Biology subjects

Zheng, X.

Publications and source records attributed to Zheng, X..

At least 181 records · Page 10Linked to original sources

bioRxiv2023

The significant yet short-term influence of research covidization on journal citation metrics

COVID-19 has emerged as a major research hotspot in recent years, leading to increased publications and citations of related papers. While concerns exist about the potential citation boost in journals publishing these papers, the specifics are not fully understood. This study uses a generalized difference-in-differences approach to examine the impact of publishing COVID-19 papers on journal citation metrics in the Health Sciences fields. Findings indicate that journals publishing COVID-19 papers in 2020 received significantly higher citation premiums due to COVID-19 in 2020 and continued to benefit from the premium in 2021 in certain fields. In contrast, journals that began publishing COVID-19 papers in 2021 experienced weaker citation premiums. Although the publication volume of non-COVID-19 papers also surged, these papers experienced insignificant or negative citation gains, even when published in the same journals as COVID-19 papers. COVID-19 papers published in high-impact journals brought more significant citation premiums to journals in most fields. These citation premiums can affect various citation-based journal metrics, such as our simulated impact factor, to different degrees. The results highlight a "gold rush" pattern in which early entrants establish their citation advantage in research hotspots and caution against using citation-based metrics for research assessment.

scientific communication and education↗

bioRxiv2023

Multi-omic dissection of ancestral heat stress memory responses in Brachypodium distachyon

Stressful environmental conditions, including heat stress (HS), are a major limiting factor in crop yield. Understanding the molecular mechanisms of plant stress memory and resilience is important for engineering more resistant plants and improving crop yield. To study how the different gene regulatory layers change upon repeated HS and how these layers are interconnected, we performed a dense temporal atlas of gene expression, alternative splicing, small and long noncoding RNAs, and DNA methylation in Brachypodium distachyon. Results show that a second HS induces changes in coding and noncoding RNA expression and alternative splicing and that DNA demethylation is responsible for mediating differential gene expression. We identified a long noncoding RNA regulatory network and provided evidence that lncRNAs positively regulate gene expression, while miRNAs are implicated in alternative splicing events. We reconstructed the ancestral heat memory network of flowering plants by comparing the dynamic responses of Arabidopsis thaliana and Brachypodium distachyon. These findings enhance our understanding of the complex inter-layer cross-talk governing HS resilience and memory and identify novel genes essential for these processes.

plant biology↗

bioRxiv2023

Esm-1 mediates transcriptional polarization associated with diabetic kidney disease

BackgroundEsm-1, endothelial cell-specific molecule-1, is a susceptibility gene for diabetic kidney disease (DKD) and is a cytokine- and glucose-regulated, secreted proteoglycan, that is notably expressed in kidney and attenuates inflammation and albuminuria. Esm1 has restricted expression at the vascular tip during development but little is known about its expression pattern in mature tissues, and its precise effects in diabetes. MethodsWe utilized publicly available single-cell RNA sequencing data to explore the characteristics of Esm1 expression in 27,786 renal endothelial cells obtained from four adult human and three mouse databases. We validated our findings using bulk transcriptome data from an additional 20 healthy subjects and 41 patients with DKD and using RNAscope. Using correlation matrices, we relate Esm1 expression to the glomerular transcriptome and evaluated these matrices with systemic over-expression of Esm-1. ResultsIn both mice and humans, Esm1 is expressed in a subset of all renal endothelial cell types and represents a minority of glomerular endothelial cells. In patients, Esm1(+) cells exhibit a highly conserved enrichment for blood vessel development genes. With diabetes, these cells are fewer in number and profoundly shift expression to reflect chemotaxis pathways. Analysis of these gene sets highlight candidate genes such as Igfbp5 for cross talk between cell types. We also find that diabetes induces correlations in the expression of large clusters of genes, within cell type-enriched transcripts. Esm1 significantly correlates with a majority genes within these clusters, delineating a glomerular transcriptional polarization reflected by the magnitude of Esm1 deficiency. In diabetic mice, these gene clusters link Esm1 expression to albuminuria, and over-expression of Esm-1 reverses the expression pattern in many of these genes. ConclusionsA comprehensive analysis of single cell and bulk transcriptomes demonstrates that diabetes correlates with lower Esm1 expression and with changes in the functional characterization of Esm1(+) cells. Esm1 is both a marker for glomerular transcriptional polarization, and a mediator that re-orients the transcriptional program in DKD.

cell biology↗

bioRxiv2023

ABI5-FLZ13 Module Transcriptionally Represses Growth-related Genes to Delay Seed Germination in Response to ABA

The bZIP transcription factor ABSCISIC ACID INSENSITIVE5 (ABI5) is a master regulator determining seed germination and postgerminative growth in response to abscisic acid (ABA), but the detailed molecular mechanism underlying the repression function of ABI5 in plant growth remains to be characterized. In this study, we used proximity labeling (PL) to map the neighboring proteome of ABI5 and identified FCS-LIKE ZINC FINGER PROTEIN 13 (FLZ13) as an up-to-now unknown ABI5-interacting partner. Phenotypic analysis of flz13 mutants and FLZ13-overexpressing lines demonstrated that FLZ13 acts as a positive regulator of ABA signaling. Interestingly, transcriptomic analysis showed that ABI5 and FLZ13 co-downregulate the expression of ABA-repressed and growth-related genes involved in chlorophyll biosynthesis, photosynthesis and cell wall organization, thereby repressing seed germination and seedling establishment in response to ABA. Further genetic analysis proved that FLZ13 works synergistically with ABI5 to regulate seed germination. Collectively, our study reveals a previously uncharacterized transcriptional regulatory mechanism regarding ABA-inhibited seed germination and seedling establishment.

plant biology↗

bioRxiv2023

A 3D adrenocortical carcinoma tumor platform for preclinical modeling of drug response and matrix metalloproteinase activity

Adrenocortical carcinoma (ACC) has a poor prognosis, and no new drugs have been identified in decades. The absence of drug development can partly be attributed to a lack of preclinical models. Both animal models and 2D cell cultures of ACC fail to accurately mimic the disease, as animal physiology is inherently different than humans, and 2D cultures fail to represent the crucial 3D architecture. Organoids and other small 3D in vitro models of tissues or tumors can model certain complexities of human in vivo biology; however, this technology has largely yet to be applied to ACC. In this study, we describe the generation of 3D tumor constructs from an established ACC cell line, NCI-H295R. NCI-H295R cells were encapsulated to generate 3D ACC constructs. Tumor constructs were assessed for biomarker expression, viability, proliferation, and cortisol production. In addition, matrix metalloproteinase (MMP) functionality was assessed directly using fluorogenic MMP-sensitive biosensors and through infusion of NCI-H295R cells into a metastasis-on-a-chip microfluidic device platform. ACC tumor constructs showed expression of biomarkers associated with ACC, including SF-1, Melan A, and inhibin . Treatment of ACC tumor constructs with chemotherapeutics demonstrated decreased drug sensitivity compared to 2D cell culture. Since most tumor cells migrate through tissue using MMPs to break down extracellular matrix, we validated the utility of ACC tumor constructs by integrating fluorogenic MMP-sensitive peptide biosensors within the tumor constructs. Lastly, in our metastasis-on-a-chip device, NCI-H295R cells successfully engrafted in a downstream lung cell line-based construct, but invasion distance into the lung construct was decreased by MMP inhibition. These studies, which would not be possible using 2D cell cultures, demonstrated that NCI-H295R cells secreted active MMPs that are used for invasion in 3D. This work represents the first evidence of a 3D tumor constructs platform for ACC that can be deployed for future mechanistic studies as well as development of new targets for intervention and therapies. SignificanceThe paucity of preclinical research models has contributed to lack of progress in treatment of adrenocortical carcinoma (ACC). Three-dimensional modeling of ACC may provide novel insights for preclinical studies and advance ACC research.

cancer biology↗

bioRxiv2023

Prion-like characteristics of Hepatitis E virus ORF3 protein are associated with virus release and pathogenesis

Hepatitis E virus (HEV) is a common causative agent of acute hepatitis. Due to the shortage of efficient in vitro model, the viral assembly and release processes are still poorly understood. In this study, we found that ORF3, an HEV structural protein showed prion-like properties. The prion domain (PrD) of yeast prion Sup35 could be functionally replaced by HEV-ORF3 and its candidate PrD (cPrD). A single amino acid substitution in the cPrD reduced the aggregation propensity of ORF3 and blocked the function of ORF3 in enhancing the stability of microtubules in HEV-infected cells, thus blocking virion release from the infected cells and resulting in reduced HEV pathogenicity in Mongolian gerbils. These data suggest that HEV-ORF3 is a novel functional prion-like protein which assembles into a filamentous structure for virion release, supporting the hypothesis that the self-propagating properties of prion proteins are widely exploited as epigenetic information carriers in nature.

microbiology↗

bioRxiv2023

Astrocytic L-lactate signaling in the anterior cingulate cortex is essential for schema memory and neuronal mitochondrial biogenesis

Astrocyte-derived L-lactate was shown to confer beneficial effects on synaptic plasticity and cognitive functions. However, how astrocytic Gi signaling in the anterior cingulate cortex (ACC) modulates L-lactate levels and schema memory is not clear. Here, using chemogenetic approach and well-established behavioral paradigm, we demonstrate that astrocytic Gi pathway activation in ACC causes significant impairment in flavor-place paired associates (PA) learning, schema formation, and PA memory retrieval in rats. It also impairs new PA learning even if a prior associative schema exists. These impairments were mediated by decreased L-lactate in ACC due to astrocytic Gi activation. Concurrent exogenous L-lactate administration bilaterally into the ACC rescues these impairments. Furthermore, we show that the impaired schema memory formation was associated with a decreased neuronal mitochondrial biogenesis caused by decreased L-lactate level in ACC upon Gi activation. Our study also reveals that L-lactate mediated mitochondrial biogenesis is dependent on monocarboxylate transporter 2 and NMDA receptor activity - discovering a previously unrecognized signaling role of L-lactate. These findings expand our understanding of the role of astrocytes and L-lactate in brain functions.

neuroscience↗

bioRxiv2022

FAM76B regulates NF-κB-mediated inflammatory pathway by influencing the translocation of hnRNPA2B1

FAM76B has been reported to be a nuclear speckle localized protein with unknown function. In this study, FAM76B was first demonstrated to inhibit the NF-{kappa}B-mediated inflammatory pathway by affecting the translocation of hnRNPA2B1 in vitro. We further showed that FAM76B suppressed inflammation by regulating the NF-{kappa}B pathway in vivo using a traumatic brain injury (TBI) model in FAM76B knockout mice. Lastly, FAM76B was shown to interact with hnRNPA2B1 in human tissues taken from patients with acute, organizing, and chronic TBI, and with different neurodegenerative diseases. The results suggested that FAM76B mediates neuroinflammation by influencing the translocation of hnRNPA2B1 in vivo during TBI repair and neurodegenerative diseases. In summary, we for the first time demonstrated the role of FAM76B in regulating inflammation and further showed that FAM76B could regulate the NF-{kappa}B-mediated inflammatory pathway by affecting hnRNPA2B1 translocation, which provides new information for studying the mechanism of inflammation regulation.

cell biology↗

bioRxiv2022

Mechanistic dissection of alga recognition and uptake in coral-algal endosymbiosis

Many corals form a mutually beneficial relationship with the dinoflagellate algae called Symbiodiniaceae. Cells in the coral gastrodermis recognize, phagocytose, and house the algae in an organelle called symbiosome, which supports algae photosynthesis and nutrient exchange with corals1-3. Rising ocean temperature disrupts this endosymbiotic relationship, leading to alga loss, coral bleaching and death, and the degradation of marine ecosystems4-6. Mitigation of coral death requires a mechanistic understanding of coral-algal endosymbiosis. We have developed genomic resources to enable the use of a soft coral Xenia species as a model to study coral-algal endosymbiosis7. Here we report an effective RNA interference (RNAi) method and its application in the functional studies of genes involved in early steps of endosymbiosis. We show that an endosymbiotic cell marker called LePin (for its Lectin and kazal Protease inhibitor domains) is a secreted lectin that binds to algae to initiate the formation of alga-containing endosymbiotic cells. The evolutionary conservation of LePin among marine endosymbiotic anthozoans suggests a general role in coral-algal recognition. Coupling bioinformatics analyses with RNAi and single cell (sc)-RNA-seq, we uncover three gene expression programs (GEP) influenced by LePin during the early and middle stages of endosymbiotic lineage development. Further studies of genes in these GEPs lead to the identification of two scavenger receptors that support the formation of alga-containing endosymbiotic cells, most likely by initiating phagocytosis and modulating coral immune response. We also identify two actin regulators for endosymbiosis, which shed light on the phagocytic machinery and a possible mechanism for symbiosome formation. Our findings should usher in an era of mechanistic studies of coral-algal endosymbiosis.

cell biology↗

bioRxiv2022

Generate a new crucian carp (Carassius auratus) strain without intermuscular bones by knocking out bmp6

Elimination of intermuscular bones (IMBs) is vital to the aquaculture industry of cyprinids. In our previous study, we characterized bmp6 as essential in the development of IMBs in zebrafish. Knockout of bmp6 results in the absence of IMBs in zebrafish without affecting growth and reproduction. Therefore, we hypothesized that bmp6 could be used to generate new cyprinid strains without IMBs by gene editing. In this study, we established a gene editing strategy for knocking out the two orthologs of bmp6 in diploid crucian carp (Carassius auratus). We obtained an F3 population with both orthologs knocked out, in which no IMBs were detected by bone staining and X-ray, indicating that the new strain without IMBs (named WUCI strain) was successfully generated. Furthermore, we extensively evaluated the performance of the new strain in growth, reproduction, nutrient components, muscle texture and structure, and metabolites in muscle. The results showed that the WUCI strain grew faster than the wild-type crucian carp at 4-month-age. The reproductive performance and flesh quality did not show significant differences between the WUCI strain and wild-type crucian carp. Moreover, the metabolomics analysis suggested that the muscle tissues of the WUCI strain significantly enriched some metabolites belonging to the Thiamine metabolism, Nicotinate and Nicotinamide Metabolism pathway, which plays beneficial effects in anti-aging, anti-oxidant, and anti-radiation damage. In conclusion, we established a strategy to eliminate IMBs in crucian carp and obtain a WUCI strain whose performance was expected compared to the wild-type crucian carp; meanwhile, the WUCI strain enriched some beneficial metabolites to human health in muscle tissue. This study is the first report that a farmed cyprinid strain without IMBs, which could be stably inherited, was obtained worldwide; it provided excellent germplasm for the cyprinids aquaculture industry and a useful molecular tool for eliminating IMBs in other cyprinids.

genetics↗

bioRxiv2022

FGFR1 governs iron metabolism via regulating post-translational modification of IRP2 in prostate cancer cells

The acquisition of ectopic fibroblast growth factor receptor 1 (FGFR1) expression is well documented in prostate cancer (PCa) progression. However, how FGFR1 facilitates PCa progression is not fully revealed, although it is known to confer tumor growth advantage and metastasis. Here we report that FGFR1 deletion in DU145 human PCa cells retards the iron metabolism and reduces transferrin receptor 1 (TFR1), which synergistically enhances the anti-cancer effect of iron chelator. FGFR1 and TFR1 are highly expressed in PCa, and FGFR1 overexpression increased TFR1 in PCa cell lines. Furthermore, we first time demonstrate that FGFR1 deletion boosts and shifts the degradation of iron regulatory proteins 2 (IRP2) to downregulate TFR1. Detailed characterization revealed that based on FGFR1 deletion the stability of IRP2 is broken, whose degradation is accelerated, which can be not observed without FGFR1 deletion. In addition, IRP2 overexpression rescue the malignancy degree of DU145 cells. Our results here unravel a novel mechanism by which FGFR1 promotes PCa progression by upregulating iron metabolism, and that the FGFR1/IRP2/TFR1 axis can be a potential target for managing PCa progression.

cancer biology↗

bioRxiv2022

An R-R-type MYB transcription factor promotes nonclimacteric pepper fruit ripening pigmentation

Carotenoids act as phytohormones and volatile compound precursors that influence plant development and confer characteristic colours, affecting both the aesthetic and nutritional value of fruits. Carotenoid pigmentation in ripening fruits is highly dependent on developmental trajectories. Transcription factors incorporate developmental and phytohormone signalling to regulate the biosynthesis process. In contrast to the well-established pathways regulating ripening-related carotenoid biosynthesis in climacteric fruit, carotenoid regulation in nonclimacteric fruit is poorly understood. Capsanthin is the primary carotenoid of nonclimacteric pepper (Capsicum) fruit; its biosynthesis is tightly associated with fruit ripening, and it confers red pigment to the ripening fruit. In this study, using a weighted gene coexpression network and expression analysis, we identified an R-R-type MYB transcription factor, DIVARICATA1, and demonstrated that it is tightly associated with the levels of carotenoid biosynthetic genes (CBGs) and capsanthin accumulation. DIVARICATA1 encodes a nucleus-localized protein that functions primarily as a transcriptional activator. Functional analyses demonstrated that DIVARICATA1 positively regulates CBG transcript levels and capsanthin contents by directly binding to and activating the CBG promoter transcription. Furthermore, the association analysis revealed a significant positive association between DIVARICATA1 transcription level and capsanthin content. Abscisic acid (ABA) promotes capsanthin biosynthesis in a DIVARICATA1-dependent manner. Comparative transcriptomic analysis of DIVARICATA1 in pepper and its orthologue in a climacteric fruit, tomato, suggests that its function might be subject to divergent evolution among the two species. This study illustrates the transcriptional regulation of capsanthin biosynthesis and offers a novel target for breeding peppers with high red colour intensity.

plant biology↗

bioRxiv2022

FAVOR: Functional Annotation of Variants Online Resource and Annotator for Variation across the Human Genome

Large-scale whole genome sequencing (WGS) studies and biobanks are rapidly generating a multitude of coding and non-coding variants. They provide an unprecedented resource for illuminating the genetic basis of human diseases. Variant functional annotations play a critical role in WGS analysis, result interpretation, and prioritization of disease- or trait-associated causal variants. Existing functional annotation databases have limited scope to perform online queries or are unable to functionally annotate the genotype data of large WGS studies and biobanks for downstream analysis. We develop the Functional Annotation of Variants Online Resources (FAVOR) to meet these pressing needs. FAVOR provides a comprehensive online multi-faceted portal with summarization and visualization of all possible 9 billion single nucleotide variants (SNVs) across the genome, and allows for rapid variant-, gene-, and region-level online queries. It integrates variant functional information from multiple sources to describe the functional characteristics of variants and facilitates prioritizing plausible causal variants influencing human phenotypes. Furthermore, a scalable annotation tool, FAVORannotator, is provided for functionally annotating and efficiently storing the genotype and variant functional annotation data of a large-scale sequencing study in an annotated GDS file format to facilitate downstream analysis. FAVOR and FAVORannotator are available at https://favor.genohub.org.

genetics↗

bioRxiv2022

HepaCAM Suppresses Glioblastoma Stem Cell Invasion in the Brain

Glioblastoma (GBM) is a malignant brain cancer that contains sub-populations of highly invasive tumor cells that drive progression and recurrence after surgery and radiochemotherapy. The exact mechanisms that enable GBM cells to disperse from the main tumor mass and navigate throughout the brain microenvironment remain largely unknown. As a result, there is a lack of effective strategies to block cancer cell invasive growth in primary and recurrent GBM. Here we report that hepatocyte cell adhesion molecule (hepaCAM), which is normally expressed in perivascular astrocytes, plays central roles in controlling the invasive growth features of GBM cells. Genetically targeting HEPACAM induces a transition from GBM cell proliferation/self-renewal to invasion. Increased invasion is due, in part, to an activation of focal adhesion signaling pathways and enhanced GBM cell adhesion to the extracellular matrix (ECM) in the brain microenvironment. Transcriptional profiling of GBM cells reveals various HEPACAM-regulated genes with links to polarity and invasion. Collectively, these data show that hepaCAM balances ECM adhesion and signaling pathways to control cancer cell proliferation versus invasion in the brain parenchyma. Targeting select components of the hepaCAM pathway may be an effective way to block tumor progression and recurrence in patients with GBM.

cancer biology↗

bioRxiv2022

Enhanced methionine cycle suppresses naïve CD8+ T-cell maturation

The metabolic pathways controlling naive CD8+ T (Tn) cell maturation following thymic egress remain mostly undefined. This is important because immature Tn are a major component of peripheral immune tolerance in newborns and under lymphopenia. In this study we demonstrate that TMRM, a mitochondrial membrane potential marker, could be applied to rapidly identify an immature Tn cell population in the periphery. Applying this marker to perform metabolic and proteomic analysis, we show that immature Tn cells maintain accelerated methionine cycle in respect to mature Tn. This unique metabolic state was associated with restricted Tbx21 locus and diminished immune response in vitro and in vivo. Following our findings, we demonstrate that inhibition of methionine cycle leads to rapid functional maturation of Tn and recovery of immune response to stimuli. Our work provides insight into the way the rate of methionine cycling regulates T cell maturation, opening a path for metabolic manipulation of immune tolerance.

immunology↗

bioRxiv2022

Spike-specific CXCR3+ TFH cells play a dominant functional role in supporting antibody responses in SARS-CoV-2 infection and vaccination

CD4+ T follicular helper (TFH) cells are required for high-quality antibody generation and maintenance. However, the longevity and functional role of these cells are poorly defined in COVID-19 convalescents and vaccine recipients. Here, we longitudinally investigated the dynamics and functional roles of spike-specific circulating TFH cells and their subsets in convalescents at the 2nd, 5th, 8th, 12th and 24th months after COVID-19 symptom onset and in vaccinees after two and three doses of inactivated vaccine. SARS-CoV-2 infection elicited robust spike-specific TFH cell and antibody responses, of which spike-specific CXCR3+ TFH cells but not spike-specific CXCR3- TFH cells and neutralizing antibodies were persistent for at least two years in more than 80% of convalescents who experienced symptomatic COVID-19, which was well coordinated between spike-specific TFH cell and antibody responses at the 5th month after infection. Inactivated vaccine immunization also induced spike-specific TFH cell and antibody responses; however, these responses rapidly declined after six months with a two-dose standard administration, and a third dose significantly promoted antibody maturation and potency. Functionally, spike-specific CXCR3+ TFH cells exhibited better responsiveness than spike-specific CXCR3- TFH cells upon spike protein stimulation in vitro and showed superior capacity in supporting spike-specific antibody secreting cell (ASC) differentiation and antibody production than spike-specific CXCR3- TFH cells cocultured with autologous memory B cells. In conclusion, spike-specific CXCR3+ TFH cells played a dominant functional role in antibody elicitation and maintenance in SARS-CoV-2 infection and vaccination, suggesting that induction of CXCR3-biased spike-specific TFH cell differentiation will benefit SARS-CoV-2 vaccine development aiming to induce long-term protective immune memory. HighlightsO_LISARS-CoV-2 infection elicited robust spike-specific TFH cell and antibody responses, which persisted for at least two years in the majority of symptomatic COVID-19 convalescent patients. C_LIO_LIInactivated vaccine immunization also elicited spike-specific TFH cell and antibody responses, which rapidly declined over time, and a third dose significantly promoted antibody maturation and potency. C_LIO_LISpike-specific CXCR3+ TFH cells exhibited more durable responses than spike-specific CXCR3- TFH cells, correlated with antibody responses and showed superior capacity in supporting ASC differentiation and antibody production than spike-specific CXCR3- TFH cells. C_LI

immunology↗

bioRxiv2022

Ezh2 knockout in B cells impairs plasmablast differentiation and ameliorates lupus-like disease in MRL/lpr mice

ObjectivesEnhancer of zeste homolog 2 (EZH2) regulates B cell development and differentiation. We have previously demonstrated increased EZH2 expression in peripheral blood mononuclear cells isolated from lupus patients. The goal of this study was to evaluate the role of B cell EZH2 expression in lupus pathogenesis. MethodsWe generated an MRL/lpr mouse with floxed Ezh2, which was crossed with CD19-Cre mice to examine the effect of B cell EZH2 deficiency in MRL/lpr lupus-prone mice. Differentiation of B cells was assessed by flow cytometry. Single cell RNA sequencing and single cell B cell receptor sequencing were used to investigate compositional and functional changes of B cell subsets. In vitro B cell culture with an XBP1 inhibitor was performed. EZH2 and XBP1 mRNA levels in CD19+ B cells isolated from SLE patients and healthy controls were analyzed. ResultsWe show that Ezh2 deletion in B cells significantly decreased autoantibody production and improved glomerulonephritis. B cell development was altered in the bone marrow and spleen of EZH2-deficient mice. Differentiation of plasmablasts was impaired. Single cell RNA sequencing showed that XBP1, a key transcription factor in B cell development, is downregulated in the absence of EZH2. Inhibiting XBP1 in vitro impairs plasmablast development similar to EZH2-deficient mice. Single cell B cell receptor RNA sequencing revealed defective immunoglobulin class switch recombination in EZH2-deficient mice. In human lupus B cells, we observed a strong correlation between EZH2 and XBP1 mRNA expression levels. ConclusionEZH2 overexpression in B cells contributes to disease pathogenesis in lupus.

immunology↗

bioRxiv2022

A model-based analysis reveals three-dimensional genome organization heterogeneity and functional sub-compartments in cell populations

The computational inference of genome organization based on Hi-C sequencing has greatly aided the understanding of chromatin and nuclear organization in three dimensions (3D). However, existing computational methods used to infer sub-compartments from Hi-C data fail to address the cell population heterogeneity. Here we describe a model-based method, called CscoreTool-M, which uses probabilistic modeling to build multiple 3D genome sub-compartments from Hi-C data. The compartment scores inferred using CscoreTool-M directly represents the probability of a genomic region locating in a specific sub-compartment. Compared to published methods, CscoreTool-M is more accurate in inferring local sub-compartment containing heterochromatin marked by Histone lysine trimethylation (H3K27me3) surrounded by the actively transcribed euchromatic regions. The compartment scores calculated by CscoreTool-M also help to quantify the levels of heterogeneity in sub-compartment localization within cell populations for different genomic regions. By comparing proliferating cells and terminally differentiated non-proliferating cells, we show that the proliferating cells have higher genome organization heterogeneity, which is likely caused by cells at different cell-cycle stages. By analyzing 10 sub-compartments, we found a sub-compartment containing chromatin potentially related to the early-G1 chromatin regions proximal to the nuclear lamina in HCT116 cells, suggesting the method can deconvolve cell cycle stage-specific genome organization among asynchronously dividing cells. Finally, we show that CscoreTool-M can further identify sub-compartments that contain genes enriched in housekeeping or cell-type-specific functions.

bioinformatics↗