Biology subjects

Ye, J.

Publications and source records attributed to Ye, J..

At least 127 records · Page 7Linked to original sources

bioRxiv2021

Comprehensive RNA-Seq Reveals Molecular Changes in Kidney Malignancy Among People Living with HIV

BackgroundMalignancy of the kidney is a rapidly progressive kidney disease and a major source of morbidity and mortality among people living with HIV (PLWH). Patients with HIV-associated kidey cancer experience higher cancer-specific mortality than the general population, and its mechanism remains poorly understood. MethodsTo heighten the awareness of kidney malignancy in patients with HIV infection to facilitate the early diagnosis of kidney cancer, we identified 2460 protein-coding transcripts in HIV-associated kidney cancer using comprehensive RNA sequencing (RNA-seq). ResultsKISS1R, CAIX, and NPTX2 mRNA expression levels were specifically increased in HIV-associated kidney cancer, and UMOD and TMEM213 mRNA were decreased in most cases based on real-time PCR analyses. These findings were similar to those noted for the general population with renal cell carcinoma. Immunohistochemical staining analysis also showed that a total of 16 of 18 kidney malignant cases among PLWH exhibited positive staining for KISS1R and CAIX. ConclusionPathway analysis of the differentially expressed mRNAs in HIV-associated kidney cancer revealed that several key pathways were involved, including voltage-gated chloride channel activity, distal tubule development, collecting duct development, fructose metabolic processes, and negative regulation of lipase activity. The identified molecular changes in kidney malignancy may offer a helpful explanation for cancer progression and open up new therapeutic avenues that may decrease mortality after a cancer diagnosis among PLWH.

cancer biology↗

bioRxiv2021

JAK-STAT Signaling Enables Lineage Plasticity-driven AR Targeted Therapy Resistance

Emerging evidence indicates that various cancers can gain resistance to targeted therapies by acquiring lineage plasticity. Although various genomic and transcriptomic aberrations correlate with lineage plasticity-driven resistance, the molecular mechanisms of acquiring lineage plasticity have not been fully elucidated. Through integrated transcriptomic and single cell RNA-Seq (scRNA-Seq) analysis of more than 80,000 cells, we reveal for the first time that the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling is a crucial executor in promoting lineage plasticity-driven AR targeted therapy resistance in prostate cancer. Ectopic activation of JAK-STAT signaling is specifically required for the AR targeted therapy resistance of subclones expressing multilineage, stem-like and epithelial-to-mesenchymal transition (EMT) lineage transcriptional programs and represents a potential therapeutic target for overcoming AR targeted therapy resistance. One-Sentence SummaryJAK-STAT signaling is a crucial executor in promoting lineage plasticity-driven AR therapy resistance in prostate cancer.

cancer biology↗

bioRxiv2021

Aldehyde dehydrogenase 3A1 deficiency leads to mitochondrial dysfunction and impacts salivary gland stem cell self-renewal, differentiation and survival

Adult salivary stem/progenitor cells (SSPC) have an intrinsic property to self-renew in order to maintain tissue architecture and homeostasis. Adult salivary glands have been documented to harbor SSPC, which have been shown to play a vital role in the regeneration of the glandular structures post radiation damage. We have previously demonstrated that activation of aldehyde dehydrogenase 3A1 (ALDH3A1) after radiation reduced aldehyde accumulation in SSPC, leading to less apoptosis and improved salivary function. We subsequently found that sustained pharmacological ALDH3A1 activation is critical to enhance regeneration of murine submandibular gland after radiation damage. Further investigation shows that ALDH3A1 function is crucial for SSPC self-renewal and differentiation even in the absence of radiation stress. Salivary glands from Aldh3a1-null mice have fewer acinar structures than wildtype mice. ALDH3A1 deletion or pharmacological inhibition in SSPC leads to a decrease in mitochondrial DNA copy number, lower expression of mitochondrial specific genes and proteins, structural abnormalities, lower membrane potential, and reduced cellular respiration. Loss or inhibition of ALDH3A1 also elevates ROS levels and accumulation of ALDH3A1 substrate 4-hydroxynonenal (4-HNE, a lipid peroxidation product), leading to decreased survival of murine SSPC that can be rescued by treatment with 4-HNE specific carbonyl scavengers. Our data indicate that ALDH3A1 activity protects mitochondrial function and is important for the development and regeneration activity of SSPC. This knowledge will help to guide our translational strategy of applying ALDH3A1 activators in the clinic to prevent radiation-related hyposalivation in head and neck cancer patients.

cell biology↗

bioRxiv2021

A Mediterranean-like fat blend protects against the development of severe colitis in the mucin-2 deficient murine model

The Mediterranean diet (MD) is a health-promoting, moderate fat diet (~ 40% energy). It is not known if the blend of fats found in the MD contribute to the beneficial protective effects. We compared the MD fat blend (high monounsaturated, 2:1 n-6:n-3 polyunsaturated and moderate saturated fat) to isocaloric diets composed with corn oil (CO, n-6 polyunsaturated-rich), olive oil (high monounsaturated-rich) or milk fat (MF, saturated-rich) on spontaneous colitis development in Muc2-/- mice. The MD resulted in lower clinical and histopathological scores, and induced tolerogenic CD103+CD11b+ dendritic, Th22 and IL-17+IL-22+ cells important for intestinal barrier repair. MD also reduced attendant insulin resistance and a shift to a higher health-promoting gut microbes including Lactobacillus B. animalis and Muribaculaceae, whereas CO showed higher prevalence of mucin-degraders (Akkermansia muciniphila) and colitis promoters (Enterobacteriaceae). Our findings suggest that the MD fat blend could be recommended as a maintenance diet for colitis.

immunology↗

bioRxiv2021

Zika virus causes placental pyroptosis and associated adverse fetal outcomes by activating GSDME

Zika virus (ZIKV) can be transmitted from mother to fetus during pregnancy, causing adverse fetal outcomes. Several studies have indicated that ZIKV can damage the fetal brain directly; however, whether the ZIKV-induced maternal placental injury contribute to adverse fetal outcomes are sparsely defined. Here, we discovered that ZIKV causes the pyroptosis of placental cells by activating the executor Gasdermin E (GSDME) in vitro and in vivo. Mechanistically, caspase-8 undergoes activation upon the recognition of 5 untranslated region of viral RNA by RIG-I, followed by the stimulation of caspase-3 to ultimately escalate the GSDME cleavage. Further analyses revealed that the ablation of GSDME in ZIKV-infected pregnant mice attenuates placental pyroptosis, which consequently confers protection against adverse fetal outcomes. In conclusion, our study unveils a novel mechanism of ZIKV-induced adverse fetal outcomes via causing placental cell pyroptosis, which could be employed for developing new therapies for ZIKV-associated diseases. Significance statementSeveral studies have elucidated the link between ZIKV infection and congenital ZIKV syndroms (CZS), but the pathogenesis yet needs further study. Here, we reported a novel pathogenic mechanism of ZIKV which leads to pyroptosis of placental cells through activating the pyroptotic executor GSDME, rather than GSDMD. Upon ZIKV infection, GSDME-mediated pyroptosis damages the structure and function of the placenta, thereby affecting the development of the fetus and contributing to the adverse fetal outcomes. Our study highlights the importance of pyroptotic executor GSDME in regulate ZIKV pathogenicity and further confirms that placental injury caused by ZIKV infection is a key factor for CZS.

microbiology↗

bioRxiv2021

Reprogramming the neuroblastoma epigenome with a mitochondrial uncoupler

Dysregulated DNA methylation is associated with poor prognosis in cancer patients, promoting tumorigenesis and therapeutic resistance1. DNA methyltransferase inhibitors (DNMTi) reduce DNA methylation and promote cancer cell differentiation, with two DNMTi already approved for cancer treatment2. However, these drugs rely on cell division to dilute existing methylation, thus the demethylation effects are achieved in a passive manner, limiting their application in slow-proliferating tumor cells. In this study we use a mitochondrial uncoupler, niclosamide ethanolamine (NEN), to actively achieve global DNA demethylation. NEN treatment promotes DNA demethylation by activating electron transport chain (ETC) to produce -ketoglutarate (-KG), a substrate for the DNA demethylase TET. In addition, NEN inhibits reductive carboxylation, a key metabolic pathway to support growth of cancer cells with defective mitochondria or under hypoxia. Importantly, NEN treatment reduces 2-hydroxyglutarate (2-HG) generation and blocks DNA hypermethylation under hypoxia. Together, these metabolic reprogramming effects of NEN actively alter the global DNA methylation landscape and promote neuroblastoma differentiation. These results not only support Warburgs original hypothesis that inhibition of ETC causes cell de-differentiation and tumorigenesis, but also suggest that mitochondrial uncoupling is an effective metabolic and epigenetic intervention that remodels the tumor epigenome for better prognosis.

cancer biology↗

bioRxiv2021

Serine Starvation Silences Estrogen Receptor Signaling through Histone Hypoacetylation

Estrogen receptor (ER) plays important roles in regulating normal development and female reproductive system function. Loss of ER pathway activity is a hallmark of breast cancer progression, associated with accelerated tumor proliferation and resistance to endocrine therapy. How ER loss occurs remains poorly understood. Here, we show that serine starvation, a metabolic stress often found in solid tumors, downregulates estrogen receptor alpha (ER) expression, represses transcriptional targets such as progesterone receptor (PR), and reduces sensitivity to antiestrogens, suggesting a transition of ER-positive (ER+) breast cancer cells to an ER/PR-negative (ER-/PR-) state. ER downregulation under serine starvation is accompanied by a global loss of histone acetylation. These chromatin changes are driven by metabolic reprogramming triggered by serine starvation, particularly lower glucose flux through glycolysis and the TCA cycle, leading to reduced acetyl-CoA levels and histone hypoacetylation. Supplementation with acetate or glycerol triacetate (GTA), precursors of acetyl-CoA, restores H3K27 acetylation and ER expression under serine starvation. Therefore, a major consequence of serine starvation in breast cancer could be global chromatin changes that influence lineage-specific gene expression.

cancer biology↗

bioRxiv2021

FEDERATED MORPHOMETRY FEATURE SELECTION FOR HIPPOCAMPAL MORPHOMETRY ASSOCIATED BETA-AMYLOID AND TAU PATHOLOGY

Amyloid-{beta} (A{beta}) plaques and tau protein tangles in the brain are now widely recognized as the defining hallmarks of Alzheimers disease (AD), followed by structural atrophy detectable on brain magnetic resonance imaging (MRI) scans. One of the particular neurodegenerative regions is the hippocampus to which the influence of A{beta}/tau on has been one of the research focuses in the AD pathophysiological progress. This work proposes a novel framework, Federated Morphometry Feature Selection (FMFS) model, to examine subtle aspects of hippocampal morphometry that are associated with A{beta}/tau burden in the brain, measured using positron emission tomography (PET). FMFS is comprised of hippocampal surface-based feature calculation, patch-based feature selection, federated group LASSO regression, federated screening rule-based stability selection, and region of interest (ROI) identification. FMFS was tested on two ADNI cohorts to understand hippocampal alterations that relate to A{beta}/tau depositions. Each cohort included pairs of MRI and PET for AD, mild cognitive impairment (MCI) and cognitively unimpaired (CU) subjects. Experimental results demonstrated that FMFS achieves an 89x speedup compared to other published state-of-the-art methods under five independent hypothetical institutions. In addition, the subiculum and cornu ammonis 1 (CA1 subfield) were identified as hippocampal subregions where atrophy is strongly associated with abnormal A{beta}/tau. As potential biomarkers for A{beta}/tau pathology, the features from the identified ROIs had greater power for predicting cognitive assessment and for survival analysis than five other imaging biomarkers. All the results indicate that FMFS is an efficient and effective tool to reveal associations between A{beta}/tau burden and hippocampal morphometry.

neuroscience↗

bioRxiv2021

Deep deconvolution of the hematopoietic stem cell regulatory microenvironment reveals a high degree of specialization and conservation between mouse and human.

Understanding the regulation of normal and malignant human hematopoiesis requires comprehensive cell atlas of the hematopoietic stem cell (HSC) regulatory microenvironment. Here, we develop a tailored bioinformatic pipeline to integrate public and proprietary single-cell RNA sequencing (scRNA-seq) datasets. As a result, we robustly identify for the first time 14 intermediate cell states and 11 stages of differentiation in the endothelial and mesenchymal BM compartments, respectively. Our data provide the most comprehensive description to date of the murine HSC-regulatory microenvironment and suggests a higher level of specialization of the cellular circuits than previously anticipated. Furthermore, this deep characterization allows to infer conserved features in human, suggesting that the layers of microenvironmental regulation of hematopoiesis may also be shared between species. Our resource and methodology are a steppingstone towards a comprehensive cell atlas of the BM microenvironment.

immunology↗

bioRxiv2021

LmbU directly regulates SLINC_RS02575, SLINC_RS05540 and SLINC_RS42780, which are located outside the lmb cluster and inhibit lincomycin biosynthesis in Streptomyces lincolnensis

The productions of antibiotics are usually regulated by cluster-situated regulators (CSRs), which can directly regulate the genes within the corresponding biosynthetic gene cluster (BGC). However, few studies have looked into the regulation of CSRs on the targets outside the BGC. Here, we screened the targets of LmbU in the whole genome of S. lincolnensis, and found 14 candidate targets, among of which, 8 targets can bind to LmbU by EMSAs. Reporter assays in vivo revealed that LmbU repressed transcription of SLINC_RS02575 and SLINC_RS05540, while activated transcription of SLINC_RS42780. In addition, disruptions of SLINC_RS02575, SLINC_RS05540 and SLINC_RS42780 promoted the production of lincomycin, and qRT-PCR showed that SLINC_RS02575, SLINC_RS05540 and SLINC_RS42780 inhibited transcription of the lmb genes, indicating that all the three regulators can negatively regulate lincomycin biosynthesis. Whats more, the homologues of LmbU and its targets SLINC_RS02575, SLINC_RS05540 and SLINC_RS42780 are widely found in actinomycetes, while the distributions of DNA-binding sites (DBS) of LmbU are diverse, indicating the regulatory mechanisms of LmbU homologues in various strains are different and complicated. IMPORTANCELincomycin is widely used in clinic treatment and animal husbandry. Our previous study firstly demonstrated that LmbU, a novel transcriptional regulator family, functions as a CSR and positively regulates lincomycin biosynthesis. Here, we revealed that LmbU may act as a pleiotropic transcriptional regulator, and directly regulates SLINC_RS02575, SLINC_RS05540 and SLINC_RS42780 which are located outside the lmb cluster and negatively regulate lincomycin biosynthesis. Interestingly, the homologues of LmbU and its targets are widely found in actinomycetes, indicating the regulatory patterns of LmbU to the targets may exist in a variety of strains. Collectively, our findings elucidated the molecular mechanism with which LmbU regulates the target genes outside the lmb culster, and draw a network diagram of LmbU regulation on lincomycin biosynthesis. This lays a solid foundation for the realization of high-yield of lincomycin in industry, and provides the theoretical basis for the functional research of LmbU family proteins.

molecular biology↗

bioRxiv2021

Endogenous RNA editing of a nuclear gene BOSS triggers flowering in tomato

RNA editing is defined as the production of transcripts with RNA sequences different from those of the DNA template. Most of previous RNA editing studies have focused on organelles, while RNA editing of nuclear transcripts is largely unknown. Here, we describe the first example of nuclear transcript RNA editing in plant, the BOSS RNA editing regulates tomato flowering. The SNP (SNP1) located in the 5UTR of BOSS gene (the Balancer of SP and SFT) is associated with tomato early flowering, and two transcripts of BOSS produced by SNP1 associated RNA editing show functional differentiation, where BOSS-{beta} transcript promotes flowering while BOSS- does not. Furthermore, these two transcripts of BOSS are shown to regulate SP (anti-florigen) pathway at transcription level in the shoot apical meristem (SAM). Our findings reveal a new layer of complexity in the control of plant stem cell proliferation and provide the evidence of RNA-editing of a single gene for flowering, suggesting that molecular breeding programs to increase the RNA-editing efficiency may improve the productivity of tomatoes and other agricultural organisms.

plant biology↗

bioRxiv2021

Accurate Virus Identification with Interpretable Raman Signatures by Machine Learning

Rapid identification of newly emerging or circulating viruses is an important first step toward managing the public health response to potential outbreaks. A portable virus capture device coupled with label-free Raman Spectroscopy holds the promise of fast detection by rapidly obtaining the Raman signature of a virus followed by a machine learning approach applied to recognize the virus based on its Raman spectrum. In this paper, we present a machine learning analysis on Raman spectra of human and avian viruses. A Convolutional Neural Network (CNN) classifier specifically designed for spectral data achieves very high accuracy for a variety of virus type or subtype identification tasks. In particular, it achieves 99% accuracy for classifying influenza virus type A vs. type B, 96% accuracy for classifying four subtypes of influenza A, 95% accuracy for differentiating enveloped and non-enveloped viruses, and 99% for differentiating avian coronavirus (infectious bronchitis virus, IBV) from other avian viruses. Furthermore, interpretation of neural net responses in the trained CNN model using a full-gradient algorithm highlights Raman spectral ranges that are most important to virus identification. By correlating ML-selected salient Raman ranges with the signature ranges of known biomolecules and chemical functional groups (e.g. amide, amino acid, carboxylic acid) we verify that our ML model effectively recognizes the Raman signatures of proteins, lipids and other vital functional groups present in different viruses and uses a weighted combination of these signatures to identify viruses. The accurate and interpretable machine learning model developed for Raman virus identification presents promising potential in a real-time virus detection system. Significance StatementA portable micro-fluidic platform for virus capture promises rapid enrichment and label-free optical identification of viruses by Raman spectroscopy. A large Raman dataset collected on a variety of viruses enables the training of machine learning (ML) models capable of highly accurate and sensitive virus identification. The trained ML models can then be integrated with the portable device to provide real-time virus detection and identification capability. We validate this conceptual framework by presenting highly accurate virus type and subtype identification results using a convolutional neural network to classify Raman spectra of viruses.

biophysics↗

bioRxiv2021

Rapid Biomarker Screening of Alzheimer's Disease by Machine Learning and Graphene-Assisted Raman Spectroscopy

As the most common cause of dementia, the study of Alzheimers disease (AD) faces challenges in terms of understanding the cause, monitoring the pathogenesis, and developing early diagnosis and effective treatment. Rapid and accurate identification of AD biomarkers in the brain is critical to provide key insights into AD and facilitate the development of early diagnosis methods. In this work, we developed a platform that enables a rapid screening of AD biomarkers by employing graphene-assisted Raman spectroscopy and machine learning interpretation in AD transgenic animal brains. Specifically, we collected Raman spectra on slices of mouse brains with and without AD and used machine learning to classify AD and non-AD spectra. By contacting monolayer graphene with the brain slices, the accuracy was significantly increased from 77% to 98% in machine learning classification. Further, using linear supporting vector machine (SVM), we identified a spectral feature importance map that reveals the importance of each Raman wavenumber in classifying AD and non-AD spectra. Based on this spectral feature importance map, we identified AD biomarkers including A{beta} and tau proteins, and other potential biomarkers, such as triolein, phosphatidylcholine, and actin, which have been confirmed by other biochemical studies. Our Raman-machine learning integrated method with interpretability is promising to greatly accelerate the study of AD and can be extended to other tissues, biofluids, and for various other diseases.

neuroscience↗

bioRxiv2021

Case study: Digital spatial profiling of metastatic clear cell carcinoma reveals intra-tumor heterogeneity in epithelial-mesenchymal gradient.

Intrinsic intra-tumor heterogeneity (ITH) has been linked to worse patient outcomes. The development of spatial profiling technology has enabled the deciphering of ITH with multiple analysis readouts. Advanced ovarian clear cell carcinoma (OCCC), known to harbor ITH, is chemoresistant, poor prognostic, and possesses distinct molecular and histological characteristics. However, detailed spatial information of the nature of ITH within OCCC remains unclear. Here, we utilized the NanoString Digital spatial profiling (DSP) GeoMx platform to perform multiplex protein expression analysis on tumor samples of primary and colonic metastatic sites from one advanced OCCC patient. The spatial resolution revealed the existence of an epithelial-mesenchymal (EM) gradient within the metastatic tumor but not the primary tumor, and similar EM gradient was not observed within the primary tumor. The EM gradient exhibited a distinct pattern from the periphery to the core of the metastatic tumor. Compared to tumor cells at the primary site, there was an intermediate zone in between the tumor periphery and the tumor core in the colonic metastasis with differential expression patterns of pan-cytokeratin (PanCK), fibronectin (FN), smooth muscle actin (SMA), neural cell adhesion molecule (NCAM), integrin alpha X (ITGAX), and Ki-67. Our study provides the first spatially resolved in situ evidence of intermediate or hybrid EM states within the tumor samples of similar morphology. This not only demonstrates the promising applications of spatial profiling in precision medicine but also provides an unprecedented view of the EM gradient during the progression of cancer such as OCCC.

cancer biology↗

bioRxiv2021

ALS and FTD-associated missense mutations in TBK1 differentially disrupt mitophagy

TANK-binding kinase 1 (TBK1) is a multi-functional kinase with an essential role in mitophagy, the selective clearance of damaged mitochondria. More than 90 distinct mutations in TBK1 are linked to amyotrophic lateral sclerosis (ALS) and fronto-temporal dementia (FTD), including missense mutations that disrupt the ability of TBK1 to dimerize, associate with the mitophagy receptor optineurin (OPTN), auto-activate, or catalyze phosphorylation. We investigated how ALS-associated mutations in TBK1 affect Parkin-dependent mitophagy using imaging to dissect the molecular mechanisms involved in clearing damaged mitochondria. Some mutations cause severe dysregulation of the pathway, while others induce limited disruption. Mutations that abolish either TBK1 dimerization or kinase activity were insufficient to fully inhibit mitophagy, while mutations that reduced both dimerization and kinase activity were more disruptive. Ultimately, both TBK1 recruitment and OPTN phosphorylation at S177 are necessary for engulfment of damaged mitochondra by autophagosomal membranes. Surprisingly, we find that ULK1 activity contributes to the phosphorylation of OPTN in the presense of either WT- or kinase inactive TBK1. In primary neurons, TBK1 mutants induce mitochondrial stress under basal conditions; network stress is exacerbated with further mitochondrial insult. Our study further refines the model for TBK1 function in mitophagy, demonstrating that some ALS-linked mutations likely contribute to disease pathogenesis by inducing mitochondrial stress or inhibiting mitophagic flux. Other TBK1 mutations exhibited much less impact on mitophagy in our assays, suggesting that cell-type specific effects, cumulative damage, or alternative TBK1-dependent pathways such as innate immunity and inflammation also factor into the development of ALS in affected individuals. SIGNIFICANCE STATEMENTMissense mutations in TANK-binding kinase 1 (TBK1) have various biophysical and biochemical effects on the molecule, and are associated with the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and fronto-temporal dementia (FTD). TBK1 plays an essential role in clearing damaged mitochondria. Here, we investigate the impact of 10 ALS-linked TBK1 mutations on the critical early stage of mitophagy. We find that both TBK1 recruitment and kinase activity contribute to the clearance of the damaged mitochondria. Furthermore, in neurons, expression of TBK1 mutants alone affects mitochondrial network health. Our investigation utilizes disease-linked mutations to further refine the current model of mitophagy, identifying crosstalk between the regulatory kinases TBK1 and ULK1, and providing new insights into the roles of TBK1 in neurodegenerative pathogenesis.

cell biology↗

bioRxiv2021

The GT factor ZmGT-3b mediates growth-defense tradeoff by regulating photosynthesis and defense response

Plant growth and development face constant threat from various environmental stresses. Transcription factors (TFs) are crucial for maintaining balance between plant growth and defense. Trihelix TFs display multifaceted functions in plant growth, development, and responses to various biotic and abiotic stresses. Here, we explore the role of a trihelix TF, ZmGT-3b, in regulating the growth-defense tradeoff in maize (Zea mays). ZmGT-3b is primed for instant response to Fusarium graminearum challenge by implementing a rapid and significant reduction of its expression to suppress seedling growth and enhance disease resistance. ZmGT-3b knockdown led to diminished growth, but improved disease resistance and drought tolerance in maize seedlings. In ZmGT-3b knockdown seedlings, the chlorophyll content and net photosynthetic rate were strongly reduced, whereas the contents of major cell wall components, such as lignin, were synchronically increased. Correspondingly, ZmGT-3b knockdown specifically downregulated photosynthesis-related genes, especially ZmHY5 (encoding a conserved central regulator of seedling development and light responses), but synchronically upregulated genes associated with secondary metabolite biosynthesis and defense-related functions. ZmGT-3b knockdown induced defense-related transcriptional reprogramming and increased biosynthesis of lignin without immune activation. These data suggest that ZmGT-3b is a regulator of plant growth-defense tradeoff that coordinates metabolism during growth-to-defense transitions by optimizing the temporal and spatial expression of photosynthesis- and defense-related genes. One-sentence summaryZmGT-3b regulates photosynthesis activity and synchronically suppresses defense response.

molecular biology↗

bioRxiv2021

Discovery of photosynthesis genes through whole-genome sequencing of acetate-requiring mutants of Chlamydomonas reinhardtii

Large-scale mutant libraries have been indispensable for genetic studies, and the development of next-generation genome sequencing technologies has greatly advanced efforts to analyze mutants. In this work, we sequenced the genomes of 660 Chlamydomonas reinhardtii acetate-requiring mutants, part of a larger photosynthesis mutant collection previously generated by insertional mutagenesis with a linearized plasmid. We identified 554 insertion events from 509 mutants by mapping the plasmid insertion sites through paired-end sequences, in which one end aligned to the plasmid and the other to a chromosomal location. Nearly all (96%) of the events were associated with deletions, duplications, or more complex rearrangements of genomic DNA at the sites of plasmid insertion, and 1405 genes in total were affected. Functional annotations of these genes were enriched in those related to photosynthesis, signaling, and tetrapyrrole synthesis as would be expected from a library enriched for photosynthesis mutants. Systematic manual analysis of the disrupted genes for each mutant generated a list of 273 higher-confidence candidate photosynthesis genes, and we experimentally validated two genes that are essential for photoautotrophic growth, CrLPA3 and CrPSBP4. The inventory of candidate genes includes 55 genes from a phylogenomically defined set of conserved genes in green algae and plants. Altogether, 68 candidate genes encode proteins with previously characterized functions in photosynthesis in Chlamydomonas, land plants, and/or cyanobacteria, 15 genes encode proteins previously shown to have functions unrelated to photosynthesis, and 190 genes encode proteins without any functional annotation, signifying that our results connect a function related to photosynthesis to these previously unknown proteins. This mutant library, with genome sequences that reveal the molecular extent of the chromosomal lesions and resulting higher-confidence candidate genes, represents a rich resource for gene discovery and protein functional analysis in photosynthesis.

plant biology↗

bioRxiv2021

DNA repair enzyme NEIL3 enables a stable neural representation of space by shaping transcription in hippocampal neurons

DNA repair enzymes are essential for the maintenance of neuronal genome and thereby proper brain functions. NEIL3 is a member of the NEIL family DNA glycosylases initiating oxidative DNA base excision repair. Recent studies show that NEIL3-deficiency leads to impaired spatial performance in mice, decreased adult neurogenesis and altered synaptic composition in the hippocampus. However, it remains elusive how NEIL3 contributes to spatial information coding in hippocampal neurons. Here, we revealed impaired spatial stability in Neil3-/- CA1 place cells, demonstrating a functional interference of NEIL3 with spatial representations. We identified NEIL3-dependent transcriptional changes in response to spatial exploration and defined its regulatory role specifically for NMDA receptor subunits and immediate early genes. Our work demonstrates a non-canonical role of NEIL3 in modulating the functional plasticity of place cells by shaping the neuronal transcriptome, thus sheds light on the molecular determinants enabling a stable neural representation of space.

neuroscience↗