Biology subjects

Zhang, W.

Publications and source records attributed to Zhang, W..

At least 613 records · Page 34Linked to original sources

bioRxiv2023

Distinct neurochemical influences on fMRI response polarity in the striatum

The striatum is the primary input nucleus of the basal ganglia, widely studied for its complex roles in health and disease. Functional magnetic resonance imaging (fMRI) studies are essential for discerning striatal function, however the relationship between neuronal and hemodynamic activity, critical for interpreting fMRI signals, has not been rigorously examined in striatum. We find that optogenetic stimulation of striatal neurons or afferents evokes negative striatal fMRI responses in rats that can occur despite broad increases in local neuronal activity. Intra-striatal pharmacological manipulations suggest that opioidergic, but not dopaminergic transmission contributes to negative striatal fMRI signals (the latter instead associated with positive signals). Striatal neuronal activity peaks are also associated with negative hemodynamic signals in behaving rats. Negative fMRI responses are observed in human striatum under conditions of anticipated neuronal activity increases. Our results prompt consideration of local cellular and neurochemical environments along with neuronal activity in fMRI signal interpretation.

neuroscience↗

bioRxiv2023

Integrated Cell Landscape and Dynamics in the Progression of Bone Repair

Bone homeostasis and repair is a systematic progress with spatiotemporal interaction of multiple cell types involved in skeletal and immune system. Precise spatiotemporal regulation of cell type-specific functions in bone repair contributes to further development of tissue engineering and regenerative medicine. Here, we utilized single-cell RNA sequencing to illustrate a map of cell landscape and dynamics in the progression of rodent bone self-healing and a perturbation by lymphoid cell-deficiency. We identified different functions of myeloid cell and lymphoid cell to osteogenesis and angiogenesis during bone repair and their mutual complementation under lymphoid cell-deficient condition. Additionally, we used CD34+ humanized reconstituted mice to reveal further insights into the mechanism of human bone homeostasis and repair. Our integrated cellular analysis of bone repair explores the functional diversity and complementation between myeloid cells and lymphoid cells during bone healing process and provides further therapeutic implications for the treatment of bone disease and degeneration following ageing.

cell biology↗

bioRxiv2023

Signaling from the C. elegans Hypodermis Non-autonomously Facilitates Short-term Associative Memory

Memory loss is one of the most debilitating symptoms of aging. While we normally think of memory regulation as autonomous to the brain, other factors outside of the brain can also affect neuron function. We have shown that the longevity insulin/IGF-1 signaling (IIS) pathway regulates neuron-specific activity, but whether the maintenance of memory through the IIS pathway is completely autonomous to the nervous system, or if there are systemic inputs, is unknown. We address this question using the auxin-inducible degradation (AID) system to degrade the IIS receptor, DAF-2, in specific tissues. Surprisingly, DAF-2 degradation specifically in the hypodermis improves memory in both young and aged C. elegans through the hypodermal expression of the diffusible Notch ligand, OSM-11. The Notch receptor LIN-12 is required for OSM-11s effect on memory, as are the downstream transcription factor LAG-1 and co-activator SEL-8. Furthermore, mid-life overexpression of the Notch ligand OSM-11 improves memory and slows cognitive decline. Hypodermal DAF-2 degradation suppresses the expression of ins-19, whose downregulation extends memory. Together, our data suggest a model in which the hypodermis, a metabolic tissue, can non-autonomously regulate neuronal activity and function, indicating a systemic connection between metabolism and memory regulation.

genetics↗

bioRxiv2023

Reconstructing cellular differentiation networks and identifying cell fate-determining features with CIBER

Trajectory inference methods are frequently used for cell fate analysis, however, most of them are similarity-based and lack an understanding of the causality underlying differentiation processes. Here, we present CIBER, a Causal Inference-Based framework for the Evaluation of feature effects and the Reconstruction of cellular differentiation networks. CIBER provides a novel paradigm for dissecting cell state transitions other than trajectory inference and differential analysis. It is a versatile framework that can be applied to various types of data, including transcriptomic, epigenomic and microarray data. It can identify both known and potential cell-lineage structures with minimal prior knowledge. By integrating the CIBER-learned network with structural causal model and applying in silico perturbation as inventions, we generated an effect matrix that quantifies the impact of different features on each differentiation branch. Using this effect matrix, CIBER can identify crucial features involved in haematopoiesis, even if these features show no significant difference in expression between lineages. Moreover, CIBER can predict novel regulation associations and provide insight into the potential mechanism underlying the influence of transcription factors on biological processes. To validate CIBERs capabilities, we conducted in vivo experiments on Bcl11b, a non-differentially expressed transcription factor identified by CIBER. Our results demonstrate that dysfunction of Bcl11b leads to a bias towards myeloid lineage differentiation at the expense of lymphoid lineage, which is consistent with our predictions.

systems biology↗

bioRxiv2023

Neutralization of SARS-CoV-2 BQ.1.1 and XBB.1.5 by Breakthrough Infection Sera from Previous and Current Waves in China

SARS-CoV-2 is continuing to evolve and diversify, with an array of various Omicron sub-lineages, including BA.5, BA.2.75, BN.1, BF.7, BQ.1, BQ.1.1, XBB and XBB.1.5, now circulating globally at recent time. In this study, we evaluated the neutralization sensitivity of a comprehensive panel of Omicron subvariants to sera from different clinical cohorts, including individuals who received homologous or heterologous booster vaccinations, vaccinated people who had Delta or BA.2 breakthrough infection in previous waves, and patients who had BA.5 or BF.7 breakthrough infection in the current wave in China. All the Omicron subvariants exhibited substantial neutralization evasion, with BQ.1, BQ.1.1, XBB.1, and XBB.1.5 being the strongest escaped subvariants. Sera from Omicron breakthrough infection, especially the recent BA.5 or BF.7 breakthrough infection, exhibited higher neutralizing activity against all Omicron sub-lineages, indicating the chance of BA.5 and BF.7 being entirely replaced by BQ or XBB subvariants in China in a short-term might be low. We also demonstrated that the BQ and XBB subvariants were the most resistant viruses to monoclonal antibodies. Continuing to monitor the immune escape of SARS-CoV-2 emerging variants and developing novel broad-spectrum vaccines and antibodies are still crucial.

immunology↗

bioRxiv2023

GLI1 facilitates rheumatoid arthritis by collaborative regulation of DNA methyltransferases

Rheumatoid arthritis (RA) is characterized by joint synovitis and bone destruction, the etiology of which remains to be explored. Overactivation of M1 macrophages and osteoclasts has been thought a direct cause of joint inflammation and bone destruction. Glioma-associated oncogene homolog 1 (GLI1) has been revealed to be closely linked to bone metabolism. In this study, GLI1-expression in synovial tissue of RA patients showed to be positively correlated with RA-related scores and was highly expressed in collagen-induced arthritis (CIA) mouse articular macrophage-like cells. The decreased expression and inhibition of nuclear transfer of GLI1 downregulated macrophage M1 polarization and osteoclast activation, the effect of which was achieved by modulation of DNA methyltransferases (DNMTs) via transcriptional regulation and protein interaction ways. By pharmacological inhibition of GLI1, the proportion of proinflammatory macrophages and the number of osteoclasts were significantly reduced, and the joint inflammatory response and bone destruction in CIA mice were alleviated. This study clarified the mechanism of GLI1 in macrophage phenotypic changes and activation of osteoclasts, suggesting potential applications of GLI1 inhibitor in the clinical treatment of RA.

cell biology↗

bioRxiv2023

Adolescent neurostimulation of dopamine circuit reverses genetic deficits in frontal cortex function

Dopamine system dysfunction is commonly implicated in adolescent-onset neuropsychiatric disorders. Although psychosis symptoms can be alleviated by antipsychotics, cognitive symptoms remain unresponsive to such pharmacological treatments and novel research paradigms investigating the circuit substrates underlying cognitive deficits are critically needed. The frontal cortex and its dopaminergic input from the midbrain are implicated in cognitive functions and undergo maturational changes during adolescence. Here, we used mice carrying mutations in the Arc or DISC1 genes to model mesofrontal dopamine circuit deficiencies and test circuit-based neurostimulation strategies to restore cognitive functions. We found that in a memory-guided spatial navigation task, frontal cortical neurons were activated coordinately at the decision-making point in wild-type but not Arc mutant mice. Chemogenetic stimulation of midbrain dopamine neurons or optogenetic stimulation of frontal cortical dopamine axons in a limited adolescent period consistently reversed genetic defects in mesofrontal innervation, task-coordinated neuronal activity, and memory-guided decision-making at adulthood. Furthermore, adolescent stimulation of dopamine neurons also reversed the same cognitive deficits in DISC1 mutant mice. Our findings reveal common mesofrontal circuit alterations underlying the cognitive deficits caused by two different genes and demonstrate the feasibility of adolescent neurostimulation to reverse these circuit and behavioral deficits. These results may suggest developmental windows and circuit targets for treating cognitive deficits in neurodevelopmental disorders.

neuroscience↗

bioRxiv2023

Quantitative Annotations of T-Cell Repertoire Specificity

The specificity of a T-cell receptor (TCR) repertoire determines personalized immune capacity. Existing methods have modelled the qualitative aspects of TCR specificity, while the quantitative aspects remained unaddressed. We developed a package, TCRanno, to quantify the specificity of TCR repertoires. Applying TCRanno to 4,195 TCR repertoires revealed quantitative changes in repertoire specificity upon infections, autoimmunity and cancers. Specifically, TCRanno found cytomegalovirus-specific TCRs in seronegative healthy individuals, supporting the possibility of abortive infections. TCRanno discovered age-accumulated fraction of SARS-CoV2-specific TCRs in pre-pandemic samples, which may explain the aggressive symptoms and age-related severity of COVID-19. TCRanno also identified the encounter of Hepatitis B antigens as a potential trigger of systemic lupus erythematosus. TCRanno annotations showed capability in distinguishing TCR repertoires of healthy and cancers including melanoma, lung and breast cancers. TCRanno may also facilitate single-cell TCRseq+gene expression data analyses by isolating T-cells with the specificity of interest.

bioinformatics↗

bioRxiv2023

Iron Regulatory Protein 1 is Required for the Propagation of Inflammation in Inflammatory Bowel Disease

ObjectiveInflammatory bowel diseases (IBD) are complex disorders. Iron accumulates in the inflamed tissue of IBD patients, yet neither a mechanism for the accumulation nor its implication on the course of inflammation are known. We hypothesized that the inflammation modifies iron homeostasis, affects tissue iron distribution and that this in turn perpetuates the inflammation. DesignThis study analyzed human biopsies, animal models and cellular systems to decipher the role of iron homeostasis in IBD. ResultsWe found inflammation-mediated modifications of iron distribution, and iron-decoupled activation of the iron regulatory protein (IRP)1. To understand the role of IRP1 in the course of this inflammation-associated iron pattern, a novel cellular co-culture model was established, that replicated the iron-pattern observed in vivo, and supported involvement of nitric oxide in the activation of IRP1 and the typical iron pattern in inflammation. Importantly, deletion of IRP1 from an IBD mouse model completely abolished both, the misdistribution of iron and intestinal inflammation. ConclusionThese findings suggest that IRP1 plays a central role in the coordination of the inflammatory response in the intestinal mucosa and that it is a viable candidate for therapeutic intervention in IBD. What is already known on this topicInflammatory bowel diseases (IBD) are chronic conditions that cause inflammation in the digestive tract. Iron accumulation is a common feature of IBD, but the mechanism of accumulation and its implications for the course of inflammation are not fully understood. What this study addsThis study reveals an inflammatory intestinal iron distribution-pattern, that has not been described previously involving iron accumulation in immune cells and iron deficiency in epithelial cells. We show that an inflammation mediated activation of the Iron Regulatory Protein (IRP)1 is responsible for this inflammatory iron pattern and that this drives the propagation of the inflammation in IBD. Moreover, targeted deletion of IRP1 completely abolished the intestinal inflammation. How this study might affect research, practice or policyThese findings suggest that IRP1 plays a central role in the coordination of the inflammatory response in the intestinal mucosa in IBD. This might lead to the development of novel treatment approaches for IBD focused on modulating IRP1 activity.

immunology↗

bioRxiv2023

Redistribution and activation of CD16brightCD56dim NK cell subset to fight against Omicron subvariant BA.2 after COVID-19 vaccination

With the alarming surge in COVID-19 cases globally, vaccination must be prioritised to achieve herd immunity. Immune dysfunction is detected in the majority of patients with COVID-19; however, it remains unclear whether the immune responses elicited by COVID-19 vaccination function against the Omicron subvariant BA.2. Of the 508 Omicron BA.2-infected patients enrolled, 102 were unvaccinated controls and 406 were vaccinated. Despite the presence of clinical symptoms in both groups, vaccination led to a significant decline in nausea or vomiting, abdominal pain, headache, pulmonary infection, overall clinical symptoms, and a moderate rise in body temperature. Omicron BA.2-infected individuals were also characterised by a mild increase in both serum pro- and anti-inflammatory cytokine levels after vaccination. There were no significant differences or trend changes between T and B lymphocyte subsets; however, a significant expansion of NK lymphocytes in COVID-19-vaccinated patients was observed. Moreover, the most effective CD16brightCD56dim subsets of NK cells showed increased functional capacities, as evidenced by a significantly greater IFN-{gamma} secretion and stronger cytotoxic potential in Omicron BA.2-infected patients after vaccination. Collectively, these results suggest that COVID-19 vaccination interventions promote the redistribution and activation of CD16brightCD56dim NK cell subsets against viral infections, and could facilitate the clinical management of Omicron BA.2-infected patients.

immunology↗

bioRxiv2023

Multifaceted roles of a light-responsive factor LhWRKY44 in promoting anthocyanin accumulation in Asiatic hybrid lilies (Lilium spp.)

The coloration of Asiatic hybrid lily results mostly from anthocyanin accumulation in flowers. Although anthocyanin accumulation-related genes and MBW complexes are well studied, the transcriptional regulation of WRKY transcription factors involved in anthocyanin accumulation remains poorly understood.Here, we identified a lily WRKY protein, LhWRKY44, whose expression is highly expressed downstream of LhHY5 by light and positively correlated with anthocyanin accumulation. LhWRKY44 overexpression enhanced anthocyanin accumulation and silencing decreased anthocyanin accumulation in flowers. As a trans-acting regulator, LhWRKY44 activited the anthocyanin biosynthesis pathway-related genes PAL and F3H by binding to the their promoters. And the encoded TF also participates in anthocyanin transport and targets the intracellular anthocyanin transport protein GST promoters. Additionally, a novel dual activity of LhWRKY44 and LhMYBSPLATTER regulatory module, with LhWRKY44 binds to the promoter of LhMYBSPLATTER and interacts with LhMYBSPLATTER, strongly enhanced the interaction of LhMYBSPLATTER and LhbHLH2, indirectly enhancing DFR, UFGT and GST expression targeted by LhMYBSPLATTER. These results show a regulatory mode for light-induced anthocyanin accumulation enhancement by LhWRKY44 in lily, expanding our understanding of the complex transcriptional regulatory hierarchy modulating anthocyanin accumulation.

molecular biology↗

bioRxiv2023

INKILN is a novel long noncoding RNA promoting vascular smooth muscle inflammation

BackgroundActivation of vascular smooth muscle cells (VSMCs) inflammation is vital to initiate vascular disease. However, the role of human-specific long noncoding RNAs (lncRNAs) in VSMC inflammation is poorly understood. MethodsBulk RNA-seq in differentiated human VSMCs revealed a novel human-specific lncRNA called INflammatory MKL1 Interacting Long Noncoding RNA (INKILN). INKILN expression was assessed in multiple in vitro and ex vivo models of VSMC phenotypic modulation and human atherosclerosis and abdominal aortic aneurysm (AAA) samples. The transcriptional regulation of INKILN was determined through luciferase reporter system and chromatin immunoprecipitation assay. Both loss- and gain-of-function approaches and multiple RNA-protein and protein-protein interaction assays were utilized to uncover the role of INKILN in VSMC proinflammatory gene program and underlying mechanisms. Bacterial Artificial Chromosome (BAC) transgenic (Tg) mice were utilized to study INKLIN expression and function in ligation injury-induced neointimal formation. ResultsINKILN expression is downregulated in contractile VSMCs and induced by human atherosclerosis and abdominal aortic aneurysm. INKILN is transcriptionally activated by the p65 pathway, partially through a predicted NF-{kappa}B site within its proximal promoter. INKILN activates the proinflammatory gene expression in cultured human VSMCs and ex vivo cultured vessels. Mechanistically, INKILN physically interacts with and stabilizes MKL1, a key activator of VSMC inflammation through the p65/NF-{kappa}B pathway. INKILN depletion blocks ILI{beta}-induced nuclear localization of both p65 and MKL1. Knockdown of INKILN abolishes the physical interaction between p65 and MKL1, and the luciferase activity of an NF-{kappa}B reporter. Further, INKILN knockdown enhances MKL1 ubiquitination, likely through the reduced physical interaction with the deubiquitinating enzyme, USP10. INKILN is induced in injured carotid arteries and exacerbates ligation injury-induced neointimal formation in BAC Tg mice. ConclusionsThese findings elucidate an important pathway of VSMC inflammation involving an INKILN/MKL1/USP10 regulatory axis. Human BAC Tg mice offer a novel and physiologically relevant approach for investigating human-specific lncRNAs under vascular disease conditions.

molecular biology↗

bioRxiv2023

Wheat plant height locus RHT25 encodes a PLATZ transcription factor that interacts with DELLA (RHT1)

Plant height is an important agronomic trait with a significant impact on grain yield, as demonstrated by the positive effect of the REDUCED HEIGHT (RHT) dwarfing alleles (Rht1b) on lodging and harvest index in the "Green Revolution" wheat varieties. However, these gibberellic acid (GA) insensitive alleles also reduce coleoptile length, biomass production, and yield potential in some environments, triggering the search for alternative GA-sensitive dwarfing genes. Here we report the identification, validation and characterization of the gene underlying the GA-sensitive dwarfing locus RHT25 in wheat. This gene, designated as PLATZ-A1 (TraesCS6A02G156600), is expressed mainly in the elongating stem and developing spike and encodes a plant-specific AT-rich sequence- and zinc-binding protein (PLATZ). Natural and induced loss-of-function mutations in PLATZ-A1 reduce plant height and its over-expression increases it, demonstrating that PLATZ-A1 is the causative gene of RHT25. PLATZ-A1 interacts physically and genetically with RHT1 (DELLA), and both genes have stronger effects on plant height in the presence of the wildtype than in the presence of the mutant allele of the other gene. These results suggest that PLATZ1 can modulate the effect of DELLA on wheat plant height. We identified four natural truncation mutations and one promoter insertion in PLATZ-A1 that are more frequent in modern varieties than in landraces, suggesting positive selection during wheat breeding. These mutations can be used to fine-tune wheat plant height and, in combination with other GA-sensitive dwarfing genes, to replace the GA-insensitive Rht1b alleles to search for grain yield improvements beyond those of the Green Revolution varieties. Significance StatementWe have identified and characterized a previously unknown gene controlling plant height in wheat and named it PLATZ1. Mutations in PLATZ1 reduce plant height while its overexpression results in taller plants. PLATZ1 is expressed mainly in elongating stems and developing spikes and interacts physically and genetically with the "Green Revolution" dwarfing gene REDUCED HEIGHT 1 (RHT1). We discovered five natural mutants in the A genome copy of PLATZ1 in common wheat that have been favored during breeding, suggesting an overall positive effect on wheat performance. These mutations can be used to fine-tune wheat plant height and, eventually, to replace the RHT1 dwarfing alleles that impose limitations on planting depth and grain yield potential in some environments.

plant biology↗

bioRxiv2023

Rice potassium transporter OsHAK18 mediates phloem K+ loading and redistribution

High-Affinity K+ transporters/K+ Uptake Permeases/K+ Transporters (HAK/KUP/KT) are important pathways mediating K+ transport across cell membrane, which function in maintaining K+ homeostasis during plant growth and stress response. An increasing number of studies have shown that HAK/KUP/KT transporters play important roles in potassium uptake and root-to-shoot translocation. However, whether some HAK/KUP/KT transporters mediate K+ redistribution in phloem remains unknown. In this study, we revealed that a phloem-localized HAK/KUP/KT transporter, OsHAK18 operated as a typical KUP/HAK/KT transporter mediating cell K+ uptake when expressed in yeast, E. coli and Arabidopsis. It was localized at plasma membrane. Disruption of OsHAK18 rendered rice seedlings insensitive to low-K+ stress. Compared with WT, the oshak18 mutants accumulated more K+ in shoots but less K+ in roots, leading to a higher shoot/root ratio of K+ per plant. Although disruption of OsHAK18 doesnt affect root K+ uptake and K+ level in xylem sap, it significantly decreases phloem K+ concentration and inhibits root-to-shoot-to-root K+ translocation in split-root assay. These results reveal that OsHAK18 mediates phloem K+ loading and redistribution, whose disruption is favor of shoot K+ retention under low-K+ stress. Our findings not only reveal a unique function of rice HAK/KUP/KT family member, but also provide a promising strategy to improve rice tolerance under K+ deficiency.

plant biology↗

bioRxiv2023

Replacing continuous stimulation of one set of electrodes with successive stimulation of multiple sets of electrodes can improve the focality of transcranial temporal interference stimulation (tTIS), especially the focality of stimulation towards deep brain regions: A simulation study.

Temporal interference (TI) stimulation has been proved to stimulate deep brain region while not activating the overlying cortex in the mouse brain. However, traditional TI, where two alternating currents with different frequencies are delivered by two electrode pairs, has poor focality in the human brain due to the high complexity of human brain structures, which limits the further application of TI. In traditional multipair TI, more than two alternating currents with different frequencies are injected by more than two electrode pairs at the same time. In this study, we proposed a novel multipair method which replaces continuous stimulation of one set of electrodes (eg: 1 montage for 30 minutes) with successive stimulation of multiple sets of electrodes (eg: 6 montages for 5 minutes each). By simulation using finite element method, we showed that this new method could improve the focality of TI in both neocortical regions and deep brain regions compared with traditional two-pair TI and the improvement was more significant in deep brain region. Ten realistic finite element models were used and five brain regions were tested (M1, DLPFC, ACC, NAc and hippocampus). It is expected that this new multipair TI can be used to improve the effectiveness of TI when researchers are translating TI from theoretical researches to clinical applications.

bioengineering↗

bioRxiv2022

High-quality nuclear genome and mitogenome of Bipolaris sorokiniana strain LK93, a devastating pathogen causing wheat root rot

Bipolaris sorokiniana, one of the most devastating hemibiotrophic fungal pathogens, causes root rot, crown rot, leaf blotching, and black embryos of gramineous crops worldwide, posing a serious threat to global food security. However, the host-pathogen interaction mechanism between B. sorokiniana and wheat remains poorly understood. To facilitate related studies, we sequenced and assembled the genome of B. sorokiniana strain LK93. Nanopore long reads and next generation sequencing short reads were applied in the genome assembly, and the final 36.4 Mb genome assembly contains 16 contigs with the contig N50 of 2.3 Mb. Subsequently, we annotated 11,811 protein-coding genes including 10,620 functional genes, 258 of which were identified as secretory proteins including 211 predicted effectors. Additionally, the 111,581 bp mitogenome of LK93 was assembled and annotated. The LK93 genomes presented in this study will facilitate research in the B. sorokiniana-wheat pathosystem for better control of crop diseases.

plant biology↗

bioRxiv2022

Multiscale genetic architecture of donor-recipient differences reveals intronic LIMS1 locus mismatches associated with long-term renal transplant survival

BackgroundLong-term kidney allograft survival remains suboptimal. Emerging evidence indicates donor-recipient (D-R) mismatches outside of human leukocyte antigens (HLA) contribute to graft survival but mechanisms remain unclear, specifically for those mismatches within intronic regions. MethodsWe analyzed genome-wide SNP data of D-R pairs from two well-phenotyped kidney transplant cohorts (median follow-up ~1800 days), Genomics of Chronic Allograft Rejection (GoCAR; n=385) and Clinical Trials in Organ Transplantation 1/17 (CTOT1/17; n=146), quantifying genetic mismatches outside of HLA for every D-R pair at variant, gene, and genome-wide scales. ResultsUnbiased genome-wide screen of GoCAR D-R pairs uncovered the LIMS1 locus as the topranked candidate where D-R mismatches associated with death censored graft loss (DCGL). Independent of HLA, a previously unreported relationship between mismatches at a highly linked, intronic haplotype of 30 SNPs was seen as associated with DCGL, with confirmatory association in intra-ancestry D-Rs. Validation testing within the CTOT-01/17 showed similar associations with DCGL. Haplotype D-R mismatches showed a dosage effect, and the introduction of minor alleles in the donor to major allele-carrying recipients showed a greater risk of DCGL. Both the new LIMS1 haplotype and the previously reported LIMS1 SNP rs893403 are expression quantitative trait loci (eQTL) for the gene GCC2 in recipient immune cells, without alterations in GCC2 or LIMS1 coding sequences. Transcriptome enrichment analyses performed on whole blood and within multiple T cell subsets demonstrated significant associations of GCC2 gene, and of either allelic locus, with regulation of TGF-beta-SMAD signaling, implying a role in Treg function and association with rejection. ConclusionsOur analysis unravels intronic non-HLA SNP mismatches within LIMS1 that do not induce protein sequence variation but associate with DCGL. By acting as cis-eQTLs for GCC2 expression, these SNPs modulates TGF-beta signaling and T cell function, associating with immune events and graft outcomes. The findings have clinical implications for risk assessment and individualized therapy in kidney transplant recipients.

genetics↗

bioRxiv2022

Sequencing-free Tissue-wide Spatial Profiling of Post-transcriptional Regulations

The importance of genetic or epi-genetic heterogeneity has been increasingly recognized, but it has been challenging to profile intracellular post-transcriptional targets with sufficient throughput and resolution at across large-scale tissue samples. This study describes a technique, Spectrum-FISH, for high-throughput, sequencing-free, and tissue-wide spatial profiling of various post-transcriptional targets in acute tissue sections with subcellular resolution. The platform uses a biochip with an array of vertically aligned nanoprobes to effectively extract intracellular molecules for downstream analysis in the coordinates of the large-scale of cells within a tissue slice. As a proof-of-concept, the Spectrum-FISH is used to profile the spatial dynamics of 24 miRNAs and 9 m6A-modified messenger RNAs (m6A-mRNA) in acute olfactory bulb (OB) slices of millimeter scale. The results showed potentially multiomics spatial heterogeneity for the examined post-transcriptional regulations in rodent OB, especially in the outer plexiform layer and granule layer, where highly correlated miRNAs and m6A-mRNAs groups were identified, indicating a potential cooperative involvement of different post-transcriptional regulations at these OB regions.

genomics↗