scholarly journals Molecular signatures associated with ZIKV exposure in human cortical neural progenitors

2016 ◽  
Author(s):  
Feiran Zhang ◽  
Christy Hammack ◽  
Sarah C. Ogden ◽  
Yichen Cheng ◽  
Emily M. Lee ◽  
...  
Keyword(s):  
Neural Progenitor Cells ◽  
Expression Profiles ◽  
Molecular Signatures ◽  
Zikv Infection ◽  
Host Interactions ◽  
Expression Of Genes ◽  
Dna Replication And Repair ◽  
Human Neural Progenitor Cells ◽  
Induced Apoptosis ◽  
And Function

AbstractZika virus (ZIKV) infection causes microcephaly and has been linked to other brain abnormalities. How ZIKV impairs brain development and function is unclear. Here we systematically profiled transcriptomes of human neural progenitor cells exposed to Asian ZIKVC, African ZIKVM, and dengue virus (DENV). In contrast to the robust global transcriptome changes induced by DENV, ZIKV has a more selective and larger impact on expression of genes involved in DNA replication and repair. While overall expression profiles are similar, ZIKVC, but not ZIKVM, induces upregulation of viral response genes and TP53. P53 inhibitors can block the apoptosis induced by both ZIKVC and ZIKVM in hNPCs, with higher potency against ZIKVC-induced apoptosis. Our analyses reveal virus- and strain-specific molecular signatures associated with ZIKV infection. These datasets will help to investigate ZIKV-host interactions and identify neurovirulence determinants of ZIKV.

scholarly journals Effects of Propofol Treatment in Neural Progenitors Derived from Human-Induced Pluripotent Stem Cells

2017 ◽  
Vol 2017 ◽  
pp. 1-12 ◽  
Author(s):  
Bo Long ◽  
Shenglan Li ◽  
Haipeng Xue ◽  
Li Sun ◽  
Dong H. Kim ◽  
...  
Keyword(s):  
Gene Expression ◽  
Neural Progenitor Cells ◽  
Cell Injury ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Induced Pluripotent Stem Cell ◽  
Global Gene Expression ◽  
Affect Cell Viability ◽  
Induced Pluripotent ◽  
Induced Apoptosis

Propofol is an intravenous anesthetic that has been widely used in clinics. Besides its anesthetic effects, propofol has also been reported to influence the regulation of the autonomic system. Controversies exist with regard to whether propofol exposure is safe for pregnant women and young children. In this work, human-induced pluripotent stem cell- (hiPSC-) derived neural progenitor cells (NPCs) were treated with propofol at 20, 50, 100, or 300 μM for 6 h or 24 h, and acute and subacute cell injury, cell proliferation, and apoptosis were evaluated. Comparison of genome-wide gene expression profiles was performed for treated and control iPSC-NPCs. Propofol treatment for 6 h at the clinically relevant concentration (20 or 50 μM) did not affect cell viability, apoptosis, or proliferation, while propofol at higher concentration (100 or 300 μM) decreased NPC viability and induced apoptosis. In addition, 20 μM propofol treatment for 6 h did not alter global gene expression. In summary, propofol treatment at commonly practiced clinical doses for 6 h did not have adverse effects on hiPSC-derived NPCs. In contrast, longer exposure and/or higher concentration could decrease NPC viability and induce apoptosis.

scholarly journals De novo variants in Chinese ASD trios reveal distinct genetic basis underlying autism with and without developmental delay

2021 ◽  
Author(s):  
Jincheng Wang ◽  
Juehua Yu ◽  
Mengdi Wang ◽  
Lingli Zhang ◽  
Kan Yang ◽  
...  
Keyword(s):  
Developmental Delay ◽  
Neural Progenitor Cells ◽  
De Novo ◽  
Neurodevelopmental Disorder ◽  
East Asian ◽  
Asian Population ◽  
Autism Spectrum ◽  
Expression Of Genes ◽  
Genome Wide ◽  
Human Neural Progenitor Cells

Abstract Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder causing impairments in social communication and stereotypical behaviors, often with developmental delay or intellectual disabilities (DD/ID). Accruing evidence indicates that ASD is highly heritable and genome-wide studies on ASD cohorts have defined numerous genetic contributors. Notably, since most of these studies have been performed with individuals of European and Hispanic ancestries, thus there is a paucity of genetic analyses of ASD in the East Asian population. Here, we performed whole-exome sequencing on 772 Chinese ASD trios, combining with a previous 369 ASD trios, to identify de novo variants in 1141 ASD trios. We found that ASD without DD/ID carried less disruptive de novo variants than ASD with DD/ID. Surprisingly, we found that expression of genes with de novo variants in ASD without DD/ID were enriched in a subtype of human neural progenitor cells. Importantly, some ASD risk genes identified in this study are not present in the current ASD gene database, suggesting that there may be unique genetic contributors to ASD with the East Asian ancestry. We validated one such novel ASD candidate gene – SLC35G1 by showing that mice harboring heterozygous deletion of Slc35g1 exhibited defects in social interaction behaviors. Together, this work nominates novel ASD candidate genes and suggests that genome-wide genetic studies in ASD cohorts of different ancestries are essential to reveal the comprehensive genetic architecture of ASD.

scholarly journals Zika Virus Infection Induces DNA Damage Response in Human Neural Progenitors That Enhances Viral Replication

2019 ◽  
Vol 93 (20) ◽  
Author(s):  
Christy Hammack ◽  
Sarah C. Ogden ◽  
Joseph C. Madden ◽  
Angelica Medina ◽  
Chongchong Xu ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Dna Replication ◽  
Zika Virus ◽  
Neural Progenitor Cells ◽  
S Phase ◽  
Zikv Infection ◽  
Phase Arrest ◽  
Damage Response ◽  
Human Neural Progenitor Cells

ABSTRACT Zika virus (ZIKV) infection attenuates the growth of human neural progenitor cells (hNPCs). As these hNPCs generate the cortical neurons during early brain development, the ZIKV-mediated growth retardation potentially contributes to the neurodevelopmental defects of the congenital Zika syndrome. Here, we investigate the mechanism by which ZIKV manipulates the cell cycle in hNPCs and the functional consequence of cell cycle perturbation on the replication of ZIKV and related flaviviruses. We demonstrate that ZIKV, but not dengue virus (DENV), induces DNA double-strand breaks (DSBs), triggering the DNA damage response through the ATM/Chk2 signaling pathway while suppressing the ATR/Chk1 signaling pathway. Furthermore, ZIKV infection impedes the progression of cells through S phase, thereby preventing the completion of host DNA replication. Recapitulation of the S-phase arrest state with inhibitors led to an increase in ZIKV replication, but not of West Nile virus or DENV. Our data identify ZIKV’s ability to induce DSBs and suppress host DNA replication, which results in a cellular environment favorable for its replication. IMPORTANCE Clinically, Zika virus (ZIKV) infection can lead to developmental defects in the cortex of the fetal brain. How ZIKV triggers this event in developing neural cells is not well understood at a molecular level and likely requires many contributing factors. ZIKV efficiently infects human neural progenitor cells (hNPCs) and leads to growth arrest of these cells, which are critical for brain development. Here, we demonstrate that infection with ZIKV, but not dengue virus, disrupts the cell cycle of hNPCs by halting DNA replication during S phase and inducing DNA damage. We further show that ZIKV infection activates the ATM/Chk2 checkpoint but prevents the activation of another checkpoint, the ATR/Chk1 pathway. These results unravel an intriguing mechanism by which an RNA virus interrupts host DNA replication. Finally, by mimicking virus-induced S-phase arrest, we show that ZIKV manipulates the cell cycle to benefit viral replication.

scholarly journals A global lipid map defines a network essential for Zika virus replication

2020 ◽  
Author(s):  
Hans C. Leier ◽  
Jules B. Weinstein ◽  
Jennifer E. Kyle ◽  
Joon-Yong Lee ◽  
Lisa M. Bramer ◽  
...  
Keyword(s):  
Zika Virus ◽  
Neural Progenitor Cells ◽  
Critical Role ◽  
Ectopic Expression ◽  
Cell Types ◽  
Zikv Infection ◽  
Human Neural Progenitor Cells ◽  
Replication Sites ◽  
Global Concern ◽  
Sphingolipid Biosynthesis

AbstractZika virus (ZIKV), an arbovirus of global concern, remodels intracellular membranes to form replication sites. How ZIKV dysregulates lipid networks to allow this, and consequences for disease, is poorly understood. Here, we performed comprehensive lipidomics to create a lipid network map during ZIKV infection. We found that ZIKV significantly alters host lipid composition, with the most striking changes seen within subclasses of sphingolipids. Ectopic expression of ZIKV NS4B protein resulted in similar changes, demonstrating a role for NS4B in modulating sphingolipid pathways. Disruption of sphingolipid biosynthesis in various cell types, including human neural progenitor cells, blocked ZIKV infection. Additionally, the sphingolipid ceramide redistributes to ZIKV replication sites and increasing ceramide levels by multiple pathways sensitizes cells to ZIKV infection. Thus, we identify a sphingolipid metabolic network with a critical role in ZIKV replication and show that ceramide flux is a key mediator of ZIKV infection.

scholarly journals Characterization of Host lncRNAs in Response to Vibrio splendidus Infection and Function as Efficient miRNA Sponges in Sea Cucumber

2021 ◽  
Vol 12 ◽  
Author(s):  
Siyuan Zhang ◽  
Yina Shao ◽  
Chenghua Li
Keyword(s):  
Sea Cucumber ◽  
Apostichopus Japonicus ◽  
Expression Profiles ◽  
Differentially Expressed ◽  
Vibrio Splendidus ◽  
Host Interactions ◽  
Competing Endogenous Rnas ◽  
Mirna Sponges ◽  
And Function

Long non-coding RNAs (lncRNAs) have been reported to play critical roles during pathogen infection and innate immune response in mammals. Such observation inspired us to explore the expression profiles and functions of lncRNAs in invertebrates upon bacterial infection. Here, the lncRNAs of sea cucumber (Apostichopus japonicus) involved in Vibrio splendidus infection were characterized. RNA-seq obtained 2897 differentially expressed lncRNAs from Vibrio splendidus infected coelomocytes of sea cucumbers. The potential functions of the significant differentially expressed lncRNAs were related to immunity and metabolic process based on the gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases. Moreover, we identify a lncRNA (XLOC_028509), which is downregulated with Vibrio splendidus challenged, further study indicated that XLOC_028509 adsorb miR-2008 and miR-31 as competing endogenous RNAs (ceRNAs) through base complementarity, which in turn decreased the amount of miRNAs (microRNAs) bound to the 3’UTRs (untranslated regions) of mRNAs to reduce their inhibition of target gene translation. These data demonstrated that the lncRNAs of invertebrates might be important regulators in pathogen-host interactions by sponging miRNAs.

Segment-specific responses of intestinal epithelium transcriptome to in-feed antibiotics in pigs

2017 ◽  
Vol 49 (10) ◽  
pp. 582-591 ◽  
Author(s):  
Kaifan Yu ◽  
Chunlong Mu ◽  
Yuxiang Yang ◽  
Yong Su ◽  
Weiyun Zhu
Keyword(s):  
Intestinal Epithelium ◽  
Denaturing Gradient Gel Electrophoresis ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Antibiotic Administration ◽  
Immune Functions ◽  
Host Interactions ◽  
Metabolic Functions ◽  
Expression Of Genes ◽  
Gradient Gel Electrophoresis

Despite widespread use of antibiotics for treatment of human diseases and promotion of growth of agricultural animals, our understanding of their effects on the host is still very limited. We used a model in which pigs were fed with or without a cocktail of antibiotics and found, based on the denaturing gradient gel electrophoresis (DGGE) patterns, that the fecal bacteria from the treatment and control animals were distinct. Furthermore, the total bacterial population in the feces tended to be decreased by the antibiotic treatment ( P = 0.07), and the counts of Lactobacillus and Clostridium XIVa were significantly reduced ( P < 0.05). To explore the effects of antibiotics on host intestinal epithelium, we assessed gene expression profiles of the jejunum and ileum and their response to antibiotic administration. The results indicate that in-feed antibiotics increased expression of genes involved in immune functions in both the jejunum and ileum, some of which were clustered in the coexpression network. Gene ontology terms of metabolic processes were altered predominantly in the jejunum but not in the ileum. Notably, antibiotics diminished intestinal segment-specific transcriptional changes, especially for genes associated with metabolic functions. This study reveals segment-specific responses of host intestinal epithelium to in-feed antibiotics, which can be a valuable resource for deciphering antibiotic-microbiota-host interactions.

scholarly journals Zika Virus Infection Prevents Host mRNA Nuclear Export by Disrupting UPF1 Function

2020 ◽  
Author(s):  
Kristoffer Leon ◽  
Ryan Flynn ◽  
Mir M. Khalid ◽  
Krystal A. Fontaine ◽  
Tom Nguyen ◽  
...  
Keyword(s):  
Zika Virus ◽  
Nuclear Export ◽  
Matrix Protein ◽  
Neural Progenitor Cells ◽  
Rna Virus ◽  
Mrna Export ◽  
Zikv Infection ◽  
Mrna Accumulation ◽  
Human Neural Progenitor Cells ◽  
Nonsense Mediated Mrna Decay

AbstractZika virus (ZIKV) is a mosquito-borne RNA virus that can infect fetuses in utero causing characteristic neurodevelopmental disorders including microcephaly. We previously showed that ZIKV infection downregulates expression of up-frameshift protein 1 (UPF1), a helicase/ATPase and central regulator of the nonsense-mediated mRNA decay pathway. Here, we identify a novel function of nuclear UPF1 in mRNA export. Using crosslinking immunoprecipitation of UPF1 followed by sequencing of associated transcripts as well as fluorescence in situ hybridization experiments, we find widespread mRNA accumulation in the nucleus of human neural progenitor cells (NPCs) upon ZIKV infection or UPF1 knockdown. Knockdown of FREM2, a top UPF1 target transcript encoding an extra-cellular matrix protein critical in fetal development, decreased expression of pluripotency markers and increased expressed neuronal differentiation in NPCs, consistent with the model that trapping FREM2 mRNA in the nucleus perturbs proper NPC function. Collectively, our data uncover a new posttranscriptional mechanism by which ZIKV “shuts off” host mRNA export via UPF1. As we find UPF1 linked to many neurodevelopment pathways, we propose that the lack of host mRNA export contributes to the neurodevelopmental defects associated with ZIKV infection.

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