying changes at the molecular and cellular levels. Often, the maladaptive molecular changes at the synapse are the result of global transcriptional reprogramming dictated by activity-dependent synaptic modulation. Thus far, no study has directly studied the transcriptome-wide expression changes locally at the synapse in MDD brain. Here, we have examined altered synaptic transcriptomics and their functional relevance in MDD with a focus on the dorsolateral prefrontal cortex (dlPFC). RNA was isolated from total fraction and purified synaptosomes of dlPFC from well-matched 15 non-psychiatric controls and 15 MDD subjects. Transcriptomic changes in synaptic and total fractions were detected by next-generation RNA-sequencing (NGS) and analyzed independently. The ratio of synaptic/total fraction was estimated to evaluate a shift in gene expression ratio in MDD subjects. Bioinformatics and network analyses were used to determine the biological relevance of transcriptomic changes in both total and synaptic fractions based on gene–gene network, gene ontology (GO), and pathway prediction algorithms. A total of 14,005 genes were detected in total fraction. A total of 104 genes were differentially regulated (73 upregulated and 31 downregulated) in MDD group based on 1.3-fold change threshold and p < 0.05 criteria. In synaptosomes, out of 13,236 detectable genes, 234 were upregulated and 60 were downregulated (>1.3-fold, p < 0.05). Several of these altered genes were validated independently by a quantitative polymerase chain reaction (qPCR). GO revealed an association with immune system processes and cell death. Moreover, a cluster of genes belonged to the nervous system development, and psychological disorders were discovered using gene–gene network analysis. The ratio of synaptic/total fraction showed a shift in expression of 119 genes in MDD subjects, which were primarily associated with neuroinflammation, interleukin signaling, and cell death. Our results suggest not only large-scale gene expression changes in synaptosomes, but also a shift in the expression of genes from total to synaptic fractions of dlPFC of MDD subjects with their potential role in immunomodulation and cell death. Our findings provide new insights into the understanding of transcriptomic regulation at the synapse and their possible role in MDD pathogenesis.

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Publisher Correction: Transcriptome-scale spatial gene expression in the human dorsolateral prefrontal cortex

Nature Neuroscience ◽

10.1038/s41593-021-00817-5 ◽

2021 ◽

Author(s):

Kristen R. Maynard ◽

Leonardo Collado-Torres ◽

Lukas M. Weber ◽

Cedric Uytingco ◽

Brianna K. Barry ◽

...

Keyword(s):

Gene Expression ◽

Prefrontal Cortex ◽

Dorsolateral Prefrontal Cortex ◽

Dorsolateral Prefrontal

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P.1.b.006 Cannabinoid CB2 receptor gene expression alterations in the dorsolateral prefrontal cortex and amygdala of suicide victims

European Neuropsychopharmacology ◽

10.1016/s0924-977x(12)70234-1 ◽

2012 ◽

Vol 22 ◽

pp. S166 ◽

Cited By ~ 2

Author(s):

M.S. Garcia-Gutierrez ◽

F. Navarrete ◽

S. Giner ◽

J. Manzanares

Keyword(s):

Gene Expression ◽

Prefrontal Cortex ◽

Dorsolateral Prefrontal Cortex ◽

Receptor Gene ◽

Cb2 Receptor ◽

Dorsolateral Prefrontal ◽

Gene Expression Alterations ◽

Receptor Gene Expression

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Loneliness 5 years ante-mortem is associated with disease-related differential gene expression in postmortem dorsolateral prefrontal cortex

Translational Psychiatry ◽

10.1038/s41398-017-0086-2 ◽

2018 ◽

Vol 8 (1) ◽

Cited By ~ 8

Author(s):

Turhan Canli ◽

Lei Yu ◽

Xiaoqing Yu ◽

Hongyu Zhao ◽

Debra Fleischman ◽

...

Keyword(s):

Gene Expression ◽

Prefrontal Cortex ◽

Differential Gene Expression ◽

Dorsolateral Prefrontal Cortex ◽

Dorsolateral Prefrontal ◽

Differential Gene

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DDX19B is differentially expressed in the brains of patients with psychotic disorders.

10.31219/osf.io/h3u72 ◽

2020 ◽

Author(s):

Shahan Mamoor

Keyword(s):

Gene Expression ◽

Prefrontal Cortex ◽

Microarray Data ◽

Schizoaffective Disorder ◽

Dorsolateral Prefrontal Cortex ◽

Psychotic Disorders ◽

Differentially Expressed ◽

Dorsolateral Prefrontal ◽

Significant Gene

We used public and published microarray data (1, 2) to identify the most significant gene expression changes in the brains of patients with psychotic disorders. We DDX19B as differentially expressed in the dorsolateral prefrontal cortex of patients with schizophrenia and schizoaffective disorder. In neurons of the dorsolateral prefrontal cortex from patients with psychotic disorders, DDX19B expression was significantly decreased.

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Improving Emotion Regulation Through Real-Time Neurofeedback Training on the Right Dorsolateral Prefrontal Cortex: Evidence From Behavioral and Brain Network Analyses

Frontiers in Human Neuroscience ◽

10.3389/fnhum.2021.620342 ◽

2021 ◽

Vol 15 ◽

Author(s):

Linlin Yu ◽

Quanshan Long ◽

Yancheng Tang ◽

Shouhang Yin ◽

Zijun Chen ◽

...

Keyword(s):

Emotion Regulation ◽

Prefrontal Cortex ◽

Real Time ◽

Dorsolateral Prefrontal Cortex ◽

Near Infrared ◽

Self Regulation ◽

Brain Regions ◽

Functional Near Infrared Spectroscopy ◽

Network Analyses ◽

Dorsolateral Prefrontal

We investigated if emotion regulation can be improved through self-regulation training on non-emotional brain regions, as well as how to change the brain networks implicated in this process. During the training period, the participants were instructed to up-regulate their right dorsolateral prefrontal cortex (rDLPFC) activity according to real-time functional near-infrared spectroscopy (fNIRS) neurofeedback signals, and there was no emotional element. The results showed that the training significantly increased emotion regulation, resting-state functional connectivity (rsFC) within the emotion regulation network (ERN) and frontoparietal network (FPN), and rsFC between the ERN and amygdala; however, training did not influence the rsFC between the FPN and the amygdala. However, self-regulation training on rDLPFC significantly improved emotion regulation and generally increased the rsFCs within the networks; the rsFC between the ERN and amygdala was also selectively increased. The present study also described a safe approach that may improve emotion regulation through self-regulation training on non-emotional brain regions.

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Variable telomere length across post-mortem human brain regions and specific reduction in the hippocampus of major depressive disorder

Translational Psychiatry ◽

10.1038/tp.2015.134 ◽

2015 ◽

Vol 5 (9) ◽

pp. e636-e636 ◽

Cited By ~ 51

Author(s):

F Mamdani ◽

B Rollins ◽

L Morgan ◽

R M Myers ◽

J D Barchas ◽

...

Keyword(s):

Major Depressive Disorder ◽

Prefrontal Cortex ◽

Depressive Disorder ◽

Telomere Length ◽

Dorsolateral Prefrontal Cortex ◽

Brain Regions ◽

Cellular Aging ◽

Post Mortem ◽

Major Depressive ◽

Dorsolateral Prefrontal

Abstract Stress can be a predisposing factor to psychiatric disorders and has been associated with decreased neurogenesis and reduced hippocampal volume especially in depression. Similarly, in white blood cells chronic psychological stress has been associated with telomere shortening and with mood disorders and schizophrenia (SZ). However, in previous post-mortem brain studies from occipital cortex and cerebellum, no difference in telomere length was observed in depression. We hypothesized that in psychiatric disorders, stress-driven accelerated cellular aging can be observed in brain regions particularly sensitive to stress. Telomere length was measured by quantitative-PCR in five brain regions (dorsolateral prefrontal cortex, hippocampus (HIPP), amygdala, nucleus accumbens and substantia nigra (SN)) in major depressive disorder (MDD), bipolar disorder, SZ and normal control subjects (N=40, 10 subjects per group). We observed significant differences in telomere length across brain regions suggesting variable levels of cell aging, with SN and HIPP having the longest telomeres and the dorsolateral prefrontal cortex the shortest. A significant decrease (P<0.02) in telomere length was observed specifically in the HIPP of MDD subjects even after controlling for age. In the HIPP of MDD subjects, several genes involved in neuroprotection and in stress response (FKBP5, CRH) showed altered levels of mRNA. Our results suggest the presence of hippocampal stress-mediated accelerated cellular aging in depression. Further studies are needed to investigate the cellular specificity of these findings.

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