Multiple Omics Analyses Research Articles

Multi-Omics Analysis of GNL3L Expression, Prognosis, and Immune Value in Pan-Cancer.

Simple SummaryGuanine nucleotide-binding protein-like 3-like (GNL3L) is a novel GTP-binding nucleolar protein. In this study, we analyzed the expression, prognosis, and immune roles of GNL3L in pan-cancer from multiple omics analyses. The final results showed that GNL3L is differentially expressed in a variety of cancers, plays a prognostic role, and has good immune value. Moreover, GNL3L may affect the occurrence of cancer through processes such as ribonucleoprotein, ribosomal RNA processing, and cell proliferation. At the same time, we established an esophageal cancer (ESCA) prediction model with strong predictive ability and proved that GNL3L can significantly affect the proliferation ability of esophageal cancer cells through clone formation assays. In conclusion, GNL3L is an important biomarker.Guanine nucleotide-binding protein-like 3-like protein (GNL3L) is a novel, evolutionarily conserved, GTP-binding nucleolar protein. This study aimed to investigate the expression, prognosis, and immune value of GNL3L in pan-cancer from multiple omics analyses. Firstly, the expression and prognostic value of GNL3L in pan-cancer were discussed using the TIMER2 database, the GEPIA database, the cBioportal database, COX regression analysis, and enrichment analysis. The association of GNL3L with tumor mutational burden (TMB), tumor microsatellite instability (MSI), mismatch repair (MMR) genes, and immune cells was then analyzed. Finally, an esophageal cancer (ESCA) prediction model was established, and GNL3L clone formation assays were performed. The final results showed that GNL3L is differentially expressed in the vast majority of cancers, is associated with the prognosis of various cancers, and may affect cancer occurrence through processes such as ribonucleoprotein, ribosomal RNA processing, and cell proliferation. At the same time, it was found that the correlation between GNL3L and TMB, MSI, MMR, and various immune cells is significant. The established ESCA prediction model had a strong predictive ability, and GNL3L could significantly affect the proliferation of esophageal cancer cells. In conclusion, GNL3L may serve as an important prognostic biomarker and play an immunomodulatory role in tumors.

Multiomic analysis revealed the regulatory role of the KRT14 gene in eggshell quality.

Background: Eggshell strength and thickness are critical factors in reducing the egg breaking rate and preventing economic losses. The calcite biomineralization process is very important for eggshell quality. Therefore, we employed transcriptional sequencing and proteomics to investigate the differences between the uteruses of laying hens with high- and low-breaking-strength shells. Results: A total of 1,028 differentially expressed genes (DEGs) and 270 differentially expressed proteins (DEPs) were identified. The analysis results of GO terms and KEGG pathways showed that most of the DEGs and DEPs were enriched in vital pathways related to processes such as calcium metabolism, hormone and amino acid biosynthesis, and cell proliferation and apoptosis. Several DEGs and DEPs that were coexpressed at mRNA and protein levels were verified. KRT14 (keratin-14) is a candidate gene (protein) obtained by multiple omics analysis due to the fold difference of KRT14 being the largest. After the overexpression of KRT14 in uterine epithelial cells, the expressions of OC116 (ovocleididin-116), CALB1 (calbindin 1), and BST1 (ADP-ribosyl cyclase 2) were found to be increased significantly, while the expression of OC17 (ovocleididin-17) was found to be decreased significantly. Conclusion: In summary, this study confirms that during normal calcification, there are differences in ion transport between the uterus of hens producing high-breaking-strength eggshells and those producing low-breaking-strength eggshells, which may help elucidate the eggshell calcification process. The KRT14 gene may promote calcium metabolism and deposition of calcium carbonate in eggshells.

Systematic Identification of the RNA-Binding Protein STAU2 as a Key Regulator of Pancreatic Adenocarcinoma

Simple SummaryPancreatic adenocarcinoma (PAAD) is one of the most common tumors of the gastrointestinal tract and is difficult to diagnose and treat due to tumor heterogeneity and the immunosuppressive tumor microenvironment. RNA-binding proteins have been studied and their dysregulation has been found to play a key role in altering RNA metabolism in various malignancies. STAU2 is one of them. To investigate the role of STAU2 in PAAD, we monitored the signaling pathway by regulating substrate mRNA and experimentally confirmed that STAU2 is the most potential biomarker for the occurrence and development of PAAD. Furthermore, we found that high expression of STAU2 not only contributes to immune evasion but also correlates with sensitivity to chemotherapeutic agents, suggesting that STAU2 may be a potential target for combined natural therapy. These results demonstrate that STAU2 is a novel prognostic and diagnostic biomarker for PAAD, revealing STAU2′s utility in cancer therapy and drug development.Pancreatic adenocarcinoma (PAAD) is a highly aggressive cancer. RNA-binding proteins (RBPs) regulate highly dynamic post-transcriptional processes and perform very important biological functions. Although over 1900 RBPs have been identified, most are considered markers of tumor progression, and further information on their general role in PAAD is not known. Here, we report a bioinformatics analysis that identified five hub RBPs and produced a high-value prognostic model based on The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) datasets. Among these, the prognostic signature of the double-stranded RNA binding protein Staufen double-stranded RNA (STAU2) was identified. Firstly, we found that it is a highly expressed critical regulator of PAAD associated with poor clinical outcomes. Accordingly, the knockdown of STAU2 led to a profound decrease in PAAD cell growth, migration, and invasion and induced apoptosis of PAAD cells. Furthermore, through multiple omics analyses, we identified the key target genes of STAU2: Palladin cytoskeletal associated protein (PALLD), Heterogeneous nuclear ribonucleoprotein U (HNRNPU), SERPINE1 mRNA Binding Protein 1 (SERBP1), and DEAD-box polypeptide 3, X-Linked (DDX3X). Finally, we found that a high expression level of STAU2 not only helps PAAD evade the immune response but is also related to chemotherapy drug sensitivity, which implies that STAU2 could serve as a potential target for combinatorial therapy. These findings uncovered a novel role for STAU2 in PAAD aggression and resistance, suggesting that it probably represents a novel therapeutic and drug development target.

Cross-feeding between cyanobacterium Synechococcus and Escherichia coli in an artificial autotrophic–heterotrophic coculture system revealed by integrated omics analysis

BackgroundLight-driven consortia, which consist of sucrose-secreting cyanobacteria and heterotrophic species, have attracted considerable attention due to their capability for the sustainable production of valuable chemicals directly from CO2. In a previous study, we achieved a one-step conversion of sucrose secreted from cyanobacteria to fine chemicals by constructing an artificial coculture system consisting of sucrose-secreting Synechococcus elongateus cscB+ and 3-hydroxypropionic acid (3-HP) producing Escherichia coli ABKm. Analyses of the coculture system showed that the cyanobacterial cells grew better than their corresponding axenic cultures. To explore the underlying mechanism and to identify the metabolic nodes with the potential to further improve the coculture system, we conducted integrated transcriptomic, proteomic and metabolomic analyses.ResultsWe first explored how the relieved oxidative stress affected cyanobacterial cell growth in a coculture system by supplementing additional ascorbic acid to CoBG-11 medium. We found that the cell growth of cyanobacteria was clearly improved with an additional 1 mM ascorbic acid under axenic culture; however, its growth was still slower than that in the coculture system, suggesting that the improved growth of Synechococcus cscB+ may be caused by multiple factors, including reduced oxidative stress. To further explore the cellular responses of cyanobacteria in the system, quantitative transcriptomics, proteomics and metabolomics were applied to Synechococcus cscB+. Analyses of differentially regulated genes/proteins and the abundance change of metabolites in the photosystems revealed that the photosynthesis of the cocultured Synechococcus cscB+ was enhanced. The decreased expression of the CO2 transporter suggested that the heterotrophic partner in the system might supplement additional CO2 to support the cell growth of Synechococcus cscB+. In addition, the differentially regulated genes and proteins involved in the nitrogen and phosphate assimilation pathways suggested that the supply of phosphate and nitrogen in the Co-BG11 medium might be insufficient.ConclusionAn artificial coculture system capable of converting CO2 to fine chemicals was established and then analysed by integrated omics analysis, which demonstrated that in the coculture system, the relieved oxidative stress and increased CO2 availability improved the cell growth of cyanobacteria. In addition, the results also showed that the supply of phosphate and nitrogen in the Co-BG11 medium might be insufficient, which paves a new path towards the optimization of the coculture system in the future. Taken together, these results from the multiple omics analyses provide strong evidence that beneficial interactions can be achieved from cross-feeding and competition between phototrophs and prokaryotic heterotrophs and new guidelines for engineering more intelligent artificial consortia in the future.

Proteomic Analysis of Hypothalamus and Pituitary Gland in Pre and Postpubertal Brahman Heifers.

The hypothalamus and the pituitary gland are directly involved in the complex systemic changes that drive the onset of puberty in cattle. Here, we applied integrated bioinformatics to elucidate the critical proteins underlying puberty and uncover potential molecular mechanisms from the hypothalamus and pituitary gland of prepubertal (n = 6) and postpubertal (n = 6) cattle. Proteomic analysis in the hypothalamus and pituitary gland revealed 275 and 186 differentially abundant (DA) proteins, respectively (adjusted p-value < 0.01). The proteome profiles found herein were integrated with previously acquired transcriptome profiles. These transcriptomic studies used the same tissues harvested from the same heifers at pre- and post-puberty. This comparison detected a small number of matched transcripts and protein changes at puberty in each tissue, suggesting the need for multiple omics analyses for interpreting complex biological systems. In the hypothalamus, upregulated DA proteins at post-puberty were enriched in pathways related to puberty, including GnRH, calcium and oxytocin signalling pathways, whereas downregulated proteins were observed in the estrogen signalling pathway, axon guidance and GABAergic synapse. Additionally, this study revealed that ribosomal pathway proteins in the pituitary were involved in the pubertal development of mammals. The reported molecules and derived protein-protein networks are a starting point for future experimental approaches that might dissect with more detail the role of each molecule to provide new insights into the mechanisms of puberty onset in cattle.

The Crosstalk Between Immune Infiltration, Circulating Tumor Cells, and Metastasis in Pancreatic Cancer: Identification of HMGB3 From a Multiple Omics Analysis.

Metastasis is the major cause of death in patients with pancreatic ductal adenocarcinoma (PDAC), and circulating tumor cells (CTCs) play an important role in the development of metastasis. However, few studies have uncovered the metastasis mechanism of PDAC based on CTCs. In this study, the existing bulk RNA-sequencing (bulk RNA-seq) and single-cell sequencing (scRNA-seq) data for CTCs in pancreatic cancer were obtained from the Gene Expression Omnibus (GEO) database. Analysis of tumor-infiltrating immune cells (TIICs) by CIBERSORT showed that the CTCs enriched from the peripheral blood of metastatic PDAC were found to contain a high proportion of T cell regulators (Tregs) and macrophages, while the proportion of dendritic cells (DCs) was lower than that enriched from localized PDAC. Through weighted gene co-expression network analysis (WGCNA) and the result of scRNA-seq, we identified the hub module (265 genes) and 87 marker genes, respectively, which were highly associated with metastasis. The results of functional enrichment analysis indicated that the two gene sets mentioned above are mainly involved in cell adhesion and cytoskeleton and epithelial–mesenchymal transition (EMT). Finally, we found that HMGB3 was the hub gene according to the Venn diagram. The expression of HMGB3 in PDAC was significantly higher than that in normal tissues (protein and mRNA levels). HMGB3 expression was significantly positively correlated with both EMT-related molecules and CTC cluster–related markers. Furthermore, it was also found that HMGB3 mutations were favorably related to tumor-associated immune cells through the TIMER2.0 online tool. We further demonstrated that PDAC patients with higher HMGB3 expression had significantly worse overall survival (OS) in multiple datasets. In summary, our study suggests that HMGB3 is a hub gene associated with EMT in CTCs, the formation of CTC clusters, and infiltration patterns of immune cells favorable for tumor progression and metastasis to distant organs.

Metabolomic, proteomic and lactylated proteomic analyses indicate lactate plays important roles in maintaining energy and C:N homeostasis in Phaeodactylum tricornutum

BackgroundPhaeodactylum tricornutum accumulates lipids while the growth also increases under high CO2, shedding light on its potential application in the reduction of CO2 emissions and at the same time acquiring biodiesel raw materials. However, the sensing and transducing of high C:N signals and the related response mechanism(s) remained unknown.ResultsIn this study, a multiple omics analysis was performed with P. tricornutum under low nitrogen (LN) and high CO2 (HC) conditions. The results indicated that 2-oxoglutarate was significantly increased under both LN and HC. Meanwhile, proteins involved in carbon concentration mechanism decreased, indicated that 2-oxoglutarate might regulate C:N balance through suppressing carbon fixation. Lactate, which acts in energy metabolism, signal transduction and ‘LactoylLys’ modification on proteins, was the most upregulated metabolite under both LN and HC conditions. Meanwhile, proteins involved in carbon, nitrogen and energy metabolisms were significantly regulated. Western blotting analysis suggested that non-histone L-lactylation modification was enhanced under LN and HC. Moreover, lactylated proteins were enriched in photosynthesis, central carbon metabolism, nitrogen metabolism, fatty acid synthesis and oxidative phosphorylation.ConclusionIt is suggested that lactate might play important roles in energy homeostatic maintenance and C:N balance regulation in P. tricornutum through protein lactylation modification.

A reactive oxygen species burst causes haploid induction in maize

Haploid induction (HI) is an important tool in crop breeding. Phospholipase A1 (ZmPLA1)/NOT LIKE DAD (NLD)/MATRILINEAL (MTL) is a key gene controlling HI in maize; however, the underlying molecular mechanism remains unclear. In this study, to dissect why loss of ZmPLA1 function could mediate HI we performed a comprehensive multiple omics analysis of zmpla1 mutant anthers by integrating transcriptome, metabolome, quantitative proteome, and protein modification data. Functional classes of significantly enriched or differentially abundant molecular entities were found to be associated with the oxidative stress response, suggesting that a reactive oxygen species (ROS) burst plays a critical role in HI. In support of this, we further discovered that a simple chemical treatment of pollen with ROS reagents could lead to HI. Moreover, we identified ZmPOD65, which encodes a sperm-specific peroxidase, as a new gene controlling HI. Taken together, our study revealed a likely mechanism of HI, discovered a new gene controlling HI, and created a new method for HI in maize, indicating the importance of ROS balance in maintaining normal reproduction and providing a potential route to accelerate crop breeding.

OGDHL Variant rs2293239: A Potential Genetic Driver of Chinese Familial Depressive Disorder.

Depressive disorders are a severe psychiatric and social problem that affect more than 4% of the global population. Depressive disorders have explicit hereditary characteristics; however, the precise driving genetic force behind these disorders has not yet been clearly illustrated. In the present study, we recruited a three-generation Chinese pedigree in which 5 of 17 members had long-term depression. We conducted whole-exome sequencing to identify the genetic mutation profiles of the family, and a list of susceptible genetic variations that were highly associated with depression onset was revealed via multiple omics analysis. In particular, a non-synonymous single nucleotide variation in the oxoglutarate dehydrogenase-like (OGDHL) gene, rs2293239 (p.Asn725Ser), was identified as one of the major driving genetic forces for depression onset in the family. This variant causes an important conformational change in the transketolase domain of OGDHL, thus reducing its binding affinity with the cofactor thiamine pyrophosphate and eventually resulting in the abnormal accumulation of glutamate in the brain. Brain imaging analysis further linked the rs2293239 variant with an enlarged amygdala and cerebellum in depressive family members. In summary, the present study enhances the current genetic understanding of depressive disorders. It also provides new options for prioritizing better clinical therapeutic regimens, as well as identifying a new protein target for the design of highly specific drugs to treat depressive disorders.

N6-Methyladenosine Regulator-Mediated Immue Patterns and Tumor Microenvironment Infiltration Characterization in Glioblastoma.

BackgroundEpigenetic modifications, according to emerging evidence, perform a critical role for cellular immune response and tumorigenesis. Nonetheless, the role of N6-methyladenosine modification in shaping of the glioblastoma tumor microenvironment is unknown.MethodsN6-methyladenosine(m6A) methylation patterns in GBM patients were evaluated via multiple omics analysis of 15 m6A regulators and systematically correlated with tumor immune features. For quantification of N6-methyladenosine methylation patterns of individual patients, GM-score was developed and correlated with clinical and immunological characteristics.ResultsGlioblastoma has two different m6A methylation patterns that are strongly associated with TME characteristics, tumor subtype, immunotherapy response, and patient prognosis. High-GM-score is associated with an immune tolerance phenotype dominated by the IDH1 wild molecular subtype and the Mesenchymal tissue subtype, as well as a high infiltration of immune cells and stromal cells and a poor prognosis. Furthermore, despite higher immune checkpoint expression, individuals with a high-GM-score have a poorer response to anti-CTLA4 immunotherapy regimens due to T-cells dysfunctional. Low-GM-score individuals had an immunodeficient phenotype dominated by IDH mutant molecular subtypes and Proneural tissue subtypes, with less immune cell infiltration and a better prognosis. Furthermore, patients with low-GM-scores had higher microsatellite instability (MSI) and t-cell exclusion scores, as well as a better response to anti-CTLA4 immunotherapy regimens.ConclusionThis study demonstrated that m6A modification patterns play an important role in the shaping of TME complexity and diversity. The GM-score could identify m6A modification patterns in individual patients, resulting in a more personalization and efficacious anti-tumor immunotherapy strategy.

Multiple Omics Analysis of the Rac3 Roles in Different Types of Human Cancer

Rac Family Small GTPase 3 (Rac3) is a member of the Rho family of small GTP-binding proteins which play critical roles in the occurrence, progression, and metastasis of various tumors. Nevertheless, previous studies have focused on a single type of human cancer, so that the roles of Rac3 in different cancer types have not been sufficiently clarified. With the progress of biological detection and bioinformatics technology, the emerging cancer genomics databases make it possible to perform a pan-cancer analysis. Therefore, for the first time, we performed multiple omics analysis to investigate the roles of Rac3 in differential expression, survival prognosis, mutative status, DNA methylation, functions, immune infiltration, and immunotherapy across 33 human cancer types. We found that Rac3 expression was abnormal in 17 cancer types and significantly different in both molecular and immune subtypes of 10 cancers (p<0.05). These Rac3 expression dysregulations in cancer tissues significantly affected their corresponding survival prognosis. Our results also indicated that genetic alterations of Rac3 occurred in 27 cancer types and were significantly associated with prognosis. Moreover, methylation of Rac3 was associated with dysfunctional T-cell phenotypes and affected the prognosis of the brain, melanoma, and breast tumors, and Rac3 Copy Number Alterations (CNA) might affect the infiltration levels of different immune cells in nine cancers. Rac3 and Rac3-related genes were enriched in the axon guidance, actin cytoskeleton regulation, and neurotrophin signaling pathway, and involved the regulation of cellular localization and actin cytoskeleton organization, and small GTPase mediated signal transduction. Then, we further explored the correlations between Rac3 expression and 25 immune cells and cancer-associated fibroblasts across 33 human cancers. Furthermore, we found that Rac3 achieved higher predictive power (AUC>0.5) than three standardized biomarkers of tumor immune responses and was associated with cytotoxic T-cell levels (CTLs) and the risk of immunotherapeutic responses in three cancer types. Collectively, our study contributes to a comprehensive and integrative understanding of the oncogenic roles of Rac3 across human cancers and offers a new clue for treatment strategies.

Annexin-A1 deficiency attenuates stress-induced tumor growth via fatty acid metabolism in mice: an Integrated multiple omics analysis on the stress- microbiome-metabolite-epigenetic-oncology (SMMEO) axis.

Background: High emotional or psychophysical stress levels have been correlated with an increased risk and progression of various diseases. How stress impacts the gut microbiota to influence metabolism and subsequent cancer progression is unclear.Methods: Feces and serum samples from BALB/c ANXA1+/+ and ANXA1-/- mice with or without chronic restraint stress were used for 16S rRNA gene sequencing and GC-MS metabolomics analysis to investigate the effect of stress on microbiome and metabolomics during stress and breast tumorigenesis. Breast tumors samples from stressed and non-stressed mice were used to perform Whole-Genome Bisulfite Sequencing (WGBS) and RNAseq analysis to construct the potential network from candidate hub genes. Finally, machine learning and integrated analysis were used to map the axis from chronic restraint stress to breast cancer development.Results: We report that chronic stress promotes breast tumor growth via a stress-microbiome-metabolite-epigenetic-oncology (SMMEO) axis. Chronic restraint stress in mice alters the microbiome composition and fatty acids metabolism and induces an epigenetic signature in tumors xenografted after stress. Subsequent machine learning and systemic modeling analyses identified a significant correlation among microbiome composition, metabolites, and differentially methylated regions in stressed tumors. Moreover, silencing Annexin-A1 inhibits the changes in the gut microbiome and fatty acid metabolism after stress as well as basal and stress-induced tumor growth.Conclusions: These data support a physiological axis linking the microbiome and metabolites to cancer epigenetics and inflammation. The identification of this axis could propel the next phase of experimental discovery in further understanding the underlying molecular mechanism of tumorigenesis caused by physiological stress.

Age-Related Alterations in DNA Methylation and APETALA2 (AP2) Levels in Herbaceous Peony (Paeonia lactiflora Pall.)

The ornamental and commercial values of herbaceous peony (Paeonia lactiflora Pall.) are directly related to its flower pattern. However, the molecular mechanisms underlying the type formation of P. lactiflora flowers have not been studied in great detail. Previous studies identified, using integrated multipleomics analysis, revealed that APETALA2 (AP2) is an important candidate gene that modulates type formation of P. lactiflora flowers. To further reveal the expression mechanism of AP2 in P. lactiflora petals, we examined the profile of AP2 expression in the inner and outer petals of ‘ZiFengyu’ at various developmental stages using qRT-PCR and BSP+Miseq methylation analysis. Based on our data, the AP2 levels in the outer petals were obviously increased, relative to the inner petals. In addition, the S3 levels at the bloom stage were significantly higher than at the flower-bud stage S1, thereby promoting bloom stage S2, while declining stage S4. Using chromosome walking, the 2000 bp of the 5′-end upstream promoter region was achieved. This region harbored a CpG island (−665∼−872 bp), with multiple essential transcription factor binding sites (TFBS) such as NF-kappa B, GATA-1, Sp1, and C/EBP. Methylation sequencing revealed 7 methylated CpG sites in the CpG island region of the AP2 promoter, thereinto, the methylation ratio of the CpG-3 site in the inner petals was significantly higher than in the outer petals. Correlation analysis revealed a negative association between the level of methylation (CpG-3, CpG-6), and AP2 mRNA expression. CpG-3 was located on the Sp1 transcription factor binding site. Thus, we speculated that the CpG-3 methylation may inhibit transcription factor Sp1 binding to the gene promoter, thereby regulating AP2 expression. Herein, we examined the role of AP2 in the determination of flower patterns in P. lactiflora. Our conclusion will provide theoretical guidance for the molecular breeding of the flower pattern in P. lactiflora.

Abstract 403: FAM210A Maintains Cardiac Mitochondrial Homeostasis Through Regulating Letm1-dependent Ca 2+ Efflux

Mitochondria play fundamental roles in supporting healthy myocardium function. Disturbed cardiac mitochondrial homeostasis causes mitochondrial dysfunction associated with cardiomyopathy in humans and mice. Recent genome-wide association studies (GWAS) discovered that the mutations of FAM210A (family with sequence similarity 210 member A) are associated with sarcopenia and osteoporosis. Interestingly, Fam210a is most highly expressed in the heart and multiple omics analyses in mouse hearts reveal Fam210a as a hub gene in cardiac hypertrophy. However, the molecular function of FAM210A in the heart remains elusive. Here, we discover that FAM210A is critical for maintaining cardiac mitochondrial function and homeostasis. Cardiomyocyte (CM) specific knockout (KO) of Fam210a in adult mice leads to progressive heart failure with enlarged left ventricle chamber and ultimately causes mortality at ~70 days after Fam210a KO. The FAM210A deficient CMs exhibit myofilament disarray at ~9 weeks post Fam210a KO. Moreover, Fam210a KO results in a remarkably elevated mitochondrial ROS production, dramatically compromised mitochondrial membrane potential, and reduced expression of mitochondrial electron transport chain (ETC) complex genes. As a result, the mitochondrial respiratory activity is significantly reduced and the mitochondrial cristae are disrupted in Fam210a KO CMs. In contrast, at the early stage of ~5 weeks post tamoxifen-induced Fam210a KO, we observe increased mitochondrial ROS production, disturbed mitochondrial membrane potential, and reduced respiratory activity in CMs prior to heart failure. Transcriptomic and proteomic analyses from Fam210a KO hearts indicate that FAM210A deficiency causes chronic integrated stress response (ISR) in the heart. Mechanistically, Interactome analyses show that FAM210A binds to mitochondrial Ca 2+ /H + exchanger LETM1 (leucine zipper and EF-hand containing transmembrane protein 1) and regulates LETM1-mediated mitochondrial Ca 2+ efflux. Altogether, we discover a novel function of FAM210A in maintaining the cardiac mitochondrial homeostasis by regulating mitochondrial Ca 2+ efflux, and deficiency of FAM210A causes mitochondrial dysfunction and leads to heart failure.

Abstract P307: An Exquisite Cardiac Performance And Protection Package Emerges In Mouse With Cardiac-specific Overexpression Of Adenylyl Cyclase Type 8

Young adult (three-month old) mice with cardiac-specific overexpression of AC type 8 (TGAC8) have a markedly elevated heart rate and markedly enhanced ejection fraction around the clock, mimicking cardiac responses of sympathetic autonomic input during acute exercise on a chronic base, but the TGAC8 mice do not exhibit heart failure or increased mortality up to about a year. Using this incessant young TGAC8 mouse as an ideal model to elucidate a high grade cardiac “Performance and Protection Package” (PPP) in response to chronic cardiac stress, we hypothesized that the TGAC8 heart adjusts to the chronical stress by reprogramming itself at multiple omics scales to code the exquisite cardiac PPP. To this end, we compared three-month old TGAC8 mice and their wildtype (WT) littermates using multiple omics analyses, from transcriptome to proteome, to phosphoproteome. Compared to WT, the phosphorylation level of most proteins was increased in the TGAC8 mice, including transcription factors (TF), kinases and phosphatases that are important in regulating transcription and phosphorylation. Among the 191 TFs identified in phosphoproteome, 91 were increased significantly, in line with the general upregulation in transcriptome. Many important stress response signaling pathways were enriched from phosphoproteome. Wherein, three protein quality control pathways, PI3K/AKT signaling, ERK/MAPK signaling and ubiquitination, were consistently enriched across the three omics scales. Most components in PI3K/AKT signaling pathway were upregulated, especially at protein and phosphorylation levels. Consistently, PI3K/AKT substrate phosphopeptides were increased, and downstream effects and functions of PI3K/AKT signaling were activated, including energy metabolism, protein synthesis, cell growth, cardiovascular functions, and NF-kB mediated functions. In summary, profiling the transcriptome, proteome and phosphoproteome of the TGAC8 heart unraveled the mechanism that controls its PPP. The cardiac overexpression of AC8 activates the AC8-cAMP-PKA axis to increase phosphorylation; widespread phosphorylation of the TFs promotes the transcription of numerous additional molecules that also regulate phosphorylation to reprogram the heart. Thereby, the TGAC8 mouse upregulates many stress response signaling pathways to activate the exquisite cardiac PPP.

A Genome Doubling Event Reshapes Rice Morphology and Products by Modulating Chromatin Signatures and Gene Expression Profiling

Evolutionarily, polyploidy represents a smart method for adjusting agronomically important in crops through impacts on genomic abundance and chromatin condensation. Autopolyploids have a relatively concise genetic background with great diversity and provide an ideal system to understand genetic and epigenetic mechanisms attributed to the genome-dosage effect. However, whether and how genome duplication events during autopolyploidization impact chromatin signatures are less understood in crops. To address it, we generated an autotetraploid rice line from a diploid progenitor, Oryza sativa ssp. indica 93-11. Using transposase-accessible chromatin sequencing, we found that autopolyploids lead to a higher number of accessible chromatin regions (ACRs) in euchromatin, most of which encode protein-coding genes. As expected, the profiling of ACR densities supported that the effect of ACRs on transcriptional gene activities relies on their positions in the rice genome, regardless of genome doubling. However, we noticed that genome duplication favors genic ACRs as the main drivers of transcriptional changes. In addition, we probed intricate crosstalk among various kinds of epigenetic marks and expression patterns of ACR-associated gene expression in both diploid and autotetraploid rice plants by integrating multiple-omics analyses, including chromatin immunoprecipitation sequencing and RNA-seq. Our data suggested that the combination of H3K36me2 and H3K36me3 may be associated with dynamic perturbation of ACRs introduced by autopolyploidization. As a consequence, we found that numerous metabolites were stimulated by genome doubling. Collectively, our findings suggest that autotetraploids reshape rice morphology and products by modulating chromatin signatures and transcriptional profiling, resulting in a pragmatic means of crop genetic improvement.

A multi-modal data harmonisation approach for discovery of COVID-19 drug targets.

Despite the volume of experiments performed and data available, the complex biology of coronavirus SARS-COV-2 is not yet fully understood. Existing molecular profiling studies have focused on analysing functional omics data of a single type, which captures changes in a small subset of the molecular perturbations caused by the virus. As the logical next step, results from multiple such omics analysis may be aggregated to comprehensively interpret the molecular mechanisms of SARS-CoV-2. An alternative approach is to integrate data simultaneously in a parallel fashion to highlight the inter-relationships of disease-driving biomolecules, in contrast to comparing processed information from each omics level separately. We demonstrate that valuable information may be masked by using the former fragmented views in analysis, and biomarkers resulting from such an approach cannot provide a systematic understanding of the disease aetiology. Hence, we present a generic, reproducible and flexible open-access data harmonisation framework that can be scaled out to future multi-omics analysis to study a phenotype in a holistic manner. The pipeline source code, detailed documentation and automated version as a R package are accessible. To demonstrate the effectiveness of our pipeline, we applied it to a drug screening task. We integrated multi-omics data to find the lowest level of statistical associations between data features in two case studies. Strongly correlated features within each of these two datasets were used for drug–target analysis, resulting in a list of 84 drug–target candidates. Further computational docking and toxicity analyses revealed seven high-confidence targets, amsacrine, bosutinib, ceritinib, crizotinib, nintedanib and sunitinib as potential starting points for drug therapy and development.

Is Neuron-Vascular Communication Disturbed in the Delayed Prenatal Brain Development of a Mouse Model of Down Syndrome?

Developmental retardation of the brain with reduced cortical neurogenesis is observed in Ts1Cje mice, a model of Down syndrome (DS) as it is in people with DS; however, the mechanisms and the responsible gene(s) remain unknown. The goal of the present study is to establish a therapeutic approach for treating the delayed brain development in DS. To achieve this, we have utilized multiple OMICS analyses, including proteomics and transcriptomics, to uncover the molecular alterations in the brains of DS model mice. Furthermore, we have elucidated that a transcriptional factor, the Erg gene, which is coded in the trisomic region, contributed to reduced cortical neurogenesis in the embryo of a DS mouse model by a molecular genetic technique, the "in vivo gene subtraction method". In the current review, I will introduce our recent work, the identification of the gene responsible for delayed brain development in the DS mouse model and will discuss the possibility that blood vessel dysfunction may be associated with reduced embryonic neurogenesis in DS.

Genome-wide identification and expression profiling revealed tissue-specific inducible expression of cytochrome P450s conferring cadmium tolerance in the Pacific oyster, Crassostrea gigas

Cytochrome P450s (CYPs) are present in almost all organisms and play critical roles in metabolism of endogenous substrates and detoxification of xenobiotic compounds. Oysters are a group of bivalves that are important in marine ecosystem and aquaculture program, adapting to the harsh environment in intertidal zones. The studies on CYPs and their potential involvement in dealing with toxic xenobiotics in oysters were limited. In the present study, we performed a multiple omics analyses and identified a full-set of 123 CYP genes in the Pacific oyster, Crassostrea gigas. These CYP genes were classified into 5 clans and 16 families. The phylogenetic tree constructed with other species showed extensive gene expansion of CYPs in the clan 2 and mitochondrial clan in the C. gigas. The amino acid sequence analysis showed conserved typical motifs of CYP genes. The expression profiles of CYPs quantified across different tissues (gill and digestive gland) at various time points (0d, 0.5d, 7d, 14d, 28d) revealed their roles in response to Cd exposure. Notably, CYP17A1-like_6 and CYP2C50 were expressed at significantly higher levels compared with other CYP genes, suggesting their crucial roles in the detoxification of Cd in the C. gigas. This work provides valuable information toward understanding of CYP-mediated detoxification of cadmium in mollusks, and will be important for surveillance of marine environment pollution and seafood safety.

Accessible chromatin regions and their functional interrelations with gene transcription and epigenetic modifications in sorghum genome

Accessible chromatin regions (ACRs) provide physical scaffolds to recruit transcriptional co-regulators and displace their nearby nucleosomes in multiple plant species. Characterization of ACRs and investigation of their biological effects in Sorghum bicolor has lagged behind. Regulation of gene expression relies on the transcriptional co-regulators that are recruited to ACRs to affect epigenomic modifications of surrounding nucleosomes. In this study, we employed transposase-accessible chromatin sequencing to identify ACRs and decipher how the presence of ACRs affects gene expression and epigenetic signatures in the Sorghum genome. As a result, 21 077 ACRs, which are mapped to 22.9% of genes and 2.7% of repeats, were identified. The profiling of ACRs on gene structures reveals a narrow and sharp peak around the transcription start site, with relatively weak and broad signals covering the entire gene body and an explicit but wide peak from the transcription termination site to its downstream regions. We discovered that the correlations between gene expression levels and profiled ACR densities are dependent on the positions of ACRs. The occurrence of genic ACRs cumulatively enhances the transcriptional activity of intergenic ACR-associated genes. In addition, an intricate crosstalk among ACRs, gene expression, and epigenetic marks has been unveiled by integrating multiple-omics analyses of whole-genome bisulfite sequencing, 6mA immunoprecipitation followed by sequencing, RNA sequencing, chromatin immunoprecipitation sequencing, and DNase I hypersensitive sites sequencing datasets. Our study provides a genome-wide landscape of ACRs in sorghum, decrypts their interrelations with various epigenetic marks, and sheds new light on their roles in transcriptional regulation.