Development-related Pathways Research Articles

Negative effects of polyvinyl chloride microplastics and the plasticizer DnOP on earthworms: Co-exposure enhances oxidative stress and immune system damage in earthworms

Polyvinyl chloride microplastics (PVC-MPs) are the most used plastics in agriculture. Di-n-octyl phthalate (DnOP), a commonly used plasticizer in PVC-MPs, may be released from plastic and coexist with PVC-MPs. The effects of DnOP alone and coexisting with PVC-MPs are not known. We evaluated the effects of DnOP or/and PVC-MPs on earthworms, and used integrated biomarker response (IBR) to assess the combined toxicity. Molecular docking and transcriptomics were employed for further interpretation of possible toxicity mechanisms. The results showed that exposure to DnOP or/and PVC-MPs caused oxidative damage and interfered with reproduction, adversely affecting the growth and reproduction of earthworms. IBR results showed that toxicity of DnOP+PVC-MPs exposure was greater than that of DnOP and PVC-MPs exposure alone. DnOP has the ability to directly bind to proteins that are associated with antioxidant enzymes and alter their structure. The transcriptomics results indicated that DnOP and PVC-MPs exposure alone mainly affected growth and development-related pathways, while co-exposure affected apoptosis and immune system-related pathways more. To the best of our knowledge, this is the first comprehensive investigation of the combined toxicity of DnOP or/and PVC-MPs to earthworms from different perspectives, which gives scientifically sound evidence for the rational use of plasticizers DnOP and PVC-MPs.

Unveiling the role of circRBBP7 in myoblast proliferation and differentiation: A novel regulator of muscle development.

Muscle development is a multistep process regulated by diverse gene networks, and circRNAs are considered novel regulators mediating myogenesis. Here, we systematically analyzed the role and underlying regulatory mechanisms of circRBBP7 in myoblast proliferation and differentiation. Results showed that circRBBP7 has a typical circular structure and encodes a 13 -kDa protein. By performing circRBBP7 overexpression and RNA interference, we found that the function of circRBBP7 was positively correlated with the proliferation and differentiation of myoblasts. Using RNA sequencing, we identified 1633 and 532 differentially expressed genes (DEGs) during myoblast proliferation or differentiation, respectively. The DEGs were found mainly enriched in cell cycle- and skeletal muscle development-related pathways, such as the MDM2/p53 and PI3K-Akt signaling pathways. Further co-IP and IF co-localization analysis revealed that VEGFR-1 is a target of circRBBP7 in myoblasts. qRT-PCR and WB analysis further confirmed the positive correlation between VEGFR-1 and circRBBP7. Moreover, we found that invivo transfection of circRBBP7 into injured muscle tissues significantly promoted the regeneration and repair of myofibers in mice. Therefore, we speculate that circRBBP7 may affect the activity of MDM2 by targeting VEGFR-1, altering the expression of muscle development-related genes by mediating p53 degradation, and ultimately promoting myoblast development and muscle regeneration. This study provides essential evidence that circRBBP7 can serve as a potential target for myogenesis regulation and a reference for the application of circRBBP7 in cattle genetic breeding and muscle injury treatment.

Integrative analysis of Iso-Seq and RNA-seq data reveals transcriptome complexity and differential isoform in skin tissues of different hair length Yak

BackgroundThe hair follicle development process is regulated by sophisticated genes and signaling networks, and the hair grows from the hair follicle. The Tianzhu white yak population exhibits differences in hair length, especially on the forehead and shoulder region. However, the genetic mechanism is still unclear. Isoform sequencing (Iso-seq) technology with advantages in long reads sequencing. Hence, we combined the Iso-seq and RNA-seq methods to investigate the transcript complexity and difference between long-haired yak (LHY) and normal-haired yak (NHY).ResultsThe hair length measurement result showed a significant difference between LHY and NHY on the forehead and the shoulder (P-value < 0.001). The skin samples from the forehead and the shoulder of LHY and NHY were pooled for isoform sequencing (Iso-seq). We obtained numerous long transcripts, including novel isoforms, long non-coding RNA, alternative splicing events, and alternative polyadenylation events. Combined with RNA-seq data, we performed differential isoforms (DEIs) analysis between LHY and NHY. We found that some hair follicle and skin development-related DEIs, like BMP4, KRT2, IGF2R, and COL1A2 in the forehead skin; BMP1, KRT1, FGF5, COL2A1, and IGFBP5 in the shoulder skin. Enrichment analysis revealed that DEIs in both two comparable groups significantly participated in skin and hair follicle development-related pathways, like ECM-receptor interaction, focal adhesion, and PI3K-Akt signaling pathways. The results indicated that the hair follicle development of Tianzhu white yak may influence the hair length difference. Besides, the protein-protein interaction (PPI) network of DEIs showed COL2A1 and COL3A1 exhibited a high degree of centrality, and these two genes were suggested as potential candidates for the hair length growth of Tianzhu white yak.ConclusionsThe results provided a comprehensive analysis of the transcriptome complexity and identified differential transcripts that enhance our understanding of the molecular mechanisms underlying the variation in hair length growth in Tianzhu white yak.

Strand-Specific RNA Sequencing Reveals Gene Expression Patterns in F1 Chick Breast Muscle and Liver after Hatching.

Heterosis refers to the phenomenon where hybrids exhibit superior performance compared to the parental phenotypes and has been widely utilized in crossbreeding programs for animals and crops, yet the molecular mechanisms underlying this phenomenon remain enigmatic. A better understanding of the gene expression patterns in post-hatch chickens is very important for exploring the genetic basis underlying economically important traits in the crossbreeding of chickens. In this study, breast muscle and liver tissues (n = 36) from full-sib F1 birds and their parental pure lines were selected to identify gene expression patterns and differentially expressed genes (DEGs) at 28 days of age by strand-specific RNA sequencing (ssRNA-seq). This study indicates that additivity is the predominant gene expression pattern in the F1 chicken post-hatch breast muscle (80.6% genes with additivity) and liver (94.2% genes with additivity). In breast muscle, Gene Ontology (GO) enrichment analysis revealed that a total of 11 biological process (BP) terms closely associated with growth and development were annotated in the identified DEG sets and non-additive gene sets, including STAT5A, TGFB2, FGF1, IGF2, DMA, FGF16, FGF12, STAC3, GSK3A, and GRB2. Kyoto Encyclopedia of Genes and Genomes (KEGG) annotation presented that a total of six growth- and development-related pathways were identified, involving key genes such as SLC27A4, GLUL, TGFB2, COX17, and GSK3A, including the PPAR signaling pathway, TGF-beta signaling pathway, and mTOR signaling pathway. Our results may provide a theoretical basis for crossbreeding in domestic animals.

Conserved and specific gene expression patterns in the embryonic development of tardigrades.

Tardigrades, commonly known as water bears, are enigmatic organisms characterized by their remarkable resilience to extreme environments despite their simple and compact body structure. To date, there is still much to understand about their evolutionary and developmental features contributing to their special body plan and abilities. This research provides preliminary insights on the conserved and specific gene expression patterns during embryonic development of water bears, focusing on the species Hypsibius exemplaris. The developmental dynamic expression analysis of the genes with various evolutionary age grades indicated that the mid-conserved stage of H. exemplaris corresponds to the period of ganglia and midgut development, with the late embryonic stage showing a transition from non-conserved to conserved state. Additionally, a comparison with Drosophila melanogaster highlighted the absence of certain pathway nodes in development-related pathways, such as Maml and Hairless, which are respectively the transcriptional co-activator and co-repressor of NOTCH regulated genes. We also employed Weighted Gene Co-expression Network Analysis (WGCNA) to investigate the expression patterns of tardigrade-specific genes during embryo development. Our findings indicated that the module containing the highest proportion of tardigrade-specific genes (TSGs) exhibits high expression levels before the mid-conserved stage, potentially playing a role in glutathione and lipid metabolism. These functions may be associated to the ecdysone synthesis and storage cell formation, which is unique to tardigrades.

DIA-Based Proteomic Analysis Reveals MYOZ2 as a Key Protein Affecting Muscle Growth and Development in Hybrid Sheep.

Hybridization of livestock can be used to improve varieties, and different hybrid combinations produce unique breeding effects. In this study, male Southdown and Suffolk sheep were selected to hybridize with female Hu sheep to explore the effects of male parentage on muscle growth and the development of offspring. Using data-independent acquisition technology, we identified 119, 187, and 26 differentially abundant proteins (DAPs) between Hu × Hu (HH) versus Southdown × Hu (NH), HH versus Suffolk × Hu (SH), and NH versus SH crosses. Two DAPs, MYOZ2 and MYOM3, were common to the three hybrid groups and were mainly enriched in muscle growth and development-related pathways. At the myoblast proliferation stage, MYOZ2 expression decreased cell viability and inhibited proliferation. At the myoblast differentiation stage, MYOZ2 expression promoted myoblast fusion and enhanced the level of cell fusion. These findings provide new insights into the key proteins and metabolic pathways involved in the effect of male parentage on muscle growth and the development of hybrid offspring in sheep.

LUM as a novel prognostic marker and its correlation with immune infiltration in gastric cancer: a study based on immunohistochemical analysis and bioinformatics

BackgroundGastric cancer (GC) is considered the sixth highly prevailing malignant neoplasm and is ranked third in terms of cancer mortality rates. To enable an early and efficient diagnosis of GC, it is important to detect the fundamental processes involved in the oncogenesis and progression of gastric malignancy. The understanding of molecular signaling pathways can facilitate the development of more effective therapeutic strategies for GC patients.MethodsThe screening of genes that exhibited differential expression in early and advanced GC was performed utilizing the Gene Expression Omnibus databases (GSE3438). Based on this, the protein and protein interaction network was constructed to screen for hub genes. The resulting list of hub genes was evaluated with bioinformatic analysis and selected genes were validated the protein expression by immunohistochemistry (IHC). Finally, a competing endogenous RNA network of GC was constructed.ResultsThe three genes (ITGB1, LUM, and COL5A2) overexpressed in both early and advanced GC were identified for the first time. Their upregulation has been linked with worse overall survival (OS) time in patients with GC. Only LUM was identified as an independent risk factor for OS among GC patients by means of additional analysis. IHC results demonstrated that the expression of LUM protein was increased in GC tissue, and was positively associated with the pathological T stage. LUM expression can effectively differentiate tumorous tissue from normal tissue (area under the curve = 0.743). The area under 1-, 3-, and 5-year survival relative operating characteristics were greater than 0.6. Biological function enrichment analyses suggested that the genes related to LUM expression were involved in extracellular matrix development-related pathways and enriched in several cancer-related pathways. LUM affects the infiltration degree of cells linked to the immune system in the tumor microenvironment. In GC progression, the AC117386.2/hsa-miR-378c/LUM regulatory axis was also identified.ConclusionCollectively, a thorough bioinformatics analysis was carried out and an AC117386.2/hsa-miR-378c/LUM regulatory axis in the stomach adenocarcinoma dataset was detected. These findings should serve as a guide for future experimental investigations and warrant confirmation from larger studies.

Longitudinal development of the human white matter structural connectome and its association with brain transcriptomic and cellular architecture

From childhood to adolescence, the spatiotemporal development pattern of the human brain white matter connectome and its underlying transcriptomic and cellular mechanisms remain largely unknown. With a longitudinal diffusion MRI cohort of 604 participants, we map the developmental trajectory of the white matter connectome from global to regional levels and identify that most brain network properties followed a linear developmental trajectory. Importantly, connectome-transcriptomic analysis reveals that the spatial development pattern of white matter connectome is potentially regulated by the transcriptomic architecture, with positively correlated genes involve in ion transport- and development-related pathways expressed in excitatory and inhibitory neurons, and negatively correlated genes enriches in synapse- and development-related pathways expressed in astrocytes, inhibitory neurons and microglia. Additionally, the macroscale developmental pattern is also associated with myelin content and thicknesses of specific laminas. These findings offer insights into the underlying genetics and neural mechanisms of macroscale white matter connectome development from childhood to adolescence.

Exosomal derived miR-1246 from hydroquinone-transformed cells drives S phase accumulation arrest by targeting cyclin G2 in TK6 cells

BackgroundHydroquinone (HQ), a major metabolite of benzene and known hematotoxic carcinogen. MicroRNA 1246 (miR-1246), an oncogene, regulates target genes in carcinogenesis including leukemia. This study investigates the impact of exosomal derived miR-1246 from HQ-transformed (HQ19) cells on cell-to-cell communication in recipient TK6 cells. MethodsRNA sequencing was used to identify differentially expressed exosomal miRNAs in HQ19 cells and its phosphate buffered solution control cells (PBS19), which were then confirmed using qRT-PCR. The impact of exosomal miR-1246 derived from HQ-transformed cells on cell cycle distribution was investigated in recipient TK6 cells. ResultsRNA sequencing analysis revealed that 34 exosomal miRNAs were upregulated and 158 miRNAs were downregulated in HQ19 cells compared with PBS19 cells. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses predicted that their targets are enriched in cancer development-related pathways, such as MAPK signaling, microRNAs in cancer, apoptosis, PI3K-Akt signaling, cell cycle, Ras signaling, and Chronic myeloid leukemia. Eleven miRNAs were confirmed to have differential expression through qRT-PCR, with 6 upregulated (miR-140–3p, miR-551b-3p, miR-7-5p, miR-1290, miR-92a-3p, and miR-1246) and 5 downregulated (miR-183–5p, miR-26a-5p, miR-30c-5p, miR-205–5p, and miR-99b-3p). Among these, miR-1246 exhibited the highest expression level. HQ exposure resulted in a concentration-dependent increase in miR-1246 levels and decrease Cyclin G2 (CCNG2) levels in TK6 cells. Similarly, exosomes from HQ19 exhibited similar effects as HQ exposure. Dual luciferase reporter gene assays indicated that miR-1246 could band to CCNG2. After HQ exposure, exosomal miR-1246 induced cell cycle arrest at the S phase, elevating the expression of genes like pRb, E2F1, and Cyclin D1 associated with S phase checkpoint. However, silencing miR-1246 caused G2/M-phase arrest. ConclusionHQ-transformed cells’ exosomal miR-1246 targets CCNG2, regulating TK6 cell cycle arrest, highlighting its potential as a biomarker for HQ-induced malignant transformation.

LncRNAs regulate the cyclic growth and development of hair follicles in Dorper sheep.

Hair follicles in Dorper sheep are characterized by seasonal cyclic growth and development, consequently resulting in hair shedding during spring. The cyclic growth and development of hair follicles are regulated by several influencing factors such as photoperiods, hormones, age of the animal, genes, long non-coding RNAs (lncRNAs), and signaling pathways. In the present study, skin samples of five shedding sheep (S), used as experimental animals, and three non-shedding sheep (N), used as controls, were collected at three time points (September 27, 2019; January 3, 2020; and March 17, 2020) for RNA sequencing (RNA-seq) technology. Nine different groups (S1-vs-S2, S1-vs-S3, S2-vs-S3, N1- vs-N2, N1-vs-N3, N2-vs-N3, S1-vs-N1, S2-vs-N2, and S3-vs-N3) were compared using FDR < 0.05 and log 21 FC >as thresholds to assess the differences in the expression of lncRNAs. In total, 395 differentially expressed (DE) lncRNAs were screened. Cluster heatmap analysis identified two types of expression patterns, namely, high expression during the anagen phase (A pattern) and high expression during the telogen phase (T pattern). Gene Ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses revealed that the target genes were largely enriched in the Estrogen signaling pathway, PI3K-Akt signaling pathway, Fc gamma R-mediated phagocytosis, and cell adhesion molecules (CAMs), which are associated with hair follicle cyclic growth and development-related pathways. In addition, 17 pairs of lncRNAs-target genes related to hair follicle cyclic growth and development were screened, and a regulatory network was constructed. Altogether, candidate lncRNAs and their regulated target genes were screened that contributed to sheep hair follicle cyclic growth and development. We believe these findings will provide useful insights into the underlying regulatory mechanisms.

Integrated analysis of copy number variation-associated lncRNAs identifies candidates contributing to the etiologies of congenital kidney anomalies

Congenital anomalies of the kidney and urinary tract (CAKUT) are disorders resulting from defects in the development of the kidneys and their outflow tract. Copy number variations (CNVs) have been identified as important genetic variations leading to CAKUT, whereas most CAKUT-associated CNVs cannot be attributed to a specific pathogenic gene. Here we construct coexpression networks involving long noncoding RNAs (lncRNAs) within these CNVs (CNV-lncRNAs) using human kidney developmental transcriptomic data. The results show that CNV-lncRNAs encompassed in recurrent CAKUT associated CNVs have highly correlated expression with CAKUT genes in the developing kidneys. The regulatory effects of two hub CNV-lncRNAs (HSALNG0134318 in 22q11.2 and HSALNG0115943 in 17q12) in the module most significantly enriched in known CAKUT genes (CAKUT_sig1, P = 1.150 × 10−6) are validated experimentally. Our results indicate that the reduction of CNV-lncRNAs can downregulate CAKUT genes as predicted by our computational analyses. Furthermore, knockdown of HSALNG0134318 would downregulate HSALNG0115943 and affect kidney development related pathways. The results also indicate that the CAKUT_sig1 module has function significance involving multi-organ development. Overall, our findings suggest that CNV-lncRNAs play roles in regulating CAKUT genes, and the etiologies of CAKUT-associated CNVs should take account of effects on the noncoding genome.

Exogenous zinc mitigates salinity stress by stimulating proline metabolism in proso millet (Panicum miliaceum L.).

Salinity is one of the most concerning ecological restrictions influencing plant growth, which poses a devastating threat to global agriculture. Surplus quantities of ROS generated under stress conditions have negative effects on plants' growth and survival by damaging cellular components, including nucleic acids, lipids, proteins and carbohydrates. However, low levels of ROS are also necessary because of their role as signalling molecules in various development-related pathways. Plants possess sophisticated antioxidant systems for scavenging as well as regulating ROS levels to protect cells from damage. Proline is one such crucial non-enzymatic osmolyte of antioxidant machinery that functions in the reduction of stress. There has been extensive research on improving the tolerance, effectiveness, and protection of plants against stress, and to date, various substances have been used to mitigate the adverse effects of salt. In the present study Zinc (Zn) was applied to elucidate its effect on proline metabolism and stress-responsive mechanisms in proso millet. The results of our study indicate the negative impact on growth and development with increasing treatments of NaCl. However, the low doses of exogenous Zn proved beneficial in mitigating the effects of NaCl by improving morphological and biochemical features. In salt-treated plants, the low doses of Zn (1 mg/L, 2 mg/L) rescued the negative impact of salt (150mM) as evidenced by increase in shoot length (SL) by 7.26% and 25.5%, root length (RL) by 21.84% and 39.07% and membrane stability index (MSI) by 132.57% and 151.58% respectively.The proline content improved at all concentrations with maximum increase of 66.65% at 2 mg/L Zn. Similarly, the low doses of Zn also rescued the salt induced stress at 200mM NaCl. The enzymes related to proline biosynthesis were also improved at lower doses of Zn. In salt treated plants (150mM), Zn (1 mg/L, 2 mg/L) increased the activity of P5CS by 19.344% and 21%. The P5CR and OAT activities were also improved with maximum increase of 21.66% and 21.84% at 2 mg/L Zn respectively. Similarly, the low doses of Zn also increased the activities of P5CS, P5CR and OAT at 200mM NaCl. Whereas P5CDH enzyme activity showed a decrease of 82.5% at 2mg/L Zn+150mM NaCl and 56.7% at 2mg/L Zn+200 mM NaCl. These results strongly imply the modulatory role of Zn in maintaining of proline pool during NaCl stress.

Dermal PapillaCell-Derived Exosomes Regulate Hair Follicle Stem Cell Proliferation via LEF1.

Hair follicle (HF) growth and development are controlled by various cell types, including hair follicle stem cells (HFSCs) and dermal papilla cells (DPCs). Exosomes are nanostructures that participate in many biological processes. Accumulating evidence indicates that DPC-derived exosomes (DPC-Exos) mediate HFSC proliferation and differentiation during the cyclical growth of hair follicles. In this study, we found that DPC-Exos increase ki67 expression and CCK8 cell viability readouts in HFSCs but reduce annexin staining of apoptotic cells. RNA sequencing of DPC-Exos-treated HFSCs identified 3702 significantly differentially expressed genes (DEGs), including BMP4, LEF1, IGF1R, TGFβ3, TGFα, and KRT17. These DEGs were enriched in HF growth- and development-related pathways. We further verified the function of LEF1 and showed that overexpression of LEF1 increased the expression of HF development-related genes and proteins, enhanced HFSC proliferation, and reduced HFSC apoptosis, while knockdown of LEF1 reversed these effects. DPC-Exos could also rescue the siRNA-LEF1 effect in HFSCs. In conclusion, this study demonstrates that DPC-Exos mediated cell-to-cell communication can regulate HFSCs proliferation by stimulating LEF1 and provide novel insights into HF growth and development regulatory mechanisms.

Identification of circular RNAs as regulators and noninvasive biomarkers for placenta accreta spectrum.

Placenta accreta spectrum (PAS) has an urgent need for reliable prenatal biomarkers. This study profiled the circular RNAs (circRNAs) in PAS placenta and maternal blood and identified two circRNAs can regulate trophoblast cells invasion and serve as noninvasive prenatal biomarkers for PAS prediction. PAS is one of the most alarming obstetric diseases with high mortality rates. The regulating mechanism underlying PAS remains to be investigated, and reliable blood biomarkers for PAS have not emerged. Circular RNAs (circRNAs) have become important regulators and biomarkers for disparate human diseases. However, the circRNA profiles of PAS were not reported, and the regulatory role and predictive value of circRNAs in PAS were unknown. Here, we comprehensively profiled the circRNAs in the placenta of PAS by transcriptome sequencing and analysis and uncovered 217 abnormally expressed circRNAs. Through competing endogenous RNA network analysis, we found that the target genes of upregulated circRNAs in PAS were enriched in placenta development-related pathways and further uncovered two circRNAs, circPHACTR4 and circZMYM4, that could regulate trophoblast cells invasion and migration in vitro. Finally, we verified that circPHACTR4 and circZMYM4 were also upregulated in the maternal peripheral blood of PAS women before delivery using transcriptome sequencing and RT-qPCR and evaluated their predictive value by ROC curves. We found that circPHACTR4 and circZMYM4 could serve as effective predicting biomarkers for PAS (area under the curve (AUC): 0.86 and 0.85) and propose an improved model for PAS prenatal prediction by combining the conventional ultrasound diagnosis with the new circRNA predictive factors (AUC: 0.91, specificity: 0.89, sensitivity: 0.82).Altogether, this work provides new resources for deciphering the biological roles of circRNAs in PAS, identified two circRNAs that could regulate trophoblast cells invasion during placentation, and revealed two noninvasive diagnostic markers for PAS.

Functional Characterization of the Cystine-Rich-Receptor-like Kinases (CRKs) and Their Expression Response to Sclerotinia sclerotiorum and Abiotic Stresses in Brassica napus.

Cysteine-rich receptor-like kinases (CRKs) are transmembrane proteins that bind to the calcium ion to regulate stress-signaling and plant development-related pathways, as indicated by several pieces of evidence. However, the CRK gene family hasn't been inadequately examined in Brassica napus. In our study, 27 members of the CRK gene family were identified in Brassica napus, which are categorized into three phylogenetic groups and display synteny relationship to the Arabidopsis thaliana orthologs. All the CRK genes contain highly conserved N-terminal PKINASE domain; however, the distribution of motifs and gene structure were variable conserved. The functional divergence analysis between BnaCRK groups indicates a shift in evolutionary rate after duplication events, demonstrating that BnaCRKs might direct a specific function. RNA-Seq datasets and quantitative real-time PCR (qRT-PCR) exhibit the complex expression profile of the BnaCRKs in plant tissues under multiple stresses. Nevertheless, BnaA06CRK6-1 and BnaA08CRK8 from group B were perceived to play a predominant role in the Brassica napus stress signaling pathway in response to drought, salinity, and Sclerotinia sclerotiorum infection. Insights gained from this study improve our knowledge about the Brassica napus&amp;nbsp;CRK gene family and provide a basis for enhancing the quality of rapeseed.

Novel Potential Therapeutic Targets of PTPN Families for Lung Cancer.

Despite the treatment of lung adenocarcinoma (LUAD) having partially improved in recent years, LUAD patients still have poor prognosis rates. Therefore, it is especially important to explore effective biomarkers and exploit novel therapeutic developments. High-throughput technologies are widely used as systematic approaches to explore differences in expressions of thousands of genes for both biological and genomic systems. Recently, using big data analyses in biomedicine research by integrating several high-throughput databases and tools, including The Cancer Genome Atlas (TCGA), cBioportal, Oncomine, and Kaplan-Meier plotter, is an important strategy to identify novel biomarkers for cancer therapy. Here, we used two different comprehensive bioinformatics analysis and revealed protein tyrosine phosphatase non-receptor type (PTPN) family genes, especially PTPN1 and PTPN22, were downregulated in lung cancer tissue in comparison with normal samples. The survival curves indicated that LUAD patients with high transcription levels of PTPN5 were significantly associated with a good prognosis. Meanwhile, Gene Ontology (GO) and MetaCore analyses indicated that co-expression of the PTPN1, PTPN5, and PTPN21 genes was significantly enriched in cancer development-related pathways, including GTPase activity, regulation of small GTPase-mediated signal transduction, response to mechanical stimuli, vasculogenesis, organ morphogenesis, regulation of stress fiber assembly, mitogen-activated protein kinase (MAPK) cascade, cell migration, and angiogenesis. Collectively, this study revealed that PTPN family members are both significant prognostic biomarkers for lung cancer progression and promising clinical therapeutic targets, which provide new targets for treating LUAD patients.

A Comprehensive Study of De Novo Mutations on the Protein-Protein Interaction Interfaces Provides New Insights into Developmental Delay.

Mutations, especially those at the protein-protein interaction (PPI) interface, have been associated with various diseases. Meanwhile, though de novo mutations (DNMs) have been proven important in neuropsychiatric disorders, such as developmental delay (DD), the relationship between PPI interface DNMs and DD has not been well studied. Here we curated developmental delay DNM datasets from the PsyMuKB database and showed that DD patients showed a higher rate and deleteriousness in DNM missense on the PPI interface than sibling control. Next, we identified 302 DD-related PsychiPPIs, defined as PPIs harboring a statistically significant number of DNM missenses at their interface, and 42 DD candidate genes from PsychiPPI. We observed that PsychiPPIs preferentially affected the human protein interactome network hub proteins. When analyzing DD candidate genes using gene ontology and gene spatio-expression, we found that PsychiPPI genes carrying PPI interface mutations, such as FGFR3 and ALOX5, were enriched in development-related pathways and the development of the neocortex, and cerebellar cortex, suggesting their potential involvement in the etiology of DD. Our results demonstrated that DD patients carried an excess burden of PPI-truncating DNM, which could be used to efficiently search for disease-related genes and mutations in large-scale sequencing studies. In conclusion, our comprehensive study indicated the significant role of PPI interface DNMs in developmental delay pathogenicity.

Cis- and trans-regulation by histone H4 basic patch R17/R19 in metazoan development.

The histone H4 basic patch is critical for chromatin structure and regulation of the chromatin machinery. However, the biological roles of these positively charged residues and the mechanisms by which they regulate gene expression remain unclear. In this study, we used histone mutagenesis to investigate the physiological function and downstream regulatory genes of H4 residues R17 and R19 in Drosophila. We found all histone mutations including R17A/E/H and R19A/E/H (R17 and R19 of H4 are substituted by A, E and H respectively) result in a range of growth defects and abnormalities in chromosomal high-order structures, whereas R17E mutation is embryonic lethal. RNA-seq demonstrates that downregulated genes in both R17A and R19A show significant overlap and are enriched in development-related pathways. In addition, Western and cytological analyses showed that the R17A mutation resulted in a significant reduction in H4K16 acetylation and male offspring, implying that the R17 may be involved in male dosage compensation mechanisms. R19 mutation on the other hand strongly affect Gpp (Dot1 homologue in flies)-mediated H3K79 methylation, possibly through histone crosstalk. Together these results provide insights into the differential impacts of positive charges of H4 basic patch R17/R19 on regulation of gene transcription during developmental processes.

Genome-wide detection of RNA editing events during the hair follicles cycle of Tianzhu white yak

BackgroundThe hair coat is available for the yak to live in the harsh environment of the plateau. Besides, improving the hair production of yak is necessary for its textile industry development. Hair grows from hair follicles (HFs). The HFs undergo periodic growth after birth and are regulated by the complex gene regulatory network. However, the molecular mechanism of HFs regeneration in the Tianzhu white yak remains unclear. RNA editing is a post-transcriptional mechanism that regulates gene expression and produces new transcripts. Hence, we investigated the influence of the A-to-I RNA editing events on the HFs cycle of the Tianzhu white yak.ResultsWe finally identified 54,707 adenosine-to-inosine (A-to-I) RNA editing sites (RESs) from RNA sequencing data of the HFs cycle in the Tianzhu white yak. Annotation results showed RESs caused missense amino acid changes in 7 known genes. And 202 A-to-I editing sites altered 23 target genes of 140 microRNAs. A total of 1,722 differential RESs were identified during the HFs cycle of Tianzhu white yak. GO and KEGG enrichment analysis revealed several signaling pathways and GO terms involved skin development, hair growth, and HFs cycle. Such as genes with differential RNA editing levels were significantly enriched in the peroxisome, metabolic pathways, Notch signaling pathway, and PPAR signaling pathway. Besides, the editing sites in HFs development-related genes FAS, APCDD1, WWOX, MPZL3, RUNX1, KANK2, DCN, DSC2, LEPR, HEPHL1, and PTK2B were suggested as the potential RESs involving HFs development.ConclusionThis study investigated the global A-to-I RNA editing events during the HFs cycle of yak skin tissue and expanded the knowledge of A-to-I RNA editing on the HFs cycle. Furthermore, this study revealed that RNA editing-influenced genes may regulate the HFs cycle by participating in the HFs development-related pathways. The findings might provide new insight into the regulation of RNA editing in hair growth.

CircRNAs Related to Breast Muscle Development and Their Interaction Regulatory Network in Gushi Chicken.

Circular RNAs (circRNAs) play a significant regulatory role during skeletal muscle development. To identify circRNAs during postnatal skeletal muscle development in chickens, we constructed 12 cDNA libraries from breast muscle tissues of Chinese Gushi chickens at 6, 14, 22, and 30 weeks and performed RNA sequencing. In total, 2112 circRNAs were identified, and among them 79.92% were derived from exons. CircRNAs are distributed on all chromosomes of chickens, especially chromosomes 1-9 and Z. Bioinformatics analysis showed that each circRNA had an average of 38 miRNA binding sites, 61.32% of which have internal ribosomal entry site (IRES) elements. Furthermore, in total 543 differentially expressed circRNAs (DE-circRNAs) were identified. Functional enrichment analysis revealed that DE-circRNAs source genes are engaged in biological processes and muscle development-related pathways; for example, cell differentiation, sarcomere, and myofibril formation, mTOR signaling pathway, and TGF-β signaling pathway, etc. We also established a competitive endogenous RNA (ceRNA) regulatory network associated with skeletal muscle development. The results in this report indicate that circRNAs can mediate the development of chicken skeletal muscle by means of a complex ceRNA network among circRNAs, miRNAs, genes, and pathways. The findings of this study might help increase the number of known circRNAs in skeletal muscle tissue and offer a worthwhile resource to further investigate the function of circRNAs in chicken skeletal muscle development.