Circadian Rhythm-related Genes Research Articles

A signature based on circadian rhythm-associated genes for the evaluation of prognosis and the tumour microenvironment in HNSCC

The morbidity and mortality rates of head and neck squamous cell carcinoma (HNSCC) remain high worldwide. Therefore, there is an urgent need to identify a new prognostic biomarker to guide the personalized treatment of HNSCC patients. Increasing evidence suggests that circadian rhythm genes play an important role in the development and progression of cancer. We aimed to explore the value of circadian rhythm genes in predicting prognosis and guiding the treatment of HNSCC. We first obtained a list of circadian rhythm genes from previous research. The sequencing data were retrieved from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Finally, univariate Cox proportional hazard analysis, least absolute shrinkage and selection operator (LASSO) regression, and multivariate Cox proportional hazard analysis were performed to develop a prognostic signature (Circadian Rhythm-Related Gene Prognostic Index, CRRGPI) consisting of nine circadian rhythm genes. The signature exhibited good performance in predicting overall survival. Patients with low CRRGPI scores had lower metabolic activities and an active antitumour immunity ability. Additionally, a clinical cohort was used to further evaluate the ability of the CRRGPI to predict the efficacy of immune checkpoint inhibitors. In conclusion, the novel circadian rhythm-related gene signature can provide a precise prognostic evaluation with the potential capacity to guide individualized treatment regimens for HNSCC patients.

Integrated transcriptome and metabolome analysis reveals anthocyanin biosynthesis mechanisms in pepper (Capsicum annuum L.) leaves under continuous blue light irradiation

BackgroundDifferent metabolic compounds give pepper leaves and fruits their diverse colors. Anthocyanin accumulation is the main cause of the purple color of pepper leaves. The light environment is a critical factor affecting anthocyanin biosynthesis. It is essential that we understand how to use light to regulate anthocyanin biosynthesis in plants.ResultPepper leaves were significantly blue–purple only in continuous blue light or white light (with a blue light component) irradiation treatments, and the anthocyanin content of pepper leaves increased significantly after continuous blue light irradiation. This green-to-purple phenotype change in pepper leaves was due to the expression of different genes. We found that the anthocyanin synthesis precursor-related genes PAL and 4CL, as well as the structural genes F3H, DFR, ANS, BZ1, and F3’5’H in the anthocyanin synthesis pathway, had high expression under continuous blue light irradiation. Similarly, the expression of transcription factors MYB1R1-like, MYB48, MYB4-like isoform X1, bHLH143-like, and bHLH92-like isoform X3, and circadian rhythm-related genes LHY and COP1, were significantly increased after continuous blue light irradiation. A correlation network analysis revealed that these transcription factors and circadian rhythm-related genes were positively correlated with structural genes in the anthocyanin synthesis pathway. Metabolomic analysis showed that delphinidin-3-O-glucoside and delphinidin-3-O-rutinoside were significantly higher under continuous blue light irradiation relative to other light treatments. We selected 12 genes involved in anthocyanin synthesis in pepper leaves for qRT-PCR analysis, and the accuracy of the RNA-seq results was confirmed.ConclusionsIn this study, we found that blue light and 24-hour irradiation together induced the expression of key genes and the accumulation of metabolites in the anthocyanin synthesis pathway, thus promoting anthocyanin biosynthesis in pepper leaves. These results provide a basis for future study of the mechanisms of light quality and photoperiod in anthocyanin synthesis and metabolism, and our study may serve as a valuable reference for screening light ratios that regulate anthocyanin biosynthesis in plants.

Identification of circadian rhythm-related gene classification patterns and immune infiltration analysis in heart failure based on machine learning

BackgroundCircadian rhythms play a key role in the failing heart, but the exact molecular mechanisms linking changes in the expression of circadian rhythm-related genes to heart failure (HF) remain unclear. MethodsBy intersecting differentially expressed genes (DEGs) between normal and HF samples in the Gene Expression Omnibus (GEO) database with circadian rhythm-related genes (CRGs), differentially expressed circadian rhythm-related genes (DE-CRGs) were obtained. Machine learning algorithms were used to screen for feature genes, and diagnostic models were constructed based on these feature genes. Subsequently, consensus clustering algorithms and non-negative matrix factorization (NMF) algorithms were used for clustering analysis of HF samples. On this basis, immune infiltration analysis was used to score the immune infiltration status between HF and normal samples as well as among different subclusters. Gene Set Variation Analysis (GSVA) evaluated the biological functional differences among subclusters. Results13 CRGs showed differential expression between HF patients and normal samples. Nine feature genes were obtained through cross-referencing results from four distinct machine learning algorithms. Multivariate LASSO regression and external dataset validation were performed to select five key genes with diagnostic value, including NAMPT, SERPINA3, MAPK10, NPPA, and SLC2A1. Moreover, consensus clustering analysis could divide HF patients into two distinct clusters, which exhibited different biological functions and immune characteristics. Additionally, two subgroups were distinguished using the NMF algorithm based on circadian rhythm associated differentially expressed genes. Studies on immune infiltration showed marked variances in levels of immune infiltration between these subgroups. Subgroup A had higher immune scores and more widespread immune infiltration. Finally, the Weighted Gene Co-expression Network Analysis (WGCNA) method was utilized to discern the modules that had the closest association with the two observed subgroups, and hub genes were pinpointed via protein-protein interaction (PPI) networks. GRIN2A, DLG1, ERBB4, LRRC7, and NRG1 were circadian rhythm-related hub genes closely associated with HF. ConclusionThis study provides valuable references for further elucidating the pathogenesis of HF and offers beneficial insights for targeting circadian rhythm mechanisms to regulate immune responses and energy metabolism in HF treatment. Five genes identified by us as diagnostic features could be potential targets for therapy for HF.

Transcriptomic analysis reveals the molecular basis of photoperiod-regulated sex differentiation in tropical pumpkins (Cucurbita moschata Duch.)

BackgroundPhotoperiod, or the length of the day, has a significant impact on the flowering and sex differentiation of photoperiod-sensitive crops. The “miben” pumpkin (the main type of Cucurbita moschata Duch.) is well-known for its high yield and strong disease resistance. However, its cultivation has been limited due to its sensitivity to photoperiod. This sensitivity imposes challenges on its widespread cultivation and may result in suboptimal yields in regions with specific daylength conditions. As a consequence, efforts are being made to explore potential strategies or breeding techniques to enhance its adaptability to a broader range of photoperiods, thus unlocking its full cultivation potential and further promoting its valuable traits in agriculture.ResultsThis study aimed to identify photoperiod-insensitive germplasm exhibiting no difference in sex differentiation under different day-length conditions. The investigation involved a phenotypic analysis of photoperiod-sensitive (PPS) and photoperiod-insensitive (PPIS) pumpkin materials exposed to different day lengths, including long days (LDs) and short days (SDs). The results revealed that female flower differentiation was significantly inhibited in PPS_LD, while no differences were observed in the other three groups (PPS_SD, PPIS_LD, and PPIS_SD). Transcriptome analysis was carried out for these four groups to explore the main-effect genes of sex differentiation responsive to photoperiod. The main-effect gene subclusters were identified based on the principal component and hierarchical cluster analyses. Further, functional annotations and enrichment analysis revealed significant upregulation of photoreceptors (CmCRY1, F-box/kelch-repeat protein), circadian rhythm-related genes (CmGI, CmPRR9, etc.), and CONSTANS (CO) in PPS_LD. Conversely, a significant downregulation was observed in most Nuclear Factor Y (NF-Y) transcription factors. Regarding the gibberellic acid (GA) signal transduction pathway, positive regulators of GA signaling (CmSCL3, CmSCL13, and so forth) displayed higher expression levels, while the negative regulators of GA signaling, CmGAI, exhibited lower expression levels in PPS_LD. Notably, this effect was not observed in the synthetic pathway genes. Furthermore, genes associated with ethylene synthesis and signal transduction (CmACO3, CmACO1, CmERF118, CmERF118-like1,2, CmWIN1-like, and CmRAP2-7-like) showed significant downregulation.ConclusionsThis study offered a crucial theoretical and genetic basis for understanding how photoperiod influences the mechanism of female flower differentiation in pumpkins.

Multi-omics and single-cell sequencing analyses reveal the potential significance of circadian pathways in cancer therapy

ABSTRACT Background Circadian rhythm disturbance is an independent risk factor for cancer. However, few studies have been reported on circadian rhythm related genes (CRGs) in cancer, so it is important to further explore the impact of CRGs in pan-cancer. Research design and methods The Cancer Genome Atlas database was used to collect cancer-related data such as copy number variation, single nucleotide variants, methylation, and survival differences. Immunohistochemistry (IHC) was used to verify the expression of circadian rhythm hub genes. The circadian pathway scores (CRS) were calculated using single-sample gene enrichment analysis. TIMER and GEPIA databases were used for immune-cell integration and assessment. Single-cell sequencing data was used to evaluate the abundance of CRS in tumor microenvironment cells. Results In this study, we found that the expression of circadian pathway varies between tumors. CSNK1E was significantly up-regulated in most tumors and CRY2 was significantly down-regulated in most tumors. The protein interaction network suggested CRY2 as the core gene and IHC verified its significant low expression in KIRC. In addition, CRGs were found to be protective factors in most tumors and have the potential to act as specific immune markers in different tumors. CRS was significantly lower in abundance in most tumors. CRS was significantly associated with overall survival in tumor patients and associated with the expression of many immune cells in the tumor immune microenvironment. CRS is significantly associated with tumor mutational burden and microsatellite instability scores in most tumors and may serve as a potential immunotherapeutic marker. Conclusions The circadian rhythm pathway may be a breakthrough point in regulating the tumor microenvironment meanwhile a suitable immunotherapy method in the future.

Circadian rhythm-associated lncRNA RP11-414H17.5 as a key therapeutic target in osteosarcoma affects the tumor immune microenvironment and enhances malignancy

BackgroundIt has previously been proven that circadian rhythm disruption is associated with the incidence and deterioration of several tumors, which potentially leads to increased tumor susceptibility and a worse prognosis for tumor-bearing patients. However, their potential role in osteosarcoma has yet to be sufficiently investigated.MethodsTranscriptomic and clinical data of 84 osteosarcoma samples and 70 normal bone tissue samples were obtained from the TARGET and GTEx databases, circadian rhythm-related genes were obtained from Genecards, and circadian rhythm-related lncRNAs (CRLs) were obtained by Pearson correlation analysis, differential expression analysis, and protein–protein interaction (PPI) analysis. COX regression and LASSO regression were performed on the CRLs in order to construct a circadian rhythm-related prognostic prediction signature (CRPS). CRPS reliability was verified by Kaplan–Meier (KM), principal component analysis (PCA), nomogram, and receiver operating characteristic (ROC) curve. CRPS effects on the immune microenvironment of osteosarcoma were explored by enrichment analysis and immune infiltration analysis, and the effect of critical gene RP11-414H17.5 on osteosarcoma was experimentally verified.ResultCRPS consisting of three CRLs was constructed and its area under the curve (AUC) values predicted that osteosarcoma prognosis reached 0.892 in the training group and 0.843 in the test group, with a p value of < 0.05 for the KM curve and stable performance across different clinical subgroups. PCA analysis found that CRPS could significantly distinguish between different risk subgroups, and exhibited excellent performance in the prediction of the immune microenvironment. The experiment verified that RP11-414H17.5 can promote metastasis and inhibit apoptosis of osteosarcoma cells.ConclusionThe study revealed that circadian rhythm plays a crucial role in osteosarcoma progression and identified the impact of the key gene RP11-414H17.5 on osteosarcoma, which provides novel insights into osteosarcoma diagnosis and therapy.

A three-gene random forest model for diagnosing idiopathic pulmonary fibrosis based on circadian rhythm-related genes in lung tissue

ABSTRACT Background The disorder of circadian rhythm could be a key factor mediating fibrotic lung disease Therefore, our study aims to determine the diagnostic value of circadian rhythm-related genes (CRRGs) in IPF. Methods We retrieved the data on CRRGs from previous studies and the GSE150910 dataset. The participants from the GSE150910 dataset were divided into training and internal validation sets. Next, we used several various bioinformatics methods and machine learning algorithms to screen genes. Next, we identified SEMA5A, COL7A1, and TUBB3, which were included in the random forest (RF) diagnostic model. Finally, external validation was conducted on data retrieved from the GSE184316 datasets. Results The results revealed that the RF diagnostic model could diagnose patients with IPF in the internal validation set with the area under the ROC curve (AUC) value of 0.905 and in the external validation with the AUC value of 0.767. Furthermore, real-time quantitative PCR and western blotting results revealed a significant decrease in SEMA5A (p < 0.05) expression level and an increase in COL7A1 and TUBB3 expression levels in TGF-β1-treated normal human lung fibroblasts. Conclusion We constructed an RF diagnostic model based on SEMA5A, COL7A1, and TUBB3 expression in lung tissue for diagnosing patients with IPF.

Systematic assessment of transcriptomic and metabolic reprogramming by blue light exposure coupled with aging.

The prevalent use of light-emitting diodes (LEDs) has caused revolutionary changes in modern life, but the potential hazards to health of blue light are poorly understood. N6-methyladenosine (m6A) is the most prevalent posttranscriptional modification in eukaryotes and can modulate diverse physiological processes by regulating mRNA fate. Here, to understand the effects and molecular mechanisms of daily low-intensity blue light exposure (BLE) and ascertain whether m6A methylation plays a role in BLE-induced phenotypes, we constructed a series of Drosophila models under different durations of daily low-intensity BLE and obtained multiomics profiles. Our results revealed that BLE could induce transcriptomic, m6A epitranscriptomic, and metabolomic reprogramming in Drosophila along with aging process. Importantly, the m6A methylation sites enriched in the 5' untranslated regions (UTRs) of Drosophila transcripts showed strong age specificity and could be altered by BLE. We experimentally validated that aging-related gene Tor and circadian rhythm-related gene per were regulated by 5' UTR-enriched m6A methylation. Overall, our study provides a systematic assessment of m6A RNA methylome reprogramming by BLE and aging in Drosophila model.

Relationship between circadian rhythm-related genes and extracellular matrix: implications for sleep deprivation

Abstract Background Sleep deprivation (SD) can lead to the development of various pathological disorders. The extracellular matrix (ECM) compositions and circadian rhythm genes are two pivotal variables of SD. However, their relationships remain undefined during SD. Methods A mouse SD model was established using a modified multiplatform water environment method. The expression of nerve growth factor (NGF) in mouse hippocampus was detected by an immunofluorescence (IF) method. Protein expression was assessed by western blot, and mRNA analysis was performed by quantitative real-time PCR (qRT-PCR). The differentially expressed genes after SD, the genes associated with stromal score, and gene expression correlation were analyzed by bioinformatic analysis. Results The mouse model of SD was successfully established, as evidenced by the changed morphology, increased Bax and NGF levels, and downregulated Bcl-2 in mouse hippocampus after SD. The differentially expressed genes after SD were closely associated with the ECM compositions. The ECM composition metalloproteinase 9 (MMP9) was under-expressed in mouse hippocampus after SD. The hippocampal MMP9 expression was correlated with the expression levels of circadian genes PER2, PER3, TIMELESS, FBXL3, and NFIL3. PER2 and TIMELESS were upregulated in mouse hippocampus after SD. Conclusion The current findings suggest a correlation between ECM composition MMP9 and circadian rhythm-related genes PER2 and TIMELESS in mouse hippocampus after SD, providing a novel understanding of the disorders after SD.

Bioinformatics Integrative Analysis of Circadian Rhythms Effects on Atopic Dermatitis and Dendritic Cells.

Atopic dermatitis (AD) is an allergic inflammatory skin disease caused by aberrant and over-reactive immune response. Although circadian rhythm disruption is implicated in multiple immunoinflammatory conditions, including AD, the mechanisms at the molecular level underlying AD and circadian rhythms remain elusive. Bulk and single-cell RNA-sequencing data of AD patients were acquired from the Gene Expression Omnibus, including GSE121212, GSE120721, and GSE153760 datasets. A single-sample gene set enrichment analysis was performed to estimate circadian rhythm gene expression levels. A differential expression analysis was utilized to identify the key candidate genes in AD. CIBERSORT was used to quantify the proportions of immune cells, and the R package "Seurat" was utilized to investigate single-cell RNA-sequencing data. Circadian rhythm gene expression levels were lower in AD skin samples than in normal skin samples. Dendritic cells were significantly upregulated and negatively correlated with circadian rhythm gene expression levels in AD patients. Compared with circadian rhythm-related genes in the control samples, ARNTL2, NOCT, and RORC were differentially expressed in AD; ARNTL2 and NOCT were significantly upregulated, whereas RORC was significantly downregulated in AD. ARNTL2, NOCT, and RORC also showed robust abilities to diagnose AD. We validated that the abundance of the dendritic cell was positively correlated with the ARNTL2 and NOCT expression levels using bulk RNA-sequencing data of the GSE121212 and single-cell RNA-sequencing data of the GSE153760. Moreover, the functional enrichment analysis showed that the IL-17 and NF-κB signaling pathways, Th1 and Th2 cell differentiations, and primary immunodeficiency, were enriched in AD patients. The findings of this study suggested that the circadian rhythm is involved in the progression of AD, and RNTL2, NOCT, and RORC as well as dendritic cells are differentially expressed in AD. These findings could be used to introduce diagnostic and chronotherapeutic modalities for AD.

Role of Circadian Rhythm-Related Genes in Nocturnal Epilepsy

Role of Circadian Rhythm-Related Genes in Nocturnal Epilepsy

Day-night fluctuations in choroid plexus transcriptomics and cerebrospinal fluid metabolomics.

The cerebrospinal fluid (CSF) provides mechanical protection for the brain and serves as a brain dispersion route for nutrients, hormones, and metabolic waste. The CSF secretion rate is elevated in the dark phase in both humans and rats, which could support the CSF flow along the paravascular spaces that may be implicated in waste clearance. The similar diurnal CSF dynamics pattern observed in the day-active human and the nocturnal rat suggests a circadian regulation of this physiological variable, rather than sleep itself. To obtain a catalog of potential molecular drivers that could provide the day-night-associated modulation of the CSF secretion rate, we determined the diurnal fluctuation in the rat choroid plexus transcriptomic profile with RNA-seq and in the CSF metabolomics with ultraperformance liquid chromatography combined with mass spectrometry. We detected significant fluctuation of 19 CSF metabolites and differential expression of 2,778 choroid plexus genes between the light and the dark phase, the latter of which encompassed circadian rhythm-related genes and several choroid plexus transport mechanisms. The fluctuating components were organized with joint pathway analysis, of which several pathways demonstrated diurnal regulation. Our results illustrate substantial transcriptional and metabolic light-dark phase-mediated changes taking place in the rat choroid plexus and its encircling CSF. The combined data provide directions toward future identification of the molecular pathways governing the fluctuation of this physiological process and could potentially be harnessed to modulate the CSF dynamics in pathology.

Approach to Functions of BHLHE41/DEC2 in Non-Small Lung Cancer Development.

The circadian rhythm-related genes BHLHE40/DEC1 and BHLHE41/DEC2 have various functions under different cell and tissue conditions. BHLHE41/DEC2 has been reported to be both a cancer-suppressive and an oncogenic gene during cancer development. The effects of BHLHE41/DEC2 on differentiation have been examined using Bhlhe41/Dec2 knockout mice and/or in vitro differentiation models, and research has been conducted using genetic analysis of tumor cells, in vitro analysis of cancer cell lines, and immunohistochemical studies of the clinical samples. We summarize some of these studies, detail several problems, and consider possible reasons for contradictory results and the needs for further research.

Transcriptome and Metabolome Analyses Reveal Perfluorooctanoic Acid-Induced Kidney Injury by Interfering with PPAR Signaling Pathway.

Perfluorooctanoic acid (PFOA) is widely used in aviation science and technology, transportation, electronics, kitchenware, and other household products. It is stable in the environment and has potential nephrotoxicity. To investigate the effect of PFOA exposure during pregnancy on the kidneys of offspring mice, a total of 20 mice at day 0 of gestation were randomly divided into two groups (10 mice in each group), and each group was administered 0.2 mL of PFOA at a dose of 3.5 mg/kg or deionized water by gavage during gestation. The kidney weight, kidney index, histopathological observation, serum biochemistry, transcriptomics, and metabolomics of the kidneys of the 35-day offspring mice were analyzed. In addition, malondialdehyde (MDA), superoxide dismutase (SOD), and catalase (CAT) levels in the kidney were measured. Transcriptome analysis results showed that 387 genes were up-regulated and 283 genes were down-regulated compared with the control group. These differentially expressed genes (DEGs) were mainly concentrated in the peroxisome-proliferator-activated receptor (PPAR) signaling pathway and circadian rhythm. Compared with the control group, 64 and 73 metabolites were up- and down-regulated, respectively, in the PFOA group. The altered metabolites were mainly enriched in the biosynthesis of unsaturated fatty acids. PFOA can affect the expression levels of circadian rhythm-related genes in the kidneys of offspring mice, and this change is influenced by the PPAR signaling pathway. PFOA causes oxidative stress in the kidneys, which is responsible for significant changes in metabolites associated with the biosynthesis of unsaturated fatty acids.

The gut-brain axis involved in polystyrene nanoplastics-induced neurotoxicity via reprogramming the circadian rhythm-related pathways

The production of plastic is still increasing globally, which has led to an increasing number of plastic particles in the environment. Nanoplastics (NPs) can penetrate the blood-brain barrier and induce neurotoxicity, but in-depth mechanism and effective protection strategies are lacking. Here, C57BL/6 J mice were treated with 60 μg polystyrene NPs (PS-NPs, 80 nm) by intragastric administration for 42 days to establish NPs exposure model. We found that 80 nm PS-NPs could reach and cause neuronal damage in the hippocampus, and alter the expression of neuroplasticity-related molecules (5-HT, AChE, GABA, BDNF and CREB), and even affect the learning and memory ability of mice. Mechanistically, combined with the results of hippocampus transcriptome, gut microbiota 16 s ribosomal RNA and plasma metabolomics, we found that the gut-brain axis mediated circadian rhythm related pathways were involved in the neurotoxicity of NPs, especially Camk2g, Adcyap1 and Per1 may be the key genes. Both melatonin and probiotic can significantly reduce intestinal injury and restore the expression of circadian rhythm-related genes and neuroplasticity molecules, and the intervention effect of melatonin is more effective. Collectively, the results strongly suggest the gut-brain axis mediated hippocampal circadian rhythm changes involved in the neurotoxicity of PS-NPs. Melatonin or probiotics supplementation may have the application value in the prevention of neurotoxicity of PS-NPs.

Melatonin-related dysfunction in chronic restraint stress triggers sleep disorders in mice.

Stress may trigger sleep disorders and are also risk factors for depression. The study explored the melatonin-related mechanisms of stress-associated sleep disorders on a mouse model of chronic stress by exploring the alteration in sleep architecture, melatonin, and related small molecule levels, transcription and expression of melatonin-related genes as well as proteins. Mice undergoing chronic restraint stress modeling for 28days showed body weight loss and reduced locomotor activity. Sleep fragmentation, circadian rhythm disorders, and insomnia exhibited in CRS-treated mice formed sleep disorders. Tryptophan and 5-hydroxytryptamine levels were increased in the hypothalamus, while melatonin level was decreased. The transcription and expression of melatonin receptors were reduced, and circadian rhythm related genes were altered. Expression of downstream effectors to melatonin receptors was also affected. These results identified sleep disorders in a mice model of chronic stress. The alteration of melatonin-related pathways was shown to trigger sleep disorders.

Gene expression changes reveal the impact of the space environment on the skin of International Space Station astronauts.

The various types of ionizing radiation and altered gravity in the space environment present a risk to humans during space missions. Changes in the space environment lead to skin diseases, affecting the status of the aviators to fly. Therefore, it is important to explore the molecular-level changes in the skin during space missions. Bioinformatics analysis of gene arrays from hair follicle tissue of 10 astronauts was performed to explore changes in gene expression before, during and after space missions. First, STEM (Short Time-series Expression Miner) software was used to identify the expression patterns of hair follicle genes of astronauts pre-, in- and postflight. Gene Ontology Enrichment Analysis was then performed to explore the gene functions within the module. Protein-protein interaction network analysis was performed on skin-related genes. The transcriptional regulatory network within the module was constructed using the TRRUST database. The circadian rhythm-related genes within the module were screened using the MSigDB (Molecular Signatures Database). Based on differential expression analysis between the two groups, there were 327 differentially expressed genes after the astronauts entered space compared with preflight, and only 54 differentially expressed genes after returning to Earth. This outcome suggests that the expression of most genes can be recovered on return to the ground, but there are a small number of genes whose expression cannot be recovered in a short period of time. Based on time series analysis, 311 genes showed increased expression on entry into space and decreased expression on return to Earth. The genes of this expression pattern were associated with skin development, keratinocyte differentiation and cornification. Ten hub genes were identified as skin-related genes within the module, as well as nine transcription factors and three circadian genes. One hundred and seventy-nine genes decreased in expression after entry into space and increased on return to Earth. By reviewing the literature, we found that four of the genes, CSCD2, HP, CXCR1 and SSTR4, are associated with skin diseases. Through bioinformatics analysis, we found that the space environment affects skin keratinocyte differentiation, leading to skin barrier damage and inflammatory responses, and that this effect was decreased after return to Earth.

Identification and validation of a novel prognostic circadian rhythm-related gene signature for stomach adenocarcinoma

ABSTRACT Circadian rhythm genes were reported to be strongly associated with the development and prognosis of circadian rhythm disorders related to stomach adenocarcinoma (STAD), which is one of the most prevalent cancers. This study aimed to identify a circadian rhythm-related gene signature that could help predict STAD outcome. Using bioinformatics analysis approaches, 105 genes were examined in 350 patients with STAD. Overall, six hub-type circadian rhythm-associated genes (GNA11, PER1, SOX14, EZH2, MAGED1, and NR1D1) were identified using univariate and multivariate Cox regression analyses. These genes were then used to build a genetic predictive model, which was further validated using a publicly available dataset (GSE26899). Overall, genes associated with the circadian rhythm were found to be substantially correlated with the characteristics of the STAD patients (grade, sex, and M stage). In addition, the circadian rhythm-related gene signature was significantly associated with the MAPK and Notch signaling pathways, which are known risk factors for poorer STAD outcome. Taken together, these findings suggest that the herein proposed prognostic model based on six circadian rhythm-associated genes may have predictive value and potential application for clinical decision-making and for personalized treatment of STAD.

Integrative analysis of the association between circadian rhythm and lupus nephritis.

Lupus nephritis (LN) is an autoimmune nephropathy associated with systemic lupus erythematosus. Circadian rhythms are involved in the development of several diseases, especially inflammation-related diseases, but their relationship with LN is unclear. This was an integrative bioinformatics study. The expression profile from glomeruli, tubular interstitium and renal whole tissue samples was used to assess the expression levels and relevance of circadian rhythm-related genes. To screen for circadian rhythm-related signatures, we employed the LASSO and SVM-RFE algorithms. A consensus clustering algorithm was used to classify LN patients into two circadian rhythm patterns (cluster A and cluster B). We made immune cell infiltration analysis. We used the weighted gene co-expression network analysis (WGCNA) algorithm to identify cluster-specific differentially expressed genes. Nephroseq data were used to observe the relationship between genes and renal function. We found more significant differences in circadian rhythm-related gene expression in LN glomeruli compared with tubulointerstitial and whole-kidney tissues. We established a circadian rhythm-related signature consisting of eight genes that can easily distinguish LN from healthy individuals. Patients in cluster A were associated with B-cell-dominated immunity, whereas patients in cluster B were associated with T-cell-dominated immunity. As most of the patients with proliferative LN combined with membranous LN belonged to cluster B, patients in cluster B may have more severe renal pathology compared with patients in cluster A. Fifteen circadian rhythm-related genes associated with LN and LN typing were screened using the WGCNA algorithm, with COL1A2 and DOCK2 associated with renal prognosis. This study found that circadian rhythms are associated with the occurrence of LN, providing new ideas for the development of new LN treatment options from the perspective of circadian rhythms.

Circadian rhythm-related genes index: A predictor for HNSCC prognosis, immunotherapy efficacy, and chemosensitivity.

Head and neck squamous cell carcinoma (HNSCC) is the most common head and neck cancer and is highly aggressive and heterogeneous, leading to variable prognosis and immunotherapy outcomes. Circadian rhythm alterations in tumourigenesis are of equal importance to genetic factors and several biologic clock genes are considered to be prognostic biomarkers for various cancers. The aim of this study was to establish reliable markers based on biologic clock genes, thus providing a new perspective for assessing immunotherapy response and prognosis in patients with HNSCC. We used 502 HNSCC samples and 44 normal samples from the TCGA-HNSCC dataset as the training set. 97 samples from GSE41613 were used as an external validation set. Prognostic characteristics of circadian rhythm-related genes (CRRGs) were established by Lasso, random forest and stepwise multifactorial Cox. Multivariate analysis revealed that CRRGs characteristics were independent predictors of HNSCC, with patients in the high-risk group having a worse prognosis than those in the low-risk group. The relevance of CRRGs to the immune microenvironment and immunotherapy was assessed by an integrated algorithm. 6-CRRGs were considered to be strongly associated with HNSCC prognosis and a good predictor of HNSCC. The riskscore established by the 6-CRRG was found to be an independent prognostic factor for HNSCC in multifactorial analysis, with patients in the low-risk group having a higher overall survival (OS) than the high-risk group. Nomogram prediction maps constructed from clinical characteristics and riskscore had good prognostic power. Patients in the low-risk group had higher levels of immune infiltration and immune checkpoint expression and were more likely to benefit from immunotherapy. 6-CRRGs play a key predictive role for the prognosis of HNSCC patients and can guide physicians in selecting potential responders to prioritise immunotherapy, which could facilitate further research in precision immuno-oncology.