Biology subjects

Ye, J.

Publications and source records attributed to Ye, J..

11 recordsLinked to original sources

bioRxiv2018

Tau accumulation activates STAT1 triggering memory deficits via suppressing NMDA receptor expression

Intracellular tau accumulation forming neurofibrillary tangles is hallmark pathology of Alzheimer's disease (AD), but how tau accumulation induces synapse impairment is elusive. By overexpressing human full-length wildtype tau (termed hTau) to mimic tau abnormality as seen in the brain of sporadic AD patients, we found that hTau accumulation activated JAK2 to phosphorylate STAT1 (Signal Transducer and Activator of Transcription 1) at Tyr701 leading to STAT1 dimerization, nuclear translocation and its activation. STAT1 activation suppressed expression of N-methyl-D-aspartate receptors (NMDARs) through direct binding to the specific GAS element of GluN1, GluN2A and GluN2B promoters, while knockdown STAT1 by AAV-Cre in STAT1flox/flox mice or expressing dominant negative Y701F-STAT1 efficiently rescued hTau-induced suppression of NMDARs expression with amelioration of synaptic functions and memory performance. These findings indicate that hTau accumulation impairs synaptic plasticity through JAK2/STAT1-induced suppression of NMDARs expression, revealing a novel mechanism for hTau-associated synapse and memory deficits.

neuroscience↗

bioRxiv2018

Noninvasive prenatal test of methylmalonic academia cblC type through targeted sequencing of cell-free DNA in maternal plasma

Methylmalonic acidemia (MMA) cblC type is the most frequent inborn error of intracellular cobalamin metabolism which is caused by mutations of MMACHC gene. Non-invasive test of MMA for pregnant women facilitates safe and timely prenatal diagnosis of the disease. In our study, we aimed to design and validate a haplotype-based noninvasive prenatal test (NIPT) method for cblC type of MMA. Targeted capture sequencing using customized hybridization was performed utilizing gDNA (genomic DNA) of trios including parents and an affected proband to determine parental haplotypes associated with the mutant and wild allele. The fetal haplotype was inferred later based on the high depth sequencing data of maternal plasma as well as haplotype linkage analysis. The fetal genotypes deduced by NIPT were further validated by amniocentesis. Haplotype-based NIPT was successfully performed in 21 families. The results of NIPT of 21 families were all consistent with invasive prenatal diagnosis, which was interpreted in a blinded fashion. Three fetuses were identified as compound heterozygosity of MMACHC, 9 fetuses were carriers of MMACHC variant, and 9 fetuses were normal. These results indicated that the haplotype-based NIPT for MMA through small target capture region sequencing is technically accurate and feasible.

genetics↗

bioRxiv2018

The bunyavirus nonstructural protein NSs suppresses plant immunity to facilitate its own transmission by improving vector insect performance

Pandemics of vector-borne human and plant pathogens often rely on the behaviors of their arthropod vectors. Arboviruses, including many bunyaviruses, manipulate vector behavior to accelerate their own transmission to vertebrates, birds, insects, and plants. However, the molecular mechanism underlying this manipulation remains elusive. Here, we report that the non-structural protein NSs of orthotospovirus (order Bunyavirales, family Tospoviridae), is a key viral factor that indirectly modifies vector preference and increases vector performance. NSs suppresses the biosynthesis of volatile monoterpenes, which serve as repellents of the vector Western flower thrips (WFT, Frankliniella occidentalis) instead of using its known silencing suppressor activity. NSs directly interacts with and relocalizes the jasmonate (JA) signaling master regulator MYC2 and its two close homologs, MYC3 and MYC4, to disable JA-mediated activation of terpene synthase genes. The dysfunction of the MYCs subsequently attenuates host defenses, increases the attraction of thrips, and improves thrips fitness. These findings elucidate the molecular mechanism through which a bunyavirus manipulates vector behaviors and therefore facilitate disease transmission. Our results provide important insights into the molecular mechanisms by which tospoviruses NSs counteracts host immunity for pathogen transmission.\n\nAuthor summaryMost bunyaviruses are transmitted by insect vectors, and some of them can modify the behaviors of their arthropod vectors to increase transmission to mammals, birds, and plants. NSs is a non-structural bunyavirus protein with multiple functions that acts as an avirulence determinant and silencing suppressor. In this study, we identified a new function of NSs as a manipulator of vector behavior, independent of its silencing suppressor activity. NSs manipulates jasmonate-mediated immunity against thrips by directly interacting with several homologs of MYC transcription factors, the core regulators of the jasmonate-signaling pathway. This hijacking by NSs enhances thrips preference and performance. Many human- and animal-infecting members of the Bunyaviridales also encode NSs and could manipulate vector behavior to accelerate their own transmission. Therefore, our data support the hypothesis that the NSs protein may play conserved roles among various members of the Bunyaviridales in the modification of vector feeding behavior that evolved as a mechanism to enhance virus transmission.

microbiology↗

bioRxiv2018

Autophagy determines osimertinib resistance through regulation of stem cell-like properties in EGFR-mutant lung cancer

Drug resistance to Osimertinib, a 3rd-generation EGFR-TKI is inevitable. Autophagy plays a contradictory role in resistance of 1st and 2nd generation EGFR-TKI, and its significance in osimertinib resistance is much less clear. We therefore investigated whether autophagy determines osimertinib resistance. First, osimertinib induced autophagy to a much greater extent than that of gefitinib, and autophagy inhibition further increased osimertinib efficacy. Next, enhanced autophagy was found in osimertinib resistant cells and autophagy inhibition partially reversed osimertinib resistance. Enhanced stem-cell like properties were found in resistant cells, and siRNA-knock down of SOX2 or ALDH1A1reversed osimertinib resistance. Of note, autophagy inhibition or siRNA-knock down of Beclin-1 decreased expression of SOX2 and ALDH1A1 and stem-cell like properties. Next, autophagy inhibition and osimertinib in combination effectively blocked tumor growth in xenografts, which was associated with decreased autophagy and stem cell-like properties in vivo. Finally, enhanced autophagy was found in lung cancer patients with resistance to osimertinib. In conclusion, the current study delineates a previously unknown function of autophagy in determining osimertinib resistance through promoting stem-cell like properties.

cancer biology↗

bioRxiv2018

Combining high-throughput micro-CT-RGB phenotyping and genome-wide association study to dissect the genetic architecture of tiller growth in rice

Traditional phenotyping of rice tillers is time consuming and labor intensive and lags behind the rapid development of rice functional genomics. Thus, dynamic phenotyping of rice tiller traits at a high spatial resolution and high-throughput for large-scale rice accessions is urgently needed. In this study, we developed a high-throughput micro-CT-RGB (HCR) imaging system to non-destructively extract 730 traits from 234 rice accessions at 9 time points. We used these traits to predict the grain yield in the early growth stage, and 30% of the grain yield variance was explained by 2 tiller traits in the early growth stage. A total of 402 significantly associated loci were identified by GWAS, and dynamic and static genetic components were found across the nine time points. A major locus associated with tiller angle was detected at nine time points, which contained a major gene TAC1. Significant variants associated with tiller angle were enriched in the 3'-UTR of TAC1. Three haplotypes for the gene were found and tiller angles of rice accessions containing haplotype H3 were much smaller. Further, we found two loci contained associations with both vigor-related HCR traits and yield. The superior alleles would be beneficial for breeding of high yield and dense planting.\n\nHighlightCombining high-throughput micro-CT-RGB phenotyping facility and genome-wide association study to dissect the genetic architecture of rice tiller development by using the indica subpopulation.

genetics↗

bioRxiv2018

Identification of loci where DNA methylation potentially mediate genetic risk of type 1 diabetes

The risk of Type 1 Diabetes (T1D) comprises both genetic and environmental components. We investigated whether genetic susceptibility to T1D could be mediated by changes in DNA methylation, an epigenetic mechanism that potentially plays a role in autoimmune diabetes. Using data from a non-diabetic population comprising blood samples taken at birth (n=844), childhood (n=911) and adolescence (n=907), we evaluated the associations between 65 top GWAS single nucleotide polymorphisms (SNPs) and genome-wide DNA methylation levels. We identified 159 proximal SNP-cytosine phosphate guanine (CpG) pairs (cis), and 7 distal SNP-CpG associations (trans) at birth, childhood, and adolescence. There was also a systematic enrichment for methylation related SNPs to be associated with T1D across the genome, after controlling for genomic characteristics of the SNPs, implying that methylation could either be on the causal pathway to T1D or a non-causal biomarker. Combining the principles of Mendelian Randomization and genetic colocalization analysis, we provided evidence that at 5 loci, ITGB3BP, AFF3, PTPN2, CTSH and CTLA4, DNA methylation is potentially on the causal pathway to T1D.

genomics↗

bioRxiv2017

Cell-type specific parallel circuits in the bed nucleus of the stria terminalis and the central nucleus of the amygdala of the mouse

The central extended amygdala (EAc) is a forebrain macrosystem which has been widely implicated in fear, anxiety and pain. Its two key structures, the lateral bed nucleus of the stria terminalis (STL) and the central nucleus of amygdala (CeA), share similar mesoscale connectivity. However, it is not known whether they also share similar cell-specific neuronal circuits. We addressed this question using tract-tracing and immunofluorescence to reveal the connectivity of two neuronal populations expressing either protein kinase C delta (PKC{delta}) or somatostatin (SOM). PKC{delta} and SOM are expressed predominantly in the dorsal part of STL (STLD) and in the lateral/capsular parts of CeA (CeL/C). We found that, in both STLD and CeL/C, PKC{delta}+ cells are the main recipient of extra-EAc inputs from the external lateral part of the parabrachial nucleus (LPBE), while SOM+ cells are the sources of long-range projections to extra-EAc targets, including LPBE and periaqueductal gray. PKC{delta}+ cells can also integrate inputs from posterior basolateral nucleus of amygdala or insular cortex. Within EAc, PKC{delta}+, but not SOM+ neurons, serve as the major source of projections to the ventral part of STL and to the medial part of CeA. However, both cell types mediate interconnections between STLD and CeL/C. These results unveil the pivotal positions of PKC{delta} and SOM neurons in organizing parallel cell-specific neuronal circuits of CeA and STL, which further support the idea of EAc as a structural and functional macrostructure.

neuroscience↗

bioRxiv2017

Singleton Variants Dominate the Genetic Architecture of Human Gene Expression

The vast majority of human mutations have minor allele frequencies (MAF) under 1%, with the plurality observed only once (i.e., \"singletons\"). While Mendelian diseases are predominantly caused by rare alleles, their cumulative contribution to complex phenotypes remains largely unknown. We develop and rigorously validate an approach to jointly estimate the contribution of all alleles, including singletons, to phenotypic variation. We apply our approach to transcriptional regulation, an intermediate between genetic variation and complex disease. Using whole genome DNA and lymphoblastoid cell line RNA sequencing data from 360 European individuals, we conservatively estimate that singletons contribute ~25% of cis-heritability across genes (dwarfing the contributions of other frequencies). Strikingly, the majority (~76%) of singleton heritability derives from ultra-rare variants absent from thousands of additional samples. We develop a novel inference procedure to demonstrate that our results are consistent with rampant purifying selection shaping the regulatory architecture of most human genes.

evolutionary biology↗

bioRxiv2017

Splicing-dependent NMD requires Prp17 in Saccharomyces cerevisiae

Nonsense mediated mRNA decay (NMD) is regarded as the function of a specialized cytoplasmic translation-coupled mRNA decay pathway in eukaryotes, however, whether a premature translation termination codon (PTC) will lead to NMD often depends on splicing a downstream intron in the nucleus. Deposition of the exon junction complex (EJC) on mRNA is understood to mediate such splicing-dependent NMD in mammalian cells. The budding yeast, Saccharomyces cerevisiae, which has introns in only 5% of its genes, characteristically at the start of the coding region, and lacks proteins essential for EJC assembly, is not expected to undergo splicing-dependent NMD. However, we found that the presence of an intron near a PTC can also enhance NMD in this organism, regardless of whether it is downstream or upstream. These data provide evidence for a hitherto unsuspected EJC-independent mechanism linking translation and pre-mRNA in S. cerevisiae.

molecular biology↗

bioRxiv2017

Multiplexing droplet-based single cell RNA-sequencing using natural genetic barcodes

Droplet-based single-cell RNA-sequencing (dscRNA-seq) has enabled rapid, massively parallel profiling of transcriptomes from tens of thousands of cells. Multiplexing samples for single cell capture and library preparation in dscRNA-seq would enable cost-effective designs of differential expression and genetic studies while avoiding technical batch effects, but its implementation remains challenging. Here, we introduce an in-silico algorithm demuxlet that harnesses natural genetic variation to discover the sample identity of each cell and identify droplets containing two cells. These capabilities enable multiplexed dscRNA-seq experiments where cells from unrelated individuals are pooled and captured at higher throughput than standard workflows. To demonstrate the performance of demuxlet, we sequenced 3 pools of peripheral blood mononuclear cells (PBMCs) from 8 lupus patients. Given genotyping data for each individual, demuxlet correctly recovered the sample identity of > 99% of singlets, and identified doublets at rates consistent with previous estimates. In PBMCs, we demonstrate the utility of multiplexed dscRNA-seq in two applications: characterizing cell type specificity and inter-individual variability of cytokine response from 8 lupus patients and mapping genetic variants associated with cell type specific gene expression from 23 donors. Demuxlet is fast, accurate, scalable and could be extended to other single cell datasets that incorporate natural or synthetic DNA barcodes.

bioinformatics↗

bioRxiv2017

The differential spatiotemporal expression pattern of shelterin genes throughout lifespan

Shelterin forms the core complex of telomere proteins and plays critical roles in protecting telomeres against unwanted activation of the DNA damage response and in maintaining telomere length homeostasis. Although shelterin expression is believed to be ubiquitous for stabilization of chromosomal ends, some evidence suggests that some shelterin subunits have tissue-specific functions. However, very little is known regarding how shelterin subunit gene expression is regulated during development and aging. Using two different animal models, the mouse and zebrafish, we reveal herein that shelterin subunits exhibit distinct spatial and temporal expression patterns that do not correlate with the proliferative status of the organ systems examined. Together, this work shows that the shelterin subunits exhibit distinct spatiotemporal expression patterns, suggesting important tissue-specific functions during development throughout the lifespan.

developmental biology↗