Search bioRxiv⌕ Search

Biology subjects

He, G.

Publications and source records attributed to He, G..

At least 37 records · Page 2Linked to original sources

Candida albicans induce hypoxia response via activating EGFR to promote colorectal cancer progression

Colorectal cancer (CRC) is the third leading cause of cancer-related mortality worldwide. Gut microbiota, including fungal species, are increasingly implicated in CRC progression, while the molecular mechanisms underlying host-fungal interactions in this context remain poorly understood. Here, we show that Candida albicans (C. albicans) activates pro-metastatic signaling pathways, MAPK and NF-{kappa}B, leading to upregulation of oncogenic transcription factors c-Jun and c-Myc. This cascade stabilizes and activates hypoxia-inducible factor 1 (HIF-1), a central regulator of tumor metabolic reprogramming and angiogenesis, ultimately fostering a pro-tumorigenic microenvironment. Mechanistically, we identify candidalysin, a secreted peptide toxin of C. albicans, as a critical effector that engages epidermal growth factor receptor (EGFR) and toll-like receptor 2 (TLR2) with context-dependent effects across different epithelial models. These findings are further supported by patient-derived colonic organoids. Collectively, our study delineates a C. albicans-EGFR/TLR2-ERK/NF-{kappa}B-HIF-1 axis that promotes hypoxia-like responses in CRC, revealing a previously underappreciated role of fungal pathogens in shaping the tumor microenvironment and highlighting avenues for future in vivo investigation.

cancer biology↗

PSTP: Decoding Latent Sequence Grammar through Transfer Learning and Attention for Protein Phase Separation

Phase separation (PS) is essential in various biological processes, necessitating high-accuracy predictive algorithms for studying numerous uncharacterized sequences, and accelerating experimental validation. However, many recent prediction methods face challenges in generalizability due to their reliance on engineered features. Furthermore, accurately identifying protein regions involved in PS remains challenging. To address this, we propose PSTP, a model employing a dual-language model embedding strategy and a lightweight attention module. The attention layer enables reliable residue-level phase separation predictions, identifying 84% of PS regions in PhaSePro and substantially improving correlation coefficient compared to existing models. PSTP also demonstrates robust performance in predicting PS propensity across various types of PS proteins and shows potential for predicting artificial proteins. By analyzing 160,000+ variants, PSTP characterizes the link between the incidence of pathogenic variants and residue-level PS propensities. PSTPs predictive power and broad applicability make it a valuable tool for understanding biomolecular condensates and disease mechanisms.

bioinformatics↗

An atlas of conserved transcription factor binding sites reveals the cell type-resolved gene regulatory landscape of flowering plants

Transcription factors (TFs) are proteins that bind DNA to control where and when genes are expressed. In plants, dozens of TF families interact with distinct sets of binding sites (TFBSs) that reflect each TFs role in organismal function and species-specific adaptations. However, defining these roles and understanding broader patterns of regulatory evolution remains challenging, as predicted TFBSs may lack a clear impact on transcription, and experimentally-derived TF binding maps to date are modest in scale or restricted to model organisms. Here, we present a scalable TFBS assay that we leveraged to create an atlas of nearly 3,000 genome-wide binding site maps for 360 TFs in 10 species spanning 150 million years of flowering plant evolution. We find that TF orthologs from distant species retain nearly identical binding preferences, suggesting that regulatory evolution primarily arises from gain and loss of TFBSs. Within lineages however, conserved TFBSs are over-represented and found in regions harboring signatures of functional regulatory elements. Moreover, genes with conserved TFBSs showed a striking enrichment for cell type-specific expression in single-nuclei RNA atlases, providing a robust marker of each TFs activity and developmental role. Finally, we compare distant lineages, illustrating how ancient regulatory modules were recruited and rewired to enable adaptations underlying the evolutionary success of grasses.

genomics↗

SoyOD: An Integrated Soybean Multi-omics Database for Mining Genes and Biological Research

Soybean is a globally important crop for food, feed, oil, and nitrogen fixation. A variety of multi-omics research has been carried out generating datasets ranging from genotype to phenotype. To utilise this data, a soybean multi-omics database that has broad data coverage and comprehensive data analysis tools would be of value for basic and applied research. We present the soybean omics database (SoyOD), which integrates significant new datasets with existing public datasets for the most comprehensive collection of soybean multi-omics information. Compared to the existing soybean database, SoyOD incorporates an extensive collection of novel data derived from the deep-sequencing of 984 germplasms, 162 novel transcriptome datasets from seeds at different developmental stages, 53 phenotypic datasets, and over 2500 phenotypic images. In addition, SoyOD integrates existing data resources, including 59 assembled genomes, genetic variation data from 3904 soybean accessions, 225 sets of phenotypic data, and 1097 transcriptomic sequences covering 507 different tissues and treatment conditions. SoyOD is a novel tool, as it can be used to mine and analyze candidate genes for important agronomic traits, as shown in a case study on plant height. Additionally, powerful analytical and easy-to-use toolkits enable users to easily access the available multi-omics datasets, and to rapidly search genotypic and phenotypic data in a particular germplasm. The novelty, comprehensiveness, and user-friendly features of SoyOD make it a valuable resource for soybean molecular breeding and biological research. SoyOD is publicly accessible at https://bis.zju.edu.cn/soyod.

plant biology↗

Deciphering the Cell Specific Transcript Heterogeneity and Alternative Splicing during the Early Embryonic Development of Zebrafish

Cell fate determination during early embryonic development is a complex process modulated by gene expression. The intricate interplay of transcriptional and post-transcriptional regulation is integral to the developmental trajectory of embryogenesis, yet how RNA processing may contribute to early development programming is largely elusive. Leveraging recent technological advances in single-molecule nanopore sequencing, we developed a single-cell long-read transcriptome sequencing technology, allowing a clear view of transcript diversity during zebrafish embryogenesis during pre- and post-zygotic genome activation (ZGA). A closer examination of the dynamic transcript usage and potential alternative splicing revealed that abundant stage-specific transcripts with differential coding potentials are involved in distinct biological functions. Specifically, we identified two cell populations at the onset of ZGA based on isoform diversity instead of gene profiling, which followed divergent developmental trajectories toward the ectoderm and the presumptive ectoderm. These two populations of cells were characterized by divergent splicing regulations linked to differential RNA-binding proteins, including SNRPA and SFPQ. Altogether, using the single-cell long-read transcriptome sequencing strategy, we work has revealed the cell-specific transcriptome dynamics contributing to the cell fate determination during embryogenesis.

developmental biology↗

CIB2 as a Ca2+ Sensor for Auditory Mechano-Electrical Transduction and Linked to Genetic-Heterogeneity of TMC1 in Hearing Loss

Non-syndromic sensorineural hearing loss is characterized by genetic heterogeneity, leading to potential clinical misdiagnosis. TMC1, a unique causative gene associated with deafness, exhibits variants with autosomal dominant and recessive inheritance patterns. TMC1 codes for the transmembrane channel-like 1 (TMC1), a key component of the mechano-electrical transduction (MET) machinery for hearing. However, the molecular mechanism of Ca2+ regulation in MET, which is essential for sound perception, remains unclear. CIB2, another MET component associated with deafness, can bind with calcium and may play a role in MET gating. Our study reveals that the TMC1-CIB2 complex undergoes a Ca2+-induced conformational change, highlighting the crucial role of Ca2+ in MET. We identified a vertebrate-specific binding site on TMC1, named CR3, that interacts with apo CIB2, with the binding interface linked to hearing loss. Using an in-vivo animal model, we demonstrated that disruption of the calcium-sensing site of CIB2 perturbs the MET channel conductivity, confirming its role as a Ca2+ sensor for MET. Additionally, after systematically analyzing the hearing-loss variants, we observed that dominant mutations of TMC1 are often located near the ion pore or at the binding interfaces with the Ca2+ sensor CIB2. This provides a detailed mechanism of the genetic heterogeneity of TMC1 in hearing loss at an atomic level.

molecular biology↗

Multi-omics analysis of a traditional fermented food reveals a byproduct-associated subpopulation of Neurospora intermedia for waste-to-food upcycling

Fungal solid-state fermentation (SSF) of byproducts has promise for increasing food sustainability and security, but fungal waste-to-food upcycling remains poorly understood at the molecular level. Here we use a multi-omics approach to characterize oncom - a fermented food traditionally produced from byproducts in Java, Indonesia - as a model system for understanding fungal waste conversion. Metagenomic sequencing of two oncom types (red and black) indicated that Neurospora intermedia is the fungus dominating red oncom. Further transcriptomic, metabolomic, and phylogenomic analysis revealed that oncom-derived N. intermedia utilizes pectin and cellulose degradation for substrate conversion and belongs to a distinct byproduct-associated subpopulation that differs from wild strains at the genetic and biochemical level. Finally, we found that N. intermedia grew on a range of industrially relevant byproducts, did not encode for any known mycotoxins, and could be used to create foods that were positively perceived by consumers outside Indonesia. This study uncovers the microbial and genetic basis of a traditional upcycled food, sheds light on human domestication of microbes for sustainability challenges, and establishes the edible N. intermedia as a promising fungus for byproduct upcycling in SSF and beyond.

microbiology↗

Decoding Missense Variants by Incorporating Phase Separation via Machine Learning

Computational models have made significant progress in predicting the effect of protein variants. However, deciphering numerous variants of unknown significance (VUS) located within intrinsically disordered regions (IDRs) remains challenging. To address this issue, we introduced phase separation (PS), which is tightly linked to IDRs, into the investigation of missense variants. Phase separation is vital for multiple physiological processes. By leveraging missense variants that alter phase separation propensity, we developed a machine learning approach named PSMutPred to predict the impact of missense mutations on phase separation. PSMutPred demonstrated robust performance in predicting missense variants that affect natural phase separation. In vitro experimental findings further underscore its validity. By applying PSMutPred on over 522,000 ClinVar missense variants, it significantly contributes to decoding the pathogenesis of disease variants, especially those in IDRs. Our work provides unique insights into the understanding of a vast number of VUSs in IDRs, thereby expediting clinical interpretation and diagnosis of disease variants.

bioinformatics↗

A new group of LysM-RLKs involved in symbiotic signal perception and arbuscular mycorrhiza establishment

Lipo-chitooligosaccharides (LCO) and short-chain chitooligosaccharides (CO) are produced by arbuscular mycorrhizal fungi (AMF) and activate the plant symbiosis signalling pathway, which is essential for mycorrhiza formation. High affinity LCO receptors belonging to the LysM receptor-like kinase (LysM-RLK) phylogenetic group LYR-IA play a role in AM establishment, but no plant high affinity short-chain CO receptors have yet been identified. Here we studied members of the uncharacterized LYR-IB group, and found that they show high affinity for LCO, short- and long-chain CO, and play a complementary role with the LYR-IA LCO receptors for AM establishment. While LYR-IB knock out mutants had a reduced AMF colonization in several species, constitutive/ectopic expression in wheat increased AMF colonization. LYR-IB function is conserved in all tested angiosperms, but in most japonica rice a deletion creates a frameshift in the gene, explaining differences in AM phenotypes between rice and other monocot single LYR-IA mutants. In conclusion, we identified a class of LysM-RLK receptors in angiosperms with new biochemical properties and a role in both LCO and CO perception for AM establishment.

plant biology↗

MetaWorm: A Complete Model Bridging Brain, Body and Environment of C. elegans

The behavior of an organism is profoundly influenced by the complex interplay between its brain, body, and environment. Existing data-driven models focusing on either the brain or the body-environment separately. A model that integrates these two components is yet to be developed. Here, we present MetaWorm, an integrative data-driven model of a widely studied organism, C. elegans. This model consists of two sub-models: the brain model and the body & environment model. The brain model was built by multi-compartment models with realistic morphology, connectome, and neural population dynamics based on experimental data. Simultaneously, the body & environment model employed a lifelike body and a 3D physical environment, facilitating easy behavior quantification. Through the closed-loop interaction between two sub-models, MetaWorm faithfully reproduced the realistic zigzag movement towards attractors observed in C. elegans. Notably, MetaWorm is the first model to achieve seamless integration of detailed brain, body, and environment simulations, enabling unprecedented insights into the intricate relationships between neural structures, neural activities, and behaviors. Leveraging this model, we investigated the impact of neural system structure on both neural activities and behaviors. Consequently, MetaWorm can enhance our understanding of how the brain controls the body to interact with its surrounding environment.

neuroscience↗

pH selects for distinct N2O-reducing microbiomes in tropical soil microcosms

Nitrous oxide (N2O), a greenhouse gas with ozone destruction potential, is mitigated by the microbial reduction to dinitrogen catalyzed by N2O reductase (NosZ). Bacteria with NosZ activity have been studied at circumneutral pH but the microbiology of low pH N2O reduction has remained elusive. Acidic (pH<5) tropical forest soils were collected in the Luquillo Experimental Forest in Puerto Rico, and microcosms maintained with low (0.02mM) and high (2mM) N2O assessed N2O reduction at pH 4.5 and 7.3. All microcosms consumed N2O, but long lag times of up to 7 months were observed in microcosms with 2 mM N2O. Comparative metagenome analysis revealed that Rhodocyclaceae dominated in circumneutral microcosms under both N2O feeding regimes. In acidic microcosms, Peptococcaceae dominated in high-N2O, and Hyphomicrobiaceae in low-N2O microcosms. Seventeen metagenome-assembled genomes (MAGs) recovered from these microcosms harbored nos operons, with all eight MAGs derived from acidic microcosms carrying the clade II type nosZ, lacking nitrite reductase genes (nirS, nirK). Five of these MAGs represented novel taxa indicating an unexplored N2O-reducing diversity exists in acidic tropical soils. A survey of pH 3.5-5.7 soil metagenome datasets revealed that nosZ genes commonly occur, suggesting broad distribution of N2O reduction potential in acidic soils.

microbiology↗

Paternal genomic resources from the YanHuang cohort suggested a Weakly-Differentiated Multi-source Admixture model for the formation of Hans founding ancestral lineages

The large-scale human genome revolution and rapidly advanced statistical innovation have updated our understanding of the fine-scale and complex genetic structure, the entire landscape of genetic diversity and the evolutionary trajectories of spatiotemporally different ancients and ethnolinguistically diverse modern populations. Recent ancient DNA research provided a detailed and complex admixture picture of ancient Europeans but limited insights into East Asians as the few available genomes. Y-chromosome variations in the male-specific regions, served as molecular archaeological tool, have unique evolutionary features that can be utilized to reconstruct the origin and subsequent interaction of ancient East Asian paternal lineages. We launched the YanHuang cohort using our designed highest-resolution capture sequencing panel to explore the detailed evolutionary trajectory of the Han Chinese, one of the largest ethnic groups in the world. We reported one of the largest uniparental genomic resources and observed multiple founding paternal lineages dominant in ancient western Eurasian, Siberian and East Asian participating in the formation of the gene pool of the Han Chinese. We identified fine-scale paternal genetic structure correlated with different patterns of ancient population interaction and geographical mountain barriers (Qinling-Huaihe line and Nanling Mountains), suggesting isolation-enhanced and admixture-introduced genetic differentiation enhanced the complexity of the Han Chinese genomic diversity. We observed a strong direct correlation between the frequency of multiple founding lineages of the Han Chinese and the proportion of subsistence-related ancestry sources related to western pastoralists, Holocene Mongolian Plateau people and ancient East Asians, reflecting the ancient migration events contributed to our identified patterns of Chinese paternal genomic diversity. We finally provided one novel and the most plausible admixture-by-admixture model, the Weakly-Differentiated Multi-Source Admixture model, as the major genetic mechanism to illuminate our observed pattern of complex interactions of multiple ancestral sources and landscape of the Han Chinese paternal genetic diversity. Generally, we presented one large-scale uniparental genomic resource from the YanHuang cohort, portrayed one novel admixture formation model and presented the entire genomic landscape with multiple ancestral sources related to ancient herders, hunter-gatherers and farmers who participated in the ancestral formation of the Han Chinese.

evolutionary biology↗

Sustained bacterial (N2O) reduction at acidic pH

Nitrous oxide (N2O) is a climate-active gas and emissions from terrestrial ecosystems are concerning. Microbial reduction of N2O to dinitrogen (N2) is the only known consumption process and has been studied extensively at circumneutral pH; however, N2O reduction under acidic conditions is thought to be limited. Global soil acidification, accelerated by anthropogenic practices, introduces high uncertainty into N2O emission budgets. We obtained an enrichment culture from an acidic tropical forest soil that robustly reduces N2O to N2 at pH 4.5 with the addition of pyruvate and hydrogen. Consecutive transfers at pH 4.5 yielded a co-culture and temporal analyses revealed a bimodal growth pattern with a Serratia sp. growing during the initial pyruvate fermentation phase followed by growth of a novel Desulfosporosinus sp. via hydrogenotrophic N2O reduction. The Desulfosporosinus sp. produced (3.1 {+/-} 0.11) x 108 cells per mmol of N2O consumed, on par with growth yields reported for clade II N2O reducers at circumneutral pH. Genome analysis identified a clade II nos gene cluster, but an incomplete pathway for sulfate reduction, a hallmark feature of the genus Desulfosporosinus. Physiological and metabogenomic characterization revealed interspecies nutritional interactions, with the pyruvate fermenting Serratia sp. supplying amino acids as essential growth factors to the Desulfosporosinus sp. The co-culture reduced N2O between pH 4.5 and 6 but not at or above pH 7, contradicting the paradigm that sustained microbial N2O reduction ceases under acidic pH conditions, thus confirming a previously unrecognized N2O reduction potential in acidic soils. Significance StatementProcesses generating N2O occur over a broad pH range spanning pH 3 to 12; however, the current paradigm assumes that microbial N2O consumption is limited to circumneutral pH (6 to 8). The imbalance between N2O production versus consumption has increased the atmospheric concentration of this climate active gas by 17 % over the last 100 years, and accelerated emissions due to global soil acidification are a major climate concern. From acidic soil, we obtained a bacterial culture harboring a novel Desulfosporosinus species that effectively reduces N2O at pH 4.5, but not at or above pH 7. The discovery of an N2O reducer adapted to acidic pH conditions has far-reaching implications for predicting, modeling, and potentially managing N2O emissions from low pH ecosystems. Note for publisher (this text will be removed prior to publication)This manuscript has been authored by UT-Battelle, LLC under Contract No. DE-AC05-00OR22725 with the U.S. Department of Energy. The United States Government retains and the publisher, by accepting the article for publication, acknowledges that the United States Government retains a non-exclusive, paid-up, irrevocable, world-wide license to publish or reproduce the published form of this manuscript, or allow others to do so, for United States Government purposes. The Department of Energy will provide public access to these results of federally sponsored research in accordance with the DOE Public Access Plan (http://energy.gov/downloads/doe-public-access-plan).

microbiology↗

Pan-genome of pear provides insights into the differentiation of fruit quality traits between Asian and European pears

The pear (Pyrus spp.) is a remarkable fruit, well known for its diverse flavors, textures, culinary versatility, and global horticultural importance. However, the genetic diversity responsible for its extensive phenotypic variations remains largely unexplored. Here, we de novo assembled and annotated the genomes of the maternal (PsbM) and paternal (PsbF) lines of the hybrid Yuluxiang pear and constructed the first pear pangenome of 1.15Gb by combining these two genomes with five previously published pear genomes. Using the constructed pangenome, we identified 21,224 gene PAVs and 1,158,812 SNPs in the non-reference genome that were absent in the PsbM reference genome. Compared with SNP markers, we found that PAV-based analysis provides additional insights into the pear population structure. In addition, we also revealed that some genes associated with pear fruit quality traits have differential occurrence frequencies and differential gene expression between Asian and European populations. Moreover, our analysis of the pear pangenome revealed a mutated SNP and an insertion in the promoter region of the gene PsbMGH3.1 potentially enhances sepal shedding in Xuehuali which is vital for pear quality. This research helps further capture the genetic diversity of pear populations and provides valuable genomic resources for accelerating pear breeding.

genomics↗

EX VIVO GENE EDITING AND CELL THERAPY FOR HEREDITARY TYROSINEMIA TYPE 1

Background & AimsWe previously demonstrated the successful use of in vivo CRISPR gene editing to delete 4-hydroxyphenylpyruvate dioxygenase (HPD) to rescue mice deficient in fumarylacetoacetate hydrolase (FAH), a disorder known as hereditary tyrosinemia type 1 (HT1). The goal of this study was to develop an ex vivo gene editing protocol and apply it as a cell therapy for HT1. MethodsWe isolated hepatocytes from wild-type (C57BL/6) and Fah-/- mice and then used an optimized electroporation protocol to deliver Hpd-targeting CRISPR-Cas9 ribonucleoproteins (RNP) into hepatocytes. Next, hepatocytes were transiently incubated in cytokine recovery media that we formulated to block apoptosis, followed by splenic injection into recipient Fah-/- mice. ResultsWe observed robust engraftment and expansion of transplanted gene-edited hepatocytes from wild-type donors in the liver of recipient mice when transient incubation with our cytokine recovery media was used after electroporation and negligible engraftment without the media (mean 46.8% and 0.83%, respectively, p = 0.0025). Thus, the cytokine recovery media was a critical component of our electroporation protocol. When hepatocytes from Fah-/- mice were used as donors for transplantation, we observed 35% and 28% engraftment for Hpd-Cas9 RNPs and Cas9 mRNA, respectively. Tyrosine, phenylalanine, and biochemical markers of liver injury normalized in both Hpd-targeting Cas9 RNP and mRNA groups independent of drug induced-inhibition of Hpd through nitisinone, indicating correction of disease indicators in Fah-/- mice. ConclusionsThe successful liver cell therapy for HT1 validates our protocol and, despite the known growth advantage of HT1, showcase ex vivo gene editing using electroporation in combination with liver cell therapy to cure a disease model. These advancements showcase the impacts of electroporation combined with transplantation as a cell therapy.

bioengineering↗

Ancient farmer and steppe pastoralist-related founding lineages contributed to the complex landscape of episodes in the diversification of Chinese paternal lineages

Ancient DNA advances have reported the complex genetic history of Eurasians, but how the knowledge of ancient subsistence strategy shifts and population movements influenced the fine-scale paternal genetic structure in East Asia has not been assessed. Here, we reported one integrated Y-chromosome genomic database of 15,530 people, including 1753 ancient people and newly-reported 919 individuals genotyped using our recently-developed targeted sequencing YHSeqY3000 panel, to explore Chinese genomic diversity, population evolutionary tracts and their genetic formation mechanism. We identified four major ancient technological innovations and population movements that shaped the landscape of Chinese paternal lineages. First, the expansion of millet farmers and early East Asians from the Yellow River Basin carrying the major O2/D subclades promoted the formation of the Sino-Tibetan peoples major composition and accelerated the Tibetan Plateaus permanent occupation. Second, rice farmers dispersal from the Yangtze River Valley carrying O1 and some sublineages of O2 contributed significantly to Tai-Kadai, Austronesian, Hmong-Mien, Austroasiatic people and southern Han Chinese. Third, Siberian-related paternal lineages of Q and C originated and boomed from Neolithic hunter-gatherers from the Mongolian Plateau and the Amur River Basin and significantly influenced the gene pools of northern Chinese. Fourth, western Eurasian-derived J, G and R lineages initially spread with Yamnaya steppe pastoralists and other proto-Indo-European people and further widely dispersed via the trans-Eurasian cultural communication along the Eurasian Steppe and the ancient Silk Road, remaining genetic trajectories in northwestern Chinese. Our work provided comprehensive modern and ancient genetic evidence to illuminate the impact of population interaction from the ancient farmer or herder-based societies on the genetic diversity patterns of modern people, revised our understandings of ancestral sources of Chinese paternal lineages, underscored the scientific imperative of the large-scale genomic resources of dense spatiotemporal underrepresented sampling populations to understand human evolutionary history.

genetics↗

Distinguished biological adaptation architecture aggravated population differentiation of Tibeto-Burman-speaking people inferred from 500 whole genome data from 39 populations

Tibeto-Burman (TB) people have tried to adapt to the hypoxic, cold and high-UV high-altitude Tibetan Plateau and complex disease exposure in the lowland wet and hot rainforest since the late Paleolithic period. However, the full landscape of genetic history and biological adaptation of geographically diverse TB people and their interaction mechanism remained unknown. We generated a whole-genome-based meta-database of 500 individuals from 39 TB populations from East Asia and Southeast Asia and presented a comprehensive landscape of genetic diversity, admixture history and differentiated adaptative features of geographically different TB people. We identified geography/language-related genetic differentiation among Tibetan Plateau, Tibetan-Yi-Corridor (TYC) and Southeast Asian TB people, consistent with their differentiated admixture process with incoming or indigenous ancestral source populations. A robust genetic connection between TYC people and ancient YR people supported the Northern origin hypothesis of TB people. We reported population substructure-related differentiated biological adaptative signatures between highland Tibetans and lowland TB people and between geographically different Lolo speakers. Highland adaptative EPAS1 and EGLN variants riched in Tibetans but lacked in TYC people whose adaptation is associated with the physical features and skin pigmentation (EDAR and SLC24A5), hepatic alcohol metabolism (ALDH9A1), regulation of cell-cell adhesion of muscle cells (CTNNA3) and immune/fat metabolism-related adaptative signature. TB-related genomic resources provided new insights into the genetic basis of phenotype differences and better reference for the anthropologically-informed sampling design in biomedical and genomic cohort research.

genetics↗

Single-cell RNA-sequencing identifies a novel subset of CD9+ reparative macrophages modulated by CCN2 derived from Nlrx1 deficient cardiomyocytes in the infarcted heart

RationaleNlrx1, a pattern recognition receptor belonging to the NLR family, is highly expressed in the heart and is significantly increased after myocardial infarction in vivo, however, the role of Nlrx1 in post-infarction inflammation and healing is poorly understood. Although the effects of infiltrating macrophages on survival of cardiomyocytes and healing of injured hearts have been intensely studied, whether or not and how surviving cardiomyocytes might influence the phenotype and function of macrophages in the infarcted hearts was largely unexplored. ObjectiveTo investigate the role of Nlrx1 in post-infarction inflammation and healing and to dissect the underlying mechanism. Methods and resultsSingle cell RNA-sequencing of 23,805 cells isolated from infarcted hearts revealed 7 clusters of infarct macrophages including CCR2+, Isg+, Mki67+ proliferative, and LYVE1+ cardiac resident macrophages, and identified a novel subset of CD9+Il1rn+ macrophages, which were characterized by high expression of Cd9, Il1rn, Gpnmb and Spp1, and downregulation of proinflammatory cytokines and chemokines. CD9+Il1rn+ macrophages were largely found in infarcted hearts of Nlrx1KO mice, and were transcriptionally unique with reparative phenotype. Loss of Nlrx1 attenuated ventricular dysfunction and adverse remodeling, and decreased post-infarction mortality. Flow cytometry analysis showed markedly increased number of CD9+ macrophages and higher mean fluorescence intensity of CD9 in Nlrx1KO mice. RNA-seq analysis revealed that CD9+ macrophages of Nlrx1KO infarcted hearts exhibited a reparative and anti-inflammatory phenotype as featured by upregulation of wound healing-associated genes including CD9, Spp1 and Fn1, and downregulation of proinflammatory genes. Conditioned medium from Nlrx1 deficient cardiomyocytes upon hypoxia stimulation skewed macrophage polarization towards a reparative and inflammation-suppressed phenotype. Gain-and loss-of function of Nlrx1 combined with RNA-seq analysis identified CCN2, whose expression and secretion were significantly increased in Nlrx1 deficient cardiomyocytes upon hypoxia, as a cardiomyocytes-derived mediator responsible, at least partly, for reprograming macrophage towards a reparative phenotype. In vivo, CCN2 expression was markedly elevated in Nlrx1KO infarcted hearts. Moreover, exogenous CCN2 partially mediated macrophage transition towards a reparative phenotype. ConclusionsCD9+ IL1rn+ macrophages modulated by Nlrx1 deficient cardiomyocytes-derived CCN2, is a novel subset of reparative macrophages contributing to infarct healing. Inhibition of myocardial Nlrx1 and/or activation of CCN2 to boost CD9+ IL1rn+ reparative macrophages may represent new therapeutics for infarct healing following ischemic injury.

immunology↗