Biology subjects

Price, J.

Publications and source records attributed to Price, J..

44 records · Page 3Linked to original sources

bioRxiv2019

Importance of parental genome balance in the generation of novel yet heritable epigenetic and transcriptional states during doubled haploid breeding

BackgroundDoubling the genome contribution of haploid plants has accelerated breeding in most cultivated crop species. Although plant doubled haploids are isogenic in nature, they frequently display unpredictable phenotypes, thus limiting the potential of this technology. Therefore, being able to predict the factors implicated in this phenotypic variability could accelerate the generation of desirable genomic combinations and ultimately plant breeding.\n\nResultsWe use computational analysis to assess the transcriptional and epigenetic dynamics taking place during doubled haploids generation in the genome of Brassica oleracea. We observe that doubled haploid lines display unexpected levels of transcriptional and epigenetic variation, and that this variation is largely due to imbalanced contribution of parental genomes. We reveal that epigenetic modification of transposon-related sequences during DH breeding contributes to the generation of unpredictable yet heritable transcriptional states. Targeted epigenetic manipulation of these elements using dCas9-hsTET3 confirms their role in transcriptional regulation. We have uncovered a hitherto unknown role for parental genome balance in the transcriptional and epigenetic stability of doubled haploids.\n\nConclusionsThis is the first study that demonstrates the importance of parental genome balance in the transcriptional and epigenetic stability of doubled haploids, thus enabling predictive models to improve doubled haploid-assisted plant breeding.

plant biology↗

bioRxiv2019

Antiviral signalling in human IPSC-derived neurons recapitulates neurodevelopmental disorder phenotypes

Maternal immune activation increases the risk of neurodevelopmental disorders. Elevated cytokines, such as interferon-gamma (IFN{gamma}), in offsprings brains play a central role. IFN{gamma} activates an antiviral cellular state, limiting viral entry and replication. In addition, IFN{gamma} has been implicated in brain development. Here, we hypothesise that IFN{gamma}-induced antiviral signalling contributes to molecular and cellular phenotypes associated with neurodevelopmental disorders. We find that transient IFN{gamma} treatment of neural progenitors derived from human induced pluripotent stem cells (hIPSCs) persistently increases neurite outgrowth, phenocopying hIPSC-neurons from autistic individuals. IFN{gamma} upregulates antiviral PML bodies and MHC class I (MHCI) genes, which persists through neuronal differentiation. Critically, IFN{gamma}-induced neurite outgrowth requires both PML and MHCI. We also find that IFN{gamma} disproportionately alters expression of autism and schizophrenia risk genes, suggesting convergence between these genetic and environmental risk factors. Together, these data indicate that IFN{gamma}-induced antiviral signalling may contribute to neurodevelopmental disorder aetiology.

neuroscience↗

bioRxiv2019

C. elegans transgenerationally adapts to bacterial infection by increasing the expression of cysteine synthases in progeny

Parental exposure to pathogens can prime offspring immunity in diverse organisms. The mechanisms by which this heritable priming occurs are largely unknown. Here we report that the soil bacteria Pseudomonas vranovensis is a natural pathogen of the nematode Caenorhabditis elegans and that parental exposure of animals to P. vranovensis promotes offspring resistance to infection. Furthermore, we demonstrate a transgenerational enhancement of progeny survival when three consecutive generations of animals are exposed to P. vranovensis. By investigating the mechanisms by which animals heritably adapt to P. vranovensis infection, we found that parental infection by P. vranovensis results in increased expression of the cysteine synthases CYSL-1 and CYSL-2 and the regulator of hypoxia inducible factor RHY-1 in progeny and that these three genes are required for adaptation to P. vranovensis. To our knowledge, these observations represent the largest heritable increase in offspring survival in response to a pathogen infection reported in any organism to date and establish a new CYSL-1, CYSL-2, and RHY-1 dependent mechanism by which animals adapt to infection.

genetics↗

bioRxiv2018

Δ9-tetrahydrocannabinol negatively regulates neurite outgrowth and Akt signaling in hiPSC-derived cortical neurons.

Endocannabinoids regulate different aspects of neurodevelopment. In utero exposure to the exogenous psychoactive cannabinoid {Delta}9-tetrahydrocannabinol ({Delta}9-THC), has been linked with abnormal cortical development in animal models. However, much less is known about the actions of endocannabinoids in human neurons. Here we investigated the effect of the endogenous endocannabinoid 2-arachidonoyl glycerol (2AG) and {Delta}9-THC on the development of neuronal morphology and activation of signaling kinases, in cortical glutamatergic neurons derived from human induced pluripotent stem cells (hiPSCs). Our data indicate that the cannabinoid type 1 receptor (CB1R), but not the cannabinoid 2 receptor (CB2R), GPR55 or TRPV1 receptors, is expressed in young, immature hiPSC-derived cortical neurons. Consistent with previous reports, 2AG and {Delta}9-THC negatively regulated neurite outgrowth. Interestingly, acute exposure to both 2AG and {Delta}9-THC inhibited phosphorylation of serine/threonine kinase extracellular signal-regulated protein kinases (ERK1/2), whereas {Delta}9-THC also reduced phosphorylation of Akt (aka PKB). Moreover, the CB1R inverse agonist SR 141716A attenuated the negative regulation of neurite outgrowth and ERK1/2 phosphorylation induced by 2AG and {Delta}9-THC. Taken together, our data suggest that hiPSC-derived cortical neurons express CB1Rs and are responsive to both endogenous and exogenous cannabinoids. Thus, hiPSC-neurons may represent a good cellular model for investigating the role of the endocannabinoid system in regulating cellular processes in human neurons.

neuroscience↗

bioRxiv2018

Shared gene co-expression networks in autism from induced pluripotent stem cell (iPSC) neurons

BackgroundAutism is a heterogenous collection of disorders with a complex molecular underpinning. Evidence from post-mortem brain studies using adult brains have indicated that early prenatal development may be altered in autism. Induced pluripotent stem cells (iPSCs) generated from autistic individuals with macrocephaly also indicate prenatal development as a critical period for this condition. But little is known about early altered cellular events during prenatal stages in autism. MethodsIPSCs were generated from 9 unrelated autistic individuals without macrocephaly and with heterogeneous genetic backgrounds, and 6 typically developing, control, individuals. IPSCs were differentiated towards either cortical or midbrain fates. Gene expression and high throughput cellular phenotyping was used to characterise iPSCs at different stage of differentiation. ResultsA subset of autism-iPSC cortical neurons were RNA-sequenced to reveal autism-specific signatures similar to post-mortem brain studies, indicating a potential common biological mechanism. Autism-iPSCs differentiated towards a cortical fate displayed impairments in the ability to self-form into neural rosettes. In addition, autism-iPSCs demonstrated significant differences in rate of cell type assignment of cortical precursors, and dorsal and ventral forebrain precursors. These cellular phenotypes occurred in the absence of alterations in cell proliferation during cortical differentiation, differing from previous studies. Acquisition of cell fate during midbrain differentiation was not different between control- and autism-iPSCs. ConclusionsTaken together, our data indicate that autism-iPSCs diverge from control-iPSCs at a cellular level during early stage of neurodevelopment. This suggests that unique developmental differences associated with autism may be established at early prenatal stages.

neuroscience↗

bioRxiv2018

Incomplete reprogramming of cell-specific epigenetic marks during asexual reproduction leads to heritable phenotypic variation in plants

Plants differ from animals in their capability to easily regenerate fertile adult individuals from terminally differentiated cells [1]. This unique developmental plasticity is commonly observed in nature where many species can reproduce asexually through the ectopic initiation of organogenic or embryogenic developmental programs [2, 3]. However, it is not currently known if this developmental reprogramming is coupled to a global epigenomic resetting, or what impact it has on the phenotype of the clonal progeny. Here we show that plants asexually propagated via induction of a zygotic developmental program do not fully reset cell-specific epigenetic imprints. These imprints are instead inherited even over multiple rounds of sexual reproduction, becoming fixed in hybrids and resulting in heritable molecular and physiological phenotypes that depend on the founder cell used. Our results demonstrate how novel phenotypic variation in plants can be unlocked through the incomplete reprogramming of cell-specific epigenetic marks during asexual propagation.

plant biology↗

bioRxiv2017

Cellular phenotyping of hippocampal progenitors exposed to patient serum predicts conversion to Alzheimer’s Disease

The generation of new neurons persists into adulthood in the human hippocampus and can be modulated by the circulatory systemic environment. Hippocampal neurogenesis is important for learning and memory and is altered in Alzheimers Disease (AD). Evaluating the hippocampal neurogenic process during disease progression could therefore identify neurogenesis as an important target for AD prevention and intervention as well as a biomarker for early disease detection. In this study, we used a human hippocampal progenitor cell line to design an in vitro assay evaluating over time the neurogenic impact of the systemic milieu (i.e. serum) of individuals with mild cognitive impairment (MCI) as they either converted to AD or remained cognitively stable. Cells were exposed to serum collected over several years from the same patients. Cellular phenotyping and linear mixed effects models for repeated measures revealed that decreased proliferation, increased apoptotic hippocampal progenitor cell death and increased hippocampal neurogenesis characterized progression from MCI to AD. Using stepwise logistic regression and machine learning we show that these cellular readouts for the baseline serum sample and years of education of the patient are significant predictors of conversion from MCI to AD, already 3.5 years before AD clinical diagnosis. Finally, serum proteomic analyses indicated pathways linked to the cellular readouts distinguishing MCI to AD converters from non-converters. The proposed assay is thus not only promising for AD pre-clinical diagnosis, but it also provides a proxy into temporal changes of the hippocampal neurogenic process during disease progression.\n\nOne Sentence SummaryIn this study, we demonstrate for the first time that the systemic environment (i.e. blood serum) of mild cognitively impaired patients differentially alters human hippocampal progenitor cell fate to predict conversion to Alzheimers Disease up to 3.5 years before clinical diagnosis.

neuroscience↗

bioRxiv2017

A Complete Electron Microscopy Volume Of The Brain Of Adult Drosophila melanogaster

Drosophila melanogaster has a rich repertoire of innate and learned behaviors. Its 100,000-neuron brain is a large but tractable target for comprehensive neural circuit mapping. Only electron microscopy (EM) enables complete, unbiased mapping of synaptic connectivity; however, the fly brain is too large for conventional EM. We developed a custom high-throughput EM platform and imaged the entire brain of an adult female fly. We validated the dataset by tracing brain-spanning circuitry involving the mushroom body (MB), intensively studied for its role in learning. Here we describe the complete set of olfactory inputs to the MB; find a new cell type providing driving input to Kenyon cells (the intrinsic MB neurons); identify neurons postsynaptic to Kenyon cell dendrites; and find that axonal arbors providing input to the MB calyx are more tightly clustered than previously indicated by light-level data. This freely available EM dataset will significantly accelerate Drosophila neuroscience.\n\nHIGHLIGHTS- A complete adult fruit fly brain was imaged, using electron microscopy (EM)\n- The EM volume enables brain-spanning mapping of neuronal circuits at the synaptic level\n- Olfactory projection neurons cluster more tightly in mushroom body calyx than expected from light-level data\n- The primary postsynaptic targets of Kenyon cells (KCs) in the MB are other KCs, as well as the anterior paired lateral (APL) neuron\n- A newly discovered cell type, MB-CP2, integrates input from several sensory modalities and provides microglomerular input to KCs in MB calyx\n- A software pipeline was created in which EM-traced skeletons can be searched for within existing large-scale light microscopy (LM) databases of neuronal morphology, facilitating cell type identification and discovery of relevant genetic driver lines

neuroscience↗