Comprehensive bioinformatic analysis of the expression and prognostic significance of TSC22D domain family genes in acute myeloid leukemia

Background: TSC22D domain family genes, including Tsc22d1-4, have been extensively reported to be involved in tumors. However, their expression profiles and prognostic significance in acute myeloid leukemia (AML) remain unknown. Methods: The present study investigated the expression profiles and prognostic significance of TSC22D domain family genes in AML through the use of multiple online databases, including the CCLE, EMBL-EBI, HPA, Oncomine,GEPIA2, UALCAN, BloodSpot, and GSCALite databases. The cBioPortal and GSCALite databases were used to explore the genetic alteration and copy number variation (CNV) of the Tsc22d3 gene. The TRRUST (Version 2) database was used to explore the gene ontology biological process, disease ontology, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways associated with the Tsc22d3 gene. The AnimalTFDB3.0, STRING, and Harmonizome databases were used to investigate the protein–protein interaction (PPI) network of the Tsc22d3 gene. The Harmonizome database was used for Tsc22d3 gene regulatory kinase analysis. The TargetScanHuman 7.2, MiRDB, and ENCORI databases were used to execute the analysis of the Tsc22d3 gene regulatory miRNAs. Then, the GSCALite and GEPIA2021 databases were used to investigate the correlation between Tsc22d3 expression and immune infiltration. Results: The expression of the Tsc22d3 gene was upregulated markedly in AML cells relative to normal hematopoietic stem cells. The expression of the Tsc22d3 gene was increased in AML tumor samples compared with healthy bone marrow samples. And overexpression of the Tsc22d3 gene was associated with poor OS in AML patients.This study implied that the Tsc22d3 gene is a new biomarker for predicting the prognosis of AML. Furthermore, gene ontology analysis showed that Tsc22d3 was involved in leukemia. Functional enrichment analysis showed that the Tsc22d3 gene has many biological functions, including the regulation of many genes, kinases, miRNAs, signaling pathways, and immune infiltration.Therefore, this study suggests that the Tsc22d3 gene may be a potential therapeutic target for AML. Conclusions: Tsc22d3 gene expression was upregulated in AML, and overexpression was associated with poor OS in AML patients. Therefore, the Tsc22d3 gene may serve as a novel prognostic biomarker and therapeutic target for AML.

Hypoxia-mediated YTHDF2 overexpression promotes lung squamous cell carcinoma progression by activation of the mTOR/AKT axis

Background N6-methyladenosine (m6A) is a dynamic and reversible internal RNA structure of eukaryotic mRNA. YTH domain family 2 (YTHDF2), an m6A-specific reader YTH domain family, plays fundamental roles in several types of cancer. However, the function of YTHDF2 in lung squamous cell carcinoma (LUSC) remains elusive. Methods The knockdown and overexpression of YTHDF2 in LUSC cells were conducted to detect the biological characteristics of YTHDF2. In vivo assays, the role of YTHDF2 in tumor growth was further uncovered. In vitro assays, YTHDF2 was confirmed to be involved in activating the mTOR/AKT signaling and YTHDF2 overexpression induced the EMT process in LUSC. Clinically, immunohistochemical staining revealed the relationship between YTHDF2 expression levels and the clinicopathological characteristics of lung squamous cell carcinoma patients. Moreover, quantitative PCR (qPCR), western blot, CCK8 assay, transwell assay, and wound-healing assay were used to detect the expression level and function of YTHDF2 under hypoxia exposure in LUSC cells. Results The results showed that hypoxia-mediated YTHDF2 overexpression promotes cell proliferation and invasion by activating the mTOR/AKT axis, and YTHDF2 overexpression induces the EMT process in LUSC. Moreover, YTHDF2 is closely associated with pN (pN– 37.0%, pN + 73.9%; P = 0.002) and pTNM stage (pI 50.0%, PII 43.3%, pIIIa 80.6%; P = 0.007), ultimately resulting in poor survival for LUSC patients. Conclusion In brief, the results highlight high-YTHDF2 expression predicted a worse prognosis of LUSC, while hypoxia-mediated YTHDF2 overexpression promotes lung squamous cell carcinoma progression by activation of the mTOR/AKT signaling pathway.

Biological factors in the synthetic construction of overlapping genes

Background Overlapping genes (OLGs) with long protein-coding overlapping sequences are disallowed by standard genome annotation programs, outside of viruses. Recently however they have been discovered in Archaea, diverse Bacteria, and Mammals. The biological factors underlying life’s ability to create overlapping genes require more study, and may have important applications in understanding evolution and in biotechnology. A previous study claimed that protein domains from viruses were much better suited to forming overlaps than those from other cellular organisms - in this study we assessed this claim, in order to discover what might underlie taxonomic differences in the creation of gene overlaps. Results After overlapping arbitrary Pfam domain pairs and evaluating them with Hidden Markov Models we find OLG construction to be much less constrained than expected. For instance, close to 10% of the constructed sequences cannot be distinguished from typical sequences in their protein family. Most are also indistinguishable from natural protein sequences regarding identity and secondary structure. Surprisingly, contrary to a previous study, virus domains were much less suitable for designing OLGs than bacterial or eukaryotic domains were. In general, the amount of amino acid change required to force a domain to overlap is approximately equal to the variation observed within a typical domain family. The resulting high similarity between natural sequences and those altered so as to overlap is mostly due to the combination of high redundancy in the genetic code and the evolutionary exchangeability of many amino acids. Conclusions Synthetic overlapping genes which closely resemble natural gene sequences, as measured by HMM profiles, are remarkably easy to construct, and most arbitrary domain pairs can be altered so as to overlap while retaining high similarity to the original sequences. Future work however will need to assess important factors not considered such as intragenic interactions which affect protein folding. While the analysis here is not sufficient to guarantee functional folding proteins, further analysis of constructed OLGs will improve our understanding of the origin of these remarkable genetic elements across life and opens up exciting possibilities for synthetic biology.

Role of Gasdermins in the Biogenesis of Apoptotic Cell–Derived Exosomes

The gasdermins are a family of pore-forming proteins that has recently been suggested to play a central role in the pyroptosis and the release of inflammatory cytokines. Here, we describe the novel roles of gasdermins in the biogenesis of apoptotic cell–derived exosomes. In apoptotic cells, GADMA, GSDMC, GSDMD, and GSDME increased the release of ApoExos, and both their full-length and cleaved forms were localized in the exosomal membrane. GSDMB and DFNB59, on the other hand, negatively affected the release of ApoExos. The caspase-mediated cleavage of gasdermins, especially GSDME, is suggested to increase Ca2+ influx to cytosol through endosomal pores and thus increase the biogenesis of ApoExos. In addition, the GSDME-mediated biogenesis of ApoExos depended on the ESCRT-III complex and endosomal recruitment of Ca2+-dependent proteins: annexins A2 and A7, the PEF domain family proteins sorcin and grancalcin, and the Bro1 domain protein HD-PTP. Therefore, we propose that the biogenesis of ApoExos begins when gasdermin-mediated endosomal pores increase cytosolic Ca2+, continues through the recruitment of annexin-sorcin/grancalcin-HD-PTP, and is completed when the ESCRT-III complex synthesizes intraluminal vesicles in the multivesicular bodies of dying cells. Finally, we found that GSDME-bearing tumors released ApoExos to induce inflammatory responses in the in vivo 4T1 orthotropic model of breast cancer. The data presented in this study indicate that the switch from apoptosis to pyroptosis could drive the transfer of mass signals to nearby or distant living cells and tissues by way of extracellular vesicles, and that gasdermins play critical roles in that process.

The JASMONATE ZIM-DOMAIN family proteins are the important node in jasmonic acid-abscisic acid crosstalk in regulating plant response to drought

: Plants modulate the metabolism of phytohormones and their signaling pathways under drought to regulate physiological and adaptive responses. Jasmonic acid (JA) is one of the major classes of phytohormones and has been found to potentially enhance plant tolerance to various abiotic stresses, including drought. The JASMONATE ZIM-DOMAIN (JAZ) proteins are the negative regulators in the JA-signaling pathway. The JAZ protein family is explicit to plants and involved in the regulation of numerous biological processes, including drought-responsive mechanisms. In this review, we synthesize the mechanistic insight into the roles of JAZ proteins in regulation of drought responses by connecting the JA-signaling with abscisic acid-signaling to modulate drought-responsive physiological processes.

Emerging Roles of N6-Methyladenosine Modification in Neurodevelopment and Neurodegeneration

N6-methyladenosine (m6A), the most abundant modification in messenger RNAs (mRNAs), is deposited by methyltransferases (“writers”) Mettl3 and Mettl14 and erased by demethylases (“erasers”) Fto and Alkbh5. m6A can be recognized by m6A-binding proteins (“readers”), such as Yth domain family proteins (Ythdfs) and Yth domain-containing protein 1 (Ythdc1). Previous studies have indicated that m6A plays an essential function in various fundamental biological processes, including neurogenesis and neuronal development. Dysregulated m6A modification contributes to neurological disorders, including neurodegenerative diseases. In this review, we summarize the current knowledge about the roles of m6A machinery, including writers, erasers, and readers, in regulating gene expression and the function of m6A in neurodevelopment and neurodegeneration. We also discuss the perspectives for studying m6A methylation.

CLEC2D expression associates with survival in triple negative breast cancer.

We mined published microarray data (1) to understand the most significant gene expression differences in the tumors of triple negative breast cancer patients based on survival at time of analysis: dead or alive. We observed significant transcriptome-wide differential expression of C-type lectin domain family 2, member D, encoded by CLEC2D when comparing the primary tumors of triple negative breast cancer patients dead or alive. Importantly, CLEC2D expression was significantly correlated with overall survival in basal subtype breast cancer, a molecular subtype sharing significant overlap with triple negative breast cancer. CLEC2D may be of relevance as a biomarker or as a molecule of interest in understanding the etiology or progression of triple negative breast cancer.