Biology subjects

Kong, X.

Publications and source records attributed to Kong, X..

At least 73 records · Page 4Linked to original sources

bioRxiv2023

In-vivo whole-cortex estimation of excitation-inhibition ratio indexes cortical maturation and cognitive ability in youth

A balanced excitation-inhibition ratio (E/I ratio) is critical for healthy brain function. Normative development of cortex-wide E/I ratio remains unknown. Here we non-invasively estimate a putative marker of whole-cortex E/I ratio by fitting a large-scale biophysically-plausible circuit model to resting-state functional MRI (fMRI) data. We first confirm that our model generates realistic brain dynamics in the Human Connectome Project. Next, we show that the estimated E/I ratio marker is sensitive to the GABA-agonist benzodiazepine alprazolam during fMRI. Alprazolam-induced E/I changes are spatially consistent with positron emission tomography measurement of benzodiazepine receptor density. We then investigate the relationship between the E/I ratio marker and neurodevelopment. We find that the E/I ratio marker declines heterogeneously across the cerebral cortex during youth, with the greatest reduction occurring in sensorimotor systems relative to association systems. Importantly, among children with the same chronological age, a lower E/I ratio marker (especially in association cortex) is linked to better cognitive performance. This result is replicated across North American (8.2 to 23.0 years old) and Asian (7.2 to 7.9 years old) cohorts, suggesting that a more mature E/I ratio indexes improved cognition during normative development. Overall, our findings open the door to studying how disrupted E/I trajectories may lead to cognitive dysfunction in psychopathology that emerges during youth. SignificanceHealthy brain function requires a delicate balance of neural excitation (E) and inhibition (I). In animals, this balance - the E/I ratio - is known to decrease with the maturation of inhibitory circuitry during healthy development. However, in humans, the normative development of cortex-wide E/I ratio remains unclear. Here, we use a biophysical model and non-invasive brain scans to estimate a marker of E/I ratio. Spatial changes in our E/I ratio marker are consistent with a drug that decreases E/I ratio. We also find that our cortex-wide E/I ratio marker decreases during development. Furthermore, North American and Asian children with lower E/I ratio, especially in higher-order cortex, have better cognitive performance. Overall, E/I ratio is a potential index of healthy neurocognitive development.

neuroscience↗

bioRxiv2023

Select EZH2 inhibitors enhance the viral mimicry effects of DNMT inhibition through a mechanism involving calcium-calcineurin-NFAT signaling

DNA methyltransferase (DNMT) inhibitors are FDA-approved for various hematological malignancies but have limited efficacy in solid tumors. DNA hypomethylation with these drugs is associated with elevated lysine 27 tri-methylation on histone H3 (H3K27me3). We hypothesized that this EZH2-dependent repressive mark limits the full potential of DNMT inhibition. Here, we show in cell line and tumoroid models of colorectal cancer, that low-dose DNMT inhibition sensitizes cells to selective EZH2 inhibitors that have limited single agent toxicity, and that EZH2 inhibition enhances DNMT inhibitor-driven molecular and therapeutic effects. Through integrative epigenomic analyses, we reveal that DNMT inhibition induces H3K27me3 accumulation at genomic regions poised with EZH2. Unexpectedly, combined treatment alters the epigenome landscape to promote transcriptional upregulation of the calcium-calcineurin-NFAT signaling pathway. Blocking this pathway limits the transcriptional activating effects of the drug combination, including expression of transposable elements and innate immune response genes within a viral defense pathway. Consistently, we demonstrate positive correlations between DNMT inhibitor- and innate immune response-associated transcription profiles and calcium signal activation in primary human colon cancer specimens. Collectively, our study demonstrates that compensatory EZH2 activity following DNA hypomethylation presents a barrier to the therapeutic action of DNMT inhibition in colon cancer, reveals a new application of EZH2 inhibitors beyond cancers associated with PRC2 hyperactivity, and links calcium-calcineurin-NFAT signaling to epigenetic therapy-induced viral mimicry. HighlightsO_LISelect EZH2 inhibitors enhance the transcriptional activating and antiproliferative effects of DNA hypomethylating agents in colon cancer cells. C_LIO_LIThe mechanism involves blockade of H3K27me3 accumulation in regions of the genome poised for PRC2 activity. C_LIO_LIDNMT inhibitor + EZH2 inhibitor treatment transcriptionally upregulates calcium-calcineurin- NFAT signaling, and this pathway is necessary for complete induction of viral mimicry and innate immune response pathways. C_LIO_LIThe therapeutic utility of EZH2 inhibitors may be extended beyond cancers with PRC2 hyperactivity in combination regimens with DNMT inhibitors. C_LI

cancer biology↗

bioRxiv2023

Discovery of microRNA-derived RNAs and proteins in human cells

MicroRNAs (miRNAs) are short noncoding RNAs that can regulate gene expression through the binding of their 5-ends to mRNAs. However, the biological effects of miRNA binding via their 3-ends remain unclear. Here, we discover that the exact reverse pairing of the 3-ends of miRNAs or miRNA-like RNAs, collectively termed microsized RNAs (msRNAs), with template RNAs can initiate the production of msRNA-derived RNAs (msdRs), which can subsequently be translated into polypeptides (msdPs). Using 2,632 human msRNAs from miRBase, 11,121 msdRs and 1,239 msdPs were predicted based on a 15-nucleotide pairing threshold, and the presence of representative msdRs and msdPs was confirmed in human cells. Of clinical relevance, msdP0188 is highly expressed in human lung and breast cancers, and its corresponding msRNAs and msdRs represent novel anti-cancer targets. Notably, inhibiting telomerase reverse transcriptase, a putative RNA-dependent RNA polymerase identified by bioinformatic screening, led to reduced levels of msdP0188 in human cancer cells. Our findings reveal a novel "msRNA [->] msdR [->] msdP" axis, expanding the classical central dogma and predicting many previously unrecognized RNAs and polypeptides with potential biological functions in human cells and other systems.

cell biology↗

bioRxiv2023

Temporal colonization of the gut microbiome in neonatal Bos taurus at single nucleotide resolution

BackgroundThe rumen of neonatal calves is underdeveloped and exhibits limited functionality during early life. Thus, the acquisition and colonization of microbes in the gut are key to establishing a healthy host-microbiome symbiosis for neonatal calves. Microbiome-linked health outcomes appear to be the consequences of individual strains of specific microbes. However, the temporal colonization of pioneering microbial strains and their linkages to the health and growth of neonatal calves are poorly understood. ResultsTo address this, we longitudinally profiled the gut microbiome of 36 neonatal calves from birth up to 2 months postpartum and carried out microbial transplantation (MT) to reshape their gut microbiome. Genomic reconstruction of deeply sequenced fecal samples resulted in a total of 3,931 metagenomic assembled genomes (MAGs), of which 397 were identified as new species when compared with existing databases of Bos taurus. Single nucleotide level metagenomic profiling shows a rapid influx of microbes after birth, followed by strong selection during the first few weeks of life. MT was found to reshape the genetic makeup of 33 MAGs (FDR<0.05), mainly from Prevotella and Bacteroides species. We further linked over 20 million microbial single nucleotide variations (SNVs) to 736 plasma metabolites, which enabled us to characterize 24 study-wide significant associations (P < 4.4x10-9) that identify the potential microbial genetic regulation of host immune and neuro-related metabolites, including glutathione and L-dopa. Our integration analyses further revealed that microbial genetic variations may influence the health status and growth performance of neonatal calves by modulating metabolites via structural regulation of their encoded proteins. For instance, we found that the albumin levels and total antioxidant capacity in neonatal calves were correlated with L-dopa, which was determined by SNVs via structural regulations of metabolic enzymes. ConclusionsThe current results indicate that the temporal colonization of microbial strains and MT-induced strain replacement are integral in the development of the gut microbiome of neonatal calves and may help to develop strategies that can improve the health status and growth performance of neonatal calves.

microbiology↗

bioRxiv2023

NDC80 status pinpoints mitotic kinase inhibitors as emerging therapeutic options in clear cell renal cell carcinoma

[~]30% of clear cell renal cell carcinoma (ccRCC) patients present with metastatic disease at the time of diagnosis, causing a dire 5-year survival rate of 13%. Whereas anti-PD-1 immunotherapy has improved survival, a strong need remains for new therapeutic options. Using integrated network analysis, we identified the mitotic regulator NDC80 as a predictor of ccRCC progression. Overexpression of NDC80 fosters the malignant phenotype by promoting cell cycle progression through S phase as well as boosting glycolysis and mitochondrial respiration. Despite high levels of immune infiltration, particularly derived from tumor resident CD8+ T cells with an exhausted phenotype, NDC80 defines a class of ccRCCs that poorly respond to immune checkpoint blockade. Instead, bioinformatics identified NDC80-high ccRCCs as sensitive to inhibitors of mitotic kinases, PLK1 and AURK, therapeutic approaches we validated in cell lines and mouse xenograft studies. Thus, NDC80 status pinpoints mitotic kinase inhibitors as promising therapeutic options in difficult-to-treat ccRCCs.

cancer biology↗

bioRxiv2023

Extraction of biological signals by factorization enables the reliable analysis of single-cell transcriptomics

Accurately and reliably capturing actual biological signals from single-cell transcriptomics is vital for achieving legitimate scientific results, which is unfortunately hindered by the presence of various kinds of unwanted variations. Here we described a deep auto-regressive factor model known as scPhenoXMBD, demonstrated that each genes expression can be split into discrete components that represent biological signals and unwanted variations, which effectively mitigated the effects of unwanted variations in the data of single-cell sequencing. Using scPhenoXMBD, we evaluated various factors affecting IFN {beta} -stimulated immune cells and demonstrated that biological signal extraction facilitates the identification of IFN{beta}-responsive pathways and genes. Numerous experiments were conducted to show that scPhenoXMBD could be utilized successfully in enhancing cell clustering stability, obtaining identical cell populations from diverse data sources, advancing the single-cell CRISPR screening of functional elements, and minimizing the influence of inter-subject discrepancies in the cell-disease relationships. scPhenoXMBD is anticipated to be a dependable and repeatable method for the precise analysis of single-cell data.

bioinformatics↗

bioRxiv2023

KDM2B regulates hippocampal morphogenesis by transcriptionally silencing Wnt signaling in neural progenitors

The hippocampus plays major roles in learning and memory. Similar to other parts of the brain, the development of hippocampus requires precise coordination of patterning, cell proliferation, differentiation, and migration, with both cell-intrinsic and extrinsic mechanisms involved. Here we genetically removed the chromatin-association capability of KDM2B - a key component of the variant Polycomb repressive complex 1 (PRC1) - in the progenitors of developing dorsal telencephalon (Kdm2b{Delta}CxxC) to surprisingly discover that the size of Kdm2b{Delta}CxxC hippocampus, particularly the dentate gyrus, became drastically smaller with disorganized cellular components and structure. Kdm2b{Delta}CxxC mice displayed prominent defects in spatial memory, motor learning and fear conditioning. The differentiation trajectory of the developing Kdm2b{Delta}CxxC hippocampus was greatly delayed, with a significant amount of TBR2-expressing intermediate progenitors stuck along the migratory/differentiation path. Transcriptome and chromatin immunoprecipitation studies of neonatal hippocampi and their progenitors indicated that genes implicated in stemness maintenance, especially components of canonical Wnt signaling, could not be properly silenced by PRC1 and PRC2. Activating the Wnt signaling disturbed hippocampal neurogenesis, recapitulating the effect of KDM2B loss. Together, we unveiled a previously unappreciated gene repressive program mediated by KDM2B that controls progressive fate specifications and cell migration, hence morphogenesis of hippocampus during development. Graphic AbstractLoss of KDM2B-CxxC reduces repressive histone modifications - H2AK119ub and H3K27me3 - on key Wnt signal genes, hence leading to the block of their attenuation over time. Hampered differentiation and migration of hippocampal progenitors leads to hippocampal agenesis. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=112 SRC="FIGDIR/small/525636v1_ufig1.gif" ALT="Figure 1"> View larger version (34K): org.highwire.dtl.DTLVardef@18fbbdborg.highwire.dtl.DTLVardef@17633f9org.highwire.dtl.DTLVardef@14e36b9org.highwire.dtl.DTLVardef@1eadb8a_HPS_FORMAT_FIGEXP M_FIG C_FIG

developmental biology↗

bioRxiv2023

The landscape of m1A modification and its posttranscriptional regulatory functions in primary neurons

Cerebral ischaemia-reperfusion injury, during which neurons undergo oxygen-glucose deprivation/reoxygenation (OGD/R), is a notable pathological process in many neurological diseases. N1-methyladenosine (m1A) is an RNA modification that can affect gene expression and RNA stability. The m1A landscape and potential functions of m1A modification in neurons remain poorly understood. We explored RNA (mRNA, lncRNA, and circRNA) m1A modification in normal and OGD/R-treated neurons and the effect of m1A on diverse RNAs. We investigated the m1A landscape in primary neurons, identified m1A-modified RNAs, and found that OGD/R increased the number of m1A RNAs. m1A modification might also affect the regulatory mechanisms of noncoding RNAs, e.g., lncRNA-RBP interactions and circRNA translation. We showed that m1A modification mediates the circRNA/lncRNA-miRNA-mRNA ceRNA mechanism and that 3UTR methylation of mRNAs can hinder miRNA-mRNA binding. Three methylation patterns were identified, and genes with different patterns had intrinsic mechanisms with potential m1A-regulatory specificity. Systematic analysis of the m1A landscape in normal and OGD/R neurons lays a critical foundation for understanding RNA methylation and provides new perspectives and a theoretical basis for treating and developing drugs for OGD/R pathology-related diseases.

neuroscience↗

bioRxiv2022

Identification of S1PR4 as an immune modulator for favorable prognosis in HNSCC through unbiased machine learning

As the largest family of membrane proteins, G protein-coupled receptors (GPCRs) are the most prominent family of pharmacological targets. However, only a few GPCRs have been well-defined in terms of their physiological and pathological functions. Thus, an efficient way to identify key GPCRs involved in tumour formation is urgently needed. In this study, patients with head and neck squamous cell carcinoma (HNSCC) were classified into two different subtypes based on the characteristics of GPCRs using an unbiased machine learning method. Notably, these two subtypes showed significant differences in prognosis, gene expression, and immune microenvironment, especially in the infiltration of CD8+ T cells. Based on these differences, we screened three potential key regulators (S1PR4, S1PR5, and GPR87) from all GPCRs and constructed a prognostic nomogram for patients with HNSCC. We identified S1PR4 as the key GPCR in determining the two subtypes for positive correlation with the proportion and cytotoxicity of CD8+ T cells in HNSCC and was mainly expressed in a subset of CX3CR1+CD8+ T cells. We also demonstrated that S1PR4 is an immune modulator for the favourable prognosis of HNSCC patients. We found that S1PR4 was highly expressed in CD8+ T cells from the tumours of HNSCC patients, which was significantly associated with better prognosis, and S1PR4 expression was accompanied by higher T cell cytotoxic marker expression (IFNG and GZMB). Notably, S1PR4 co-localised with CX3CR1, which has been identified as the most cytotoxic marker of CD8+ T cells. Furthermore, S1PR4 upregulation could significantly increase T cell function in CAR-T cell therapy, indicating its great potential in cancer immunotherapy. Therefore, these results identified S1PR4 as a key indicator of cytotoxicity and the proportion of tumour-infiltrating CD8+ T cells and confirmed the prognostic value of S1PR4 in HNSCC. Our findings contribute to the knowledge of S1PR4 in anti-tumour immunity, providing a potential GPCR-targeted therapeutic option for future HNSCC treatment.

cancer biology↗

bioRxiv2022

HSPB1 facilitates chemoresistance through inhibiting ferroptotic cancer cell death and regulating NF-κB signaling pathway in breast cancer

Chemoresistance is one of the major causes of therapeutic failure and poor prognosis for breast cancer patients, especially for triple-negative breast cancer patients. However, the underlying mechanism remains elusive. Here, we identified novel functional roles of heat shock protein beta-1 (HSPB1), regulating the chemoresistance and ferroptotic cell death in breast cancer. Based on TCGA and GEO databases, HSPB1 expression was upregulated in breast cancer tissues and associated with poor prognosis of breast cancer patients, which was considered as an independent prognostic factor for breast cancer. Functional assays revealed that HSPB1 could promote cancer growth and metastasis in vitro and in vivo. Furthermore, HSPB1 facilitated doxorubicin resistance through protecting breast cancer cells from drug-induced ferroptosis. Mechanistically, HSPB1 could bind with Ik{beta}- and promote its ubiquitination-mediated degradation, leading to increased nuclear translocation and activation of NF-{kappa}B signaling. In addition, HSPB1 overexpression led to enhanced secretion of IL6, which further facilitated breast cancer progression. These findings revealed that HSPB1 upregulation might be a key driver to progression and chemoresistance through regulating ferroptosis in breast cancer, while targeting HSPB1 could be an effective strategy against breast cancer.

cancer biology↗

bioRxiv2022

Engineered SMCHD1 and D4Z4 mutations reveal roles of D4Z4 heterochromatin disruption and feedforward DUX4 network activation in FSHD

Facioscapulohumeral dystrophy (FSHD) is commonly associated with contraction of D4Z4 repeats on chromosome 4q (FSHD1). Mutations in the SMCHD1 gene are linked to both minor cases with no prominent repeat loss (FSHD2) and severe cases of FSHD1. Abnormal upregulation of the transcription factor DUX4, encoded in the D4Z4 repeat, is believed to play a central role in FSHD. However, defining the disease mechanism has been hampered by the heterogeneity of patient-derived cells, difficulty to detect DUX4 in patient myocytes, and limited animal models because D4Z4 repeats are primate-specific. To overcome these limitations, we engineered isogenic human skeletal myoblast lines with D4Z4 and/or SMCHD1 mutations. We found a highly synergistic effect of double mutations on triggering two key disease processes, D4Z4 heterochromatin disruption and cross-stimulation of DUX4 targets, such as histone H3.X/Y and LEUTX transcription factor. Thus, engineered human myocyte models provide unique insights into the molecular mechanisms underpinning FSHD. TeaserFSHD mutations cause D4Z4 heterochromatin disruption and feedforward DUX4 network activation.

genetics↗

bioRxiv2022

Isoform-specific Disruption of the TP73 Gene Reveals a Critical Role for TAp73gamma in Tumorigenesis via Leptin

TP73, a member of the p53 family, is expressed as TAp73 and {Delta}Np73 along with multiple C-terminal isoforms (-{eta}). {Delta}Np73 is primarily expressed in neuronal cells and necessary for neuronal development. Interestingly, while TAp73 is a tumor suppressor and predominantly expressed in normal cells, TAp73 is found to be frequently altered in human cancers, suggesting a role of TAp73 C-terminal isoforms in tumorigenesis. To test this, the TCGA SpliceSeq database was searched and showed that exon 11 (E11) exclusion occurs frequently in several human cancers. We also found that p73 to p73{gamma} isoform switch resulting from E11 skipping occurs frequently in human prostate cancers and dog lymphomas. To determine whether p73 to p73{gamma} isoform switch plays a role in tumorigenesis, CRISPR technology was used to generate multiple cancer cell lines and a mouse model in that Trp73 E11 is deleted. Surprisingly, we found that in E11-deificient cells, p73{gamma} becomes the predominant isoform and exerts oncogenic activities by promoting cell proliferation and migration. In line with this, E11-deficient mice were more prone to obesity and B-cell lymphomas, indicating a unique role of p73{gamma} in lipid metabolism and tumorigenesis. Additionally, we found that E11-deficient mice phenocopies Trp73-deficient mice with short lifespan, infertility, and chronic inflammation. Mechanistically, Mechanistically, we showed that Leptin, a pleiotropic adipocytokine involved in energy metabolism and oncogenesis, was highly induced by p73{gamma}, necessary for p73{gamma}-mediated oncogenic activity, and associated with p73 to {gamma} isoform switch in human prostate cancer and dog lymphoma. Finally, we showed that E11-knockout promoted, whereas knockdown of p73{gamma} or Leptin suppressed, xenograft growth in mice. Our study indicates that the p73{gamma}-Leptin pathway promotes tumorigenesis and alters lipid metabolism, which may be targeted for cancer management.

cancer biology↗

bioRxiv2022

Integrated single-nucleus and spatial transcriptomics captures transitional states in soybean nodule symbiosis establishment

Legumes form symbiosis with rhizobium leading to the development of nitrogen-fixing nodules. By integrating single-nucleus and spatial transcriptomics, we established a cell atlas of soybean nodules and roots. In central infected zone of nodule, we found that uninfected cells specialize into functionally distinct sub-groups during nodule development and revealed a transitional subtype of infected cells with enriched nodulation-related genes. Overall, our results provide a single-cell perspective for understanding rhizobium-legume symbiosis.

plant biology↗

bioRxiv2022

scPheno: A deep generative model to integrate scRNA-seq with disease phenotypes and its application on prediction of COVID-19 pneumonia and severe assessment

Cell-to-cell variability is orchestrated by transcriptional variations participating in different biological processes. However, the dissection of transcriptional variability in specific biological process at single-cell level remains unavailable. Here, we present a deep generative model scPheno to integrate scRNA-seq with disease phenotypes to unravel the invisible phenotype-related transcriptional variations. We applied scPheno on COVID-19 blood scRNA-seq to separate transcriptional variations in regulating COVID-19 host immunity and transcriptional variations in maintaining cell-type identity. In silico, we found CLU+IFI27+S100A9+ monocyte as the efficient cellular marker for the prediction of COVID-19 diagnosis. Inspiringly, using only 4 genes upregulated in CLU+IFI27+S100A9+ monocytes can predict the COVID-19 diagnosis of individuals from different country with an accuracy up to 81.3%. We also found C1+CD163+ monocyte and 8 C1+CD163+ monocyte-upregulated genes as the efficient biomarkers for the prediction of severity assessment. Overall, scPheno is an effective method in dissecting the transcriptional basis of phenotype variations at single-cell level.

genomics↗

bioRxiv2022

An engineered xCas12i with high activity, high specificity and broad PAM range

The type-V CRISPR effector Cas12i, with its smaller size, short crRNA guiding, and self-processing features, is a potentially versatile genome editing tool. By screening Cas12i proteins from a metagenomic database, we identified a natural variant with high activity in mammalian cells, named as xCas12i. We further engineered the PAM-interacting, REC, and RuvC domains for enhanced cleavage activity and specificity. This variant, named as high-fidelity Cas12Max, exhibited robust genome editing activity and minimal off-target activity with a broad 5-TN recognition profile. With the fusion of deaminase TadA8e and further optimization of xCas12i, the base editor dCas12i-Tad8e also showed the high editing efficiency. This study provides highly efficient and specific tools for gene therapy.

bioengineering↗

bioRxiv2022

Cohesin mutation sensitizes cancer cells to anti-PD-1 therapy through endogenous retrovirus-mediated PD-L1 upregulation

Immune checkpoint therapy shows impressive and durable clinical responses in cancer patients, but the genetic determinants that enable cancer cells to respond to anti-PD-1 therapy are still elusive. Herein, we identified that NIPBL deficiency promotes endogenous retrovirus (ERV) expression in tumour cells, which in turn inactivates CD8+ tumour-infiltrating lymphocytes (TILs) via the PD-L1/PD-1 inhibitory checkpoint pathway. Mechanistically, NIPBL deficiency impairs DNMT1 transcription, preventing DNMT1 from suppressing ERV expression in tumour cells; ERVs stimulate PD-L1 expression by inducing the STAT2-IRF9 complex, a downstream event of double-stranded RNA (dsRNA)-MAVS-IRF3 signalling, and thereby suppress CD8 TIL-mediated immunity. An anti-PD-1 monoclonal antibody achieved remarkable therapeutic effects in Nipbl-deficient syngeneic tumour models and improved host survival by eliciting an antitumour memory immune response. Cancer patients harbouring mutations of cohesin subunits and regulators plus DNMT1 had significantly better responses to anti-PD-1 therapy than their non-mutated counterparts did. Our study reveals a novel mechanism by which cohesin complex deregulation stimulates ERV expression by impairing DNMT1 expression and fosters an immunosuppressive tumour microenvironment by activating the PD-L1/PD-1 inhibitory checkpoint.

cancer biology↗

bioRxiv2021

RNA2Immune: A Manually Curated Database of Experimentally Supported Data Linking Noncoding RNA Regulation to the Immune System

Non-coding RNAs (ncRNAs), such as microRNAs (miRNAs), long noncoding RNAs (lncRNAs), circular RNAs (circRNAs), have emerged as important regulators of the immune system and are involved in the control of immune cell biology, disease pathogenesis as well as vaccine responses. A repository of ncRNA-immune associations will facilitate our understanding of ncRNA-dependent mechanisms in the immune system and advance the development of therapeutics for immune disorders as well as vaccines. Here, we describe a comprehensive database, RNA2Immune, which aims to provide a high-quality resource of experimentally supported database linking ncRNA regulatory mechanisms to immune cell function, immune disease, cancer immunology, and vaccines. The current version of RNA2Immune documents 50,433 immune-ncRNA associations in 42 host species, including: (i) 6690 ncRNA associations with immune functions involving 31 immune cell types; (ii) 38,672 ncRNA associations with 348 immune diseases; (iii) 4833 ncRNA associations with cancer immunology; and (iv) 238 ncRNA associations with vaccine responses involving 26 vaccine types targeting 22 diseases. RNA2Immune provides a user-friendly interface for browsing, searching and downloading ncRNA-immune system associations. Collectively, RNA2Immune provides important information about how ncRNAs influence immune cell function, the pathological consequences of dysregulation of these ncRNAs (immune diseases and cancers), and how ncRNAs affect immune responses to vaccines. RNA2Immune is available at http://bio-bigdata.hrbmu.edu.cn/rna2immune/home.jsp.

immunology↗

bioRxiv2021

Progressive chromatin silencing of ABA biosynthesis gene permits seed germination in Arabidopsis

Seed germination represents a major developmental switch in plants that is vital to agricultural, but how this process is controlled at the chromatin level remains obscure. Here we demonstrate that successful germination in Arabidopsis requires a chromatin mechanism that progressively silences NCED6, which encodes a rate-limiting enzyme for abscisic acid (ABA) biosynthesis, through the cooperative action of the RNA-binding protein RZ-1 and the polycomb repressive complex 2 (PRC2). Simultaneous inactivation of RZ-1 and PRC2 blocks germination and synergistically derepresses NCEDs and hundreds of genes. At NCED6, by promoting H3 deacetylation and suppressing H3K4me3, RZ-1 facilitates transcriptional silencing and also a H3K27me3 accumulation process that occurs during seed germination and early seedling growth. Genome-wide analysis reveals RZ-1 is preferentially required for transcriptional silencing of many PRC2 targets early during seed germination when H3K27me3 is not yet established. We propose RZ-1 confers a novel silencing mechanism to compensate and coordinate with PRC2. Our work highlights the progressive chromatin silencing of ABA biosynthesis genes via synergized action of the RNA-binding protein RZ1 and PRC2, which is vital for seed germination.

plant biology↗