Single-nucleus transcriptome inventory of giant panda reveals cellular basis for fitness optimization under low metabolism.

BACKGROUND: Energy homeostasis is essential for the adaptation of animals to their environment and some wild animals keep low metabolism adaptive to their low-nutrient dietary supply. Giant panda is such a typical low-metabolic mammal exhibiting species specialization of extremely low daily energy expenditure. It has low levels of basal metabolic rate, thyroid hormone, and physical activities, whereas the cellular bases of its low metabolic adaptation remain rarely explored. RESULTS: In this study, we generate a single-nucleus transcriptome atlas of 21 organs/tissues from a female giant panda. We focused on the central metabolic organ (liver) and dissected cellular metabolic status by cross-species comparison. Adaptive expression mode (i.e., AMPK related) was prominently displayed in the hepatocyte of giant panda. In the highest energy-consuming organ, the heart, we found a possibly optimized utilization of fatty acid. Detailed cell subtype annotation of endothelial cells showed the uterine-specific deficiency of blood vascular subclasses, indicating a potential adaptation for a low reproductive energy expenditure. CONCLUSIONS: Our findings shed light on the possible cellular basis and transcriptomic regulatory clues for the low metabolism in giant pandas and helped to understand physiological adaptation response to nutrient stress.

The Lin28b/Wnt5a axis drives pancreas cancer through crosstalk between cancer associated fibroblasts and tumor epithelium.

Bidirectional signal transduction between tumor epithelial cells and tumor microenvironment (TME) is important for tumor development. Here we show that Lin28b/let-7 pathway is indispensable for modulating the expression of Wnt5a in tumor epithelium, which could be secreted and then up-regulates Lin28b in cancer-associated fibroblasts (CAFs). Moreover, we demonstrate that Lin28b in CAFs promoted growth of PDAC by inducing cytokine PCSK9's production. Using an orthotopic mouse model of PDAC, we find that depletion of Lin28b in CAFs reduced tumor weight, highlighting the importance of Lin28b in PDAC stroma. Thus, our study shows that the Lin28b-Wnt5a axis plays a critical role in bidirectional crosstalk between pancreatic tumor epithelium and TME and results in a pro-|tumorigenic contexture.

Exploring the possible mechanism(s) underlying the nephroprotective effect of Zhenwu Decoction in diabetic kidney disease: An integrated analysis.

BACKGROUND: Diabetic kidney disease (DKD) is one of the major chronic microvascular complications of diabetes and the main cause of end-stage renal failure. Zhenwu Decoction (ZWD), an ancient classic herbal formula in Chinese medicine, has been clinically used for the treatment of kidney disease in China for many years. However, there is currently limited research investigating the application of ZWD in the treatment of DKD and the underlying chemical and biochemical mechanisms involved. Therefore, in the present study, we aimed to identify active components in ZWD and unravel the possible mechanism(s) of action for ZWD in treating DKD. METHODS: The protective effect of ZWD against DKD was evaluated utilizing an in vitro model of diabetic renal proximal tubulopathy. The major chemical components from ZWD were identified by LC-MS/MS. Drug targets were predicted by submitting the SMILES (Simplified Molecular Input Line Entry System) of the compounds to SEA (Similarity Ensemble Approach) search server and SwissTargetPrediction. The differentially expressed genes (DEGs) of the disease were collected and integrated from GeneCards. The constructions of "Compounds-potential targets interaction" (CTI) network and Protein-Protein Interaction (PPI) network, as well as topology analysis were conducted by Cytoscape. Gene Ontology (GO) enrichment and Metacore pathway enrichment analysis were also performed. Lastly, molecular docking and experimental studies were adopted to validate the core target and identify an active component(s) of ZWD. RESULTS: We demonstrated that the ZWD extract could significantly rescue the palmitic acid (PA) and high glucose-induced apoptotic cell death in HK-2 cells, and the cytoprotection was accompanied by decreases in the extent of reactive oxygen species (ROS) production, mitochondrial membrane depolarization and ATP depletion. Fifty-seven compounds in the aqueous extract of ZWD were identified by LC-MS. The results of PPI analysis showed that top hub genes involved epidermal growth factor receptor (EGFR), Signal Transducer and Activator of Transcription 3 (STAT3), Serine/Threonine Kinase 1 (AKT1), Vascular Endothelial Growth Factor A (VEGFA) and Fibroblast Growth Factor 2 (FGF2). Pathway enrichment analysis revealed the involvement of S1P1 receptor signaling and EGFR pathways. The results of molecular docking analysis showed that albiflorin has a high binding affinity to EGFR. Albiflorin could also exert protective effects in an HK-2 cell model of DKD, which may be related to the inhibition of the high glucose/high lipid-induced EGFR and Akt phosphorylation. CONCLUSION: ZWD has been shown to be effective in ameliorating cell death in an experimental model of DKD. The beneficial effect of ZWD against DKD was associated with the interactions between the active ingredients and the hub genes, such as EGFR, STAT3, AKT1, and VEGF-A. Albiflorin may be one of the active components responsible for the nephroprotective effect in ZWD.

Distinct and shared endothermic strategies in the heat producing tissues of tuna and other teleosts.

Although most fishes are ectothermic, some, including tuna and billfish, achieve endothermy through specialized heat producing tissues that are modified muscles. How these heat producing tissues evolved, and whether they share convergent molecular mechanisms, remain unresolved. Here, we generated a high-quality genome from the mackerel tuna (Euthynnus affinis) and investigated the heat producing tissues of this fish by single-nucleus and bulk RNA sequencing. Compared with other teleosts, tuna-specific genetic variation is strongly associated with muscle differentiation. Single-nucleus RNA-seq revealed a high proportion of specific slow skeletal muscle cell subtypes in the heat producing tissues of tuna. Marker genes of this cell subtype are associated with the relative sliding of actin and myosin, suggesting that tuna endothermy is mainly based on shivering thermogenesis. In contrast, cross-species transcriptome analysis indicated that endothermy in billfish relies mainly on non-shivering thermogenesis. Nevertheless, the heat producing tissues of the different species do share some tissue-specific genes, including vascular-related and mitochondrial genes. Overall, although tunas and billfishes differ in their thermogenic strategies, they share similar expression patterns in some respects, highlighting the complexity of convergent evolution.

Chromosome-scale genomes reveal genomic consequences of inbreeding in the South China tiger: A comparative study with the Amur tiger.

The South China tiger (Panthera tigris amoyensis, SCT) is the most critically endangered subspecies of tiger due to functional extinction in the wild. Inbreeding depression is observed among the captive population descended from six wild ancestors, resulting in high juvenile mortality and low reproduction. We assembled and characterized the first SCT genome and an improved Amur tiger (P. t. altaica, AT) genome named AmyTig1.0 and PanTig2.0. The two genomes are the most continuous and comprehensive among any tiger genomes yet reported at the chromosomal level. By using the two genomes and resequencing data of 15 SCT and 13 AT individuals, we investigated the genomic signature of inbreeding depression of the SCT. The results indicated that the effective population size of SCT experienced three phases of decline, ~5.0-1.0 thousand years ago, 100 years ago, and since captive breeding in 1963. We found 43 long runs of homozygosity fragments that were shared by all individuals in the SCT population and covered a total length of 20.63% in the SCT genome. We also detected a large proportion of identical-by-descent segments across the genome in the SCT population, especially on ChrB4. Deleterious nonsynonymous single nucleotide polymorphic sites and loss-of-function mutations were found across genomes with extensive potential influences, despite a proportion of these loads having been purged by inbreeding depression. Our research provides an invaluable resource for the formulation of genetic management policies for the South China tiger such as developing genome-based breeding and genetic rescue strategy.

Genomic investigation of the Chinese alligator reveals wild-extinct genetic diversity and genomic consequences of their continuous decline.

Critically endangered species are usually restricted to small and isolated populations. High inbreeding without gene flow among populations further aggravates their threatened condition and reduces the likelihood of their long-term survival. Chinese alligator (Alligator sinensis) is one of the most endangered crocodiles in the world and has experienced a continuous decline over the past c. 1 million years. In order to identify the genetic status of the remaining populations and aid conservation efforts, we assembled the first high-quality chromosome-level genome of Chinese alligator and explored the genomic characteristics of three extant breeding populations. Our analyses revealed the existence of at least three genetically distinct populations, comprising two breeding populations in China (Changxing and Xuancheng) and one breeding population in an American wildlife refuge. The American population does not belong to the last two populations of its native range (Xuancheng and Changxing), thus representing genetic diversity extinct in the wild and provides future opportunities for genetic rescue. Moreover, the effective population size of these three populations has been continuously declining over the past 20 ka. Consistent with this decline, the species shows extremely low genetic diversity, a large proportion of long runs of homozygous fragments, and mutational load across the genome. Finally, to provide genomic insights for future breeding management and conservation, we assessed the feasibility of mixing extant populations based on the likelihood of introducing new deleterious alleles and signatures of local adaptation. Overall, this study provides a valuable genomic resource and important genomic insights into the ecology, evolution, and conservation of critically endangered alligators.

The chromosome-scale genome of the raccoon dog: Insights into its evolutionary characteristics.

The raccoon dog (Nyctereutes procyonoides) is an invasive canid species native to East Asia with several distinct characteristics. Here, we report a chromosome-scale genome of the raccoon dog with high contiguity, completeness, and accuracy. The intact taste receptor genes, expanded gene families, and positively selected genes related to digestion, absorption, foraging, and detoxification likely support the omnivory of raccoon dogs. Several positively selected genes and raccoon dog-specific mutations in TDRD6 and ZP3 genes may explain their high reproductivity. Enriched GO terms in energy metabolism and positively selected immune genes were speculated to be closely related to the diverse immune system of raccoon dogs. In addition, we found that several expanded gene families and positively selected genes related to lipid metabolism and insulin resistance may contribute to winter sleep of the raccoon dog. This high-quality genome provides a valuable resource for understanding the evolutionary characteristics of this species.

Chromosome-level Genome of the Muskrat (Ondatra zibethicus).

The muskrat (Ondatra zibethicus) is a semi-aquatic rodent species with ecological, economic, and medicinal importance. Here, we present an improved genome assembly, which is the first high-quality chromosome-level genome of the muskrat with high completeness and contiguity assembled using single-tube long fragment read, BGISEQ, and Hi-C sequencing technologies. The genome size of the final assembly was 2.63 Gb with 27 pseudochromosomes. The length of scaffold N50 reached 80.25 Mb with a Benchmarking Universal Single-Copy Ortholog score of 91.3%. We identified a 66.98 Mb X chromosome and a 1.14-Mb Y-linked genome region, and these sex-linked regions were validated by resequencing 32 extra male individuals. We predicted 19,396 protein-coding genes, among which 19,395 (99.99%) were functionally annotated. The expanded gene families in the muskrat genome were found to be enriched in several organic synthesis- and metabolism-related Gene Ontology terms, suggesting the likely genomic basis for the production and secretion of musk. This chromosome-level genome represents a valuable resource for improving our understanding of muskrat ecology and musk secretion.

Gene rearrangements in the mitochondrial genome of ten ascaris species and phylogenetic implications for Ascaridoidea and Heterakoidea families.

The Ascaridoidea family and Heterakoidea family are the most common and typical representative of large parasites. Although our understanding of these parasites' diversity has expanded by analyses of some mitochondrial genes, there is limited information on these species' evolutionary rates. Here we determined ten complete mitogenome sequences of five subfamilies of Ascaridoidea and one subfamily of Heterakoidea. The phylogenetic tree divided the Ascaridoidea into six monophyletic major clades, and the divergence time of Heterakoidea family and Ascaridoidea family can be placed during the early Carboniferous Period (300-360 Mya). The reconstruction of the ancestral state showed that the gene orders of all species in Ascaridoidea were conserved, and the Heterakoidea had obvious genome rearrangement. The conserved blocks between them were divided into five and the main types are tandem-duplication/random loss (TDRL). These results will help to better understand the gene rearrangements and evolutionary position of ascaris species.

Whole-genome resequencing of Chinese pangolins reveals a population structure and provides insights into their conservation.

Poaching and trafficking have a substantial negative impact on the population growth and range expansion of the Chinese pangolin (Manis pentadactyla). However, recently reported activities of Chinese pangolins in several sites of Guangdong province in China indicate a promising sign for the recovery of this threatened species. Here, we re-sequence genomes of 15 individuals and perform comprehensive population genomics analyses with previously published 22 individuals. These Chinese pangolins are found to be divided into three distinct populations. Multiple lines of evidence indicate the existence of a newly discovered population (CPA) comprises entirely of individuals from Guangdong province. The other two populations (CPB and CPC) have previously been documented. The genetic differentiation of the CPA and CPC is extremely large (FST = 0.541), which is larger than many subspecies-level differentiations. Even for the closer CPA and CPB, their differentiation (FST = 0.101) is still comparable with the population-level differentiation of many endangered species. Further analysis reveals that the CPA and CPB populations separate 2.5-4.0 thousand years ago (kya), and on the other hand, CPA and CPC diverge around 25-40 kya. The CPA population harbors more runs of homozygosity (ROHs) than the CPB and CPC populations, indicating that inbreeding is more prevalent in the CPA population. Although the CPC population has less mutational load than CPA and CPB populations, we predict that several Loss of Function (LoF) mutations will be translocated into the CPA or CPB populations by using the CPC as a donor population for genetic rescue. Our findings imply that the conservation of Chinese pangolins is challenging, and implementing genetic rescue among the three groups should be done with extreme caution.

Equus roundworms (Parascaris univalens) are undergoing rapid divergence while genes involved in metabolic as well as anthelminic resistance are under positive selection.

BACKGROUND: The evolution of parasites is often directly affected by the host's environment. Studies on the evolution of the same parasites in different hosts are of great interest and are highly relevant to our understanding of divergence. METHODS: Here we performed whole-genome sequencing of Parascaris univalens from different Equus hosts (horses, zebras and donkeys). Phylogenetic and selection analyses were performed to study the divergence and adaptability of P. univalens. RESULTS: At the genetic level, multiple lines of evidence indicate that P. univalens is mainly separated into two clades (horse-derived and zebra & donkey-derived). This divergence began 300-1000 years ago, and we found that most of the key enzymes related to glycolysis were under strong positive selection in zebra & donkey-derived roundworms, whereas the lipid-related metabolic system was under positive selection in horse-derived roundworms, indicating that the adaptive evolution of metabolism has occurred over the past few centuries. In addition, we found that some drug-related genes showed a significantly higher degree of selection in diverse populations. CONCLUSIONS: This work reports the adaptive evolution and divergence trend of P. univalens in different hosts for the first time. Its results indicate that the divergence of P. univalens is a continuous, dynamic process. Furthermore, the continuous monitoring of the effects of differences in nutritional and drug histories on the rapid evolution of roundworms is conducive to further understanding host-parasite interactions.

LcCCL28-25, Derived from Piscine Chemokine, Exhibits Antimicrobial Activity against Gram-Negative and Gram-Positive Bacteria In Vitro and In Vivo.

Antimicrobial peptides (AMPs) are currently recognized as potentially promising antibiotic substitutes. Fish are an important seawater/freshwater medicinal biological resource, and the antimicrobial peptides and proteins that are key components of their innate immune systems are potential candidates for the development of novel antibacterial agents. The rainbow trout Oncorhynchus mykiss chemokine CK11 (omCK11), classified in the C-C motif chemokine ligand 27/28 (CCL27/28) family, is the only CC-type chemokine reported to play a direct antibacterial role in the immune response; however, its antibacterial domain remains unknown. In this study, we analyzed the structure-activity relationship of omCK11 and identified the antibacterial C-terminal domain. Additionally, we performed structure-function analyses of CCL27/28 proteins from different, representative freshwater and seawater fishes, revealing their shared C-terminal antibacterial domains. Surprisingly, a synthesized cationic peptide (named lcCCL28-25), derived from the large yellow croaker Larimichthys crocea CCL28, exhibited broad-spectrum and the most acceptable bactericidal activity, as well as antibiofilm activity and negligible hemolytic and cytotoxic activity in vitro. Additionally, lcCCL28-25 conferred a protective effect in the thighs of neutropenic mice infected with Staphylococcus aureus. SYTOX green fluorescence and electron microscopy experiments revealed that lcCCL28-25 was capable of rapidly destroying the integrity and permeability of the bacterial cell membrane. Overall, this study aided in the advancement of antibacterial CC-type chemokine research and also suggested a new strategy for exploring novel AMPs. Additionally, the efficacy of lcCCL28-25 in in vivo antibacterial activity in a mammalian model revealed that this compound could be a promising agent for the development of peptide-based antibacterial therapeutics. IMPORTANCE The primary function of chemokines has been described as recruiting and activating leukocytes to participate in the immune response. Some chemokines are also broad-spectrum antibacterial proteins in mammals. The Oncorhynchus mykiss chemokine CK11 (omCK11) is the first reported and currently the only CC-type antibacterial chemokine. The present study identified the antibacterial domain of omCK11. Structure-function analysis of various fish CCL27/28 proteins identified a novel antibacterial peptide (lcCCL28-25) from Larimichthys crocea CCL28 that exhibited broad-spectrum and the most acceptable bactericidal activity in vitro, as well as a protective effect in a Staphylococcus aureus infection mouse model. The antibacterial mechanisms included membrane disruption and permeation. This study advanced the field of antibacterial chemokine research in fish and also suggested a new strategy for exploring novel AMPs. The novel peptide lcCCL28-25 may prove to be an effective antibacterial agent.

Circular RNA circASPM promotes the progression of glioblastoma by acting as a competing endogenous RNA to regulate miR-130b-3p/E2F1 axis.

Background: Glioblastoma Multiform (GBM) is the primary malignancy with the highest incidence and worst prognosis in the adult CNS. Circular RNAs (circRNAs) are a novel and widely diverse class of endogenous non-coding RNAs that can promote or inhibit gliomagenesis. Our study aimed to explore the role of circASPM in GBM and its molecular mechanism. Methods: Levels of circASPM, miR-130b-3p and E2F1 were determined by quantitative real-time PCR (qRT-PCR) or western blotting assay. MTS, Edu, neurospheres formation and extreme limiting dilution assays were used to detect the tumorigenesis and proliferation of GSCs in vitro. The interactions between miR-130b-3p and circASPM or E2F1 were demonstrated via qPCR, western blotting, dual-luciferase reporter and RNA immunoprecipitation (RIP) assays. Xenograft experiments were used to analyze tumor growth in vivo. Results: CircASPM was overexpressed in GBM and promoted the tumorigenesis and proliferation of GSCs both in vitro and in vivo. Mechanistically, circASPM up-regulated the expression of E2F1 in GSCs via miR-130b-3p sponging. We furtherly demonstrated that circAPSM could promote the GSCs proliferation via E2F1 up-regulating. Therefore, our study identified a novel circRNA and its possible mechanism in the development and tumorigenesis of GBM. Conclusions: CircASPM can promote GBM progression via regulating miR-130b-3p/E2F1 axis, suggesting that circAPSM could provide an effective biomarker for GBM diagnosis and prognostic evaluation and possibly being used for molecular targeted therapy.

Chromosome-Level Genome Assembly of the Green Peafowl (Pavo muticus).

The green peafowl (Pavo muticus) is facing a high risk of extinction due to the long-term and widespread threats of poaching and habitat conversion. Here, we present a high-quality chromosome-level genome assembly of the green peafowl with high contiguity and accuracy assembled by PacBio sequencing, DNBSEQ short-read sequencing, and Hi-C sequencing technologies. The final genome size was estimated to be 1.049 Gb, whereas 1.042 Gb of the genome was assigned to 27 pseudochromosomes. The scaffold N50 length was 75.5 Mb with a complete BUSCO score of 97.6%. We identified W and Z chromosomes and validated them by resequencing 14 additional individuals. Totally, 167.04 Mb repetitive elements were identified in the genome, accounting for 15.92% of the total genome size. We predicted 14,935 protein-coding genes, among which 14,931 genes were functionally annotated. This is the most comprehensive and complete de novo assembly of the Pavo genus, and it will serve as a valuable resource for future green peafowl ecology, evolution, and conservation studies.

Genomic and transcriptomic analysis unveils population evolution and development of pesticide resistance in fall armyworm Spodoptera frugiperda.

The fall armyworm (FAW), Spodoptera frugiperda, is a destructive pest native to America and has recently become an invasive insect pest in China. Because of its rapid spread and great risks in China, understanding of FAW genetic background and pesticide resistance is urgent and essential to develop effective management strategies. Here, we assembled a chromosome-level genome of a male FAW (SFynMstLFR) and compared re-sequencing results of the populations from America, Africa, and China. Strain identification of 163 individuals collected from America, Africa and China showed that both C and R strains were found in the American populations, while only C strain was found in the Chinese and African populations. Moreover, population genomics analysis showed that populations from Africa and China have close relationship with significantly genetic differentiation from American populations. Taken together, FAWs invaded into China were most likely originated from Africa. Comparative genomics analysis displayed that the cytochrome p450 gene family is extremely expanded to 425 members in FAW, of which 283 genes are specific to FAW. Treatments of Chinese populations with twenty-three pesticides showed the variant patterns of transcriptome profiles, and several detoxification genes such as AOX, UGT and GST specially responded to the pesticides. These findings will be useful in developing effective strategies for management of FAW in China and other invaded areas.

Chromosome-scale assembly and whole-genome sequencing of 266 giant panda roundworms provide insights into their evolution, adaptation and potential drug targets.

Helminth diseases have long been a threat to the health of humans and animals. Roundworms are important organisms for studying parasitic mechanisms, disease transmission and prevention. The study of parasites in the giant panda is of importance for understanding how roundworms adapt to the host. Here, we report a high-quality chromosome-scale genome of Baylisascaris schroederi with a genome size of 253.60 Mb and 19,262 predicted protein-coding genes. We found that gene families related to epidermal chitin synthesis and environmental information processes in the roundworm genome have expanded significantly. Furthermore, we demonstrated unique genes involved in essential amino acid metabolism in the B. schroederi genome, inferred to be essential for the adaptation to the giant panda-specific diet. In addition, under different deworming pressures, we found that four resistance-related genes (glc-1, nrf-6, bre-4 and ced-7) were under strong positive selection in a captive population. Finally, 23 known drug targets and 47 potential drug target proteins were identified. The genome provides a unique reference for inferring the early evolution of roundworms and their adaptation to the host. Population genetic analysis and drug sensitivity prediction provide insights revealing the impact of deworming history on population genetic structure of importance for disease prevention.

Single cell atlas for 11 non-model mammals, reptiles and birds.

The availability of viral entry factors is a prerequisite for the cross-species transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Large-scale single-cell screening of animal cells could reveal the expression patterns of viral entry genes in different hosts. However, such exploration for SARS-CoV-2 remains limited. Here, we perform single-nucleus RNA sequencing for 11 non-model species, including pets (cat, dog, hamster, and lizard), livestock (goat and rabbit), poultry (duck and pigeon), and wildlife (pangolin, tiger, and deer), and investigated the co-expression of ACE2 and TMPRSS2. Furthermore, cross-species analysis of the lung cell atlas of the studied mammals, reptiles, and birds reveals core developmental programs, critical connectomes, and conserved regulatory circuits among these evolutionarily distant species. Overall, our work provides a compendium of gene expression profiles for non-model animals, which could be employed to identify potential SARS-CoV-2 target cells and putative zoonotic reservoirs.

Comprehensive Analysis Identified ETV7 as a Potential Prognostic Biomarker in Bladder Cancer.

BACKGROUND: The tumor microenvironment (TME) plays a crucial role in the initiation and progression of cancer. Bladder cancer (BLCA) is a malignant tumor of the genitourinary system. Its heterogeneity results in significant differences in the prognosis of patients. To date, this is still a huge challenge for clinical treatment. In recent years, more and more evidence showed that dysregulation of transcription factors (TFs) plays an important role in tumor progression, invasion, and metastasis. Unfortunately, the role of TFs on the tumor microenvironment in bladder cancer is unclear. METHODS: The original data of BLCA and corresponding adjacent tissues were obtained from The Cancer Genome Atlas (TCGA) database. TFs were downloaded from the Animal Transcription Factor DataBase (Animal TFDB). Intersection analysis was used to obtain TFs that were differentially expressed between tumor and adjacent tissues. Gene Set Cancer Analysis (GSCALite) and CIBERSORT software were used to reveal the key differentially expressed TFs (DE-TFs). Subsequently, UALCAN and Human Protein Atlas (HPA) databases were used to disclose the expression of key DE-TFs in BLCA. The K-M curve divulged the relationship between the key DE-TFs and the patient's overall survival (OS), and the univariate and multivariate Cox regression analyses were conducted to explore independent prognostic factors. The cluster profiler package and Gene Set Enrichment Analysis (GSEA) were used for functional enrichment of genes related to the key DE-TFs. Finally, CIBERSORT software analyzed the immune landscape of BLCA. RESULTS: We obtained a total of 117 BLCA-related DE-TFs. Among them, ETV7 was identified as the key DE-TFs due to its association with the autophagy activation pathway and various immune cells in cancer. Online databases of UALCAN and HPA indicated that ETV7 was overexpressed in tumors and negatively correlated with tumor severity. The K-M curve showed that the OS of patients with high expression of ETV7 was poor, which indicated that it was an independent prognostic factor. Functional enrichment of 87 DEGs between ETV7-high and -low expression groups indicated that it was closely related to the immune response and the functions of a variety of immune cells. Finally, CIBERSORT results proved that the high and low expression of ETV7 also caused significant differences in the tumor immune microenvironment of patients. CONCLUSION: Overall, we proved that the transcription factor ETV7 was a novel prognostic factor, which may improve the individualized outcome prediction in BLCA by regulating the tumor immune microenvironment.