{"title":"Loss of a single Zn finger, but not that of two Zn fingers, of GATA3 drives skin inflammation","authors":"Tomohiro Iguchi, Makiko Toma-Hirano, Masakatsu Takanashi, Hisao Masai, Shoichiro Miyatake","doi":"10.1111/gtc.13171","DOIUrl":"10.1111/gtc.13171","url":null,"abstract":"<p>Transcription factor GATA3 is essential for the developmental processes of T cells. Recently, the silencer of a cytokine IFNγ gene was identified, the inhibitory activity of which requires GATA3. GATA3 has 2 Zn fingers and the commonly used GATA3 deficient mice lack both fingers (D2). We have established a mouse line that lacks only one Zn finger close to the C terminus (D1). The D1 mice line developed dermatitis, which was not observed in D2 mice. The expression of S100a8/S100a9 was elevated in D1 to a level higher than in D2, suggesting their roles in dermatitis development. CD8 T cells of both D1 and D2 lines expressed inhibitory receptors associated with the exhausted state. In the absence of MHC class II, the skin inflammation was exacerbated in both lines. The gene expression pattern of CD8 T cells became similar to that of effector T cells. Blocking Ab against LAG3 upregulated the expression of the effector molecules of T cells. These results suggest that the disfunction of GATA3 can lead to the spontaneous activation of CD8 T cells that causes skin inflammation, and that suppressive activity of MHC class II - LAG3 interaction ameliorates dermatitis development.</p>","PeriodicalId":12742,"journal":{"name":"Genes to Cells","volume":"29 12","pages":"1173-1189"},"PeriodicalIF":1.3,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142463123","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Genes to CellsPub Date : 2024-10-11DOI: 10.1111/gtc.13173
Daisuke Koga, Shogo Nakayama, Tsunaki Higa, Keiichi I. Nakayama
{"title":"Identification and characterization of an enhancer element regulating expression of Cdkn1c (p57 gene)","authors":"Daisuke Koga, Shogo Nakayama, Tsunaki Higa, Keiichi I. Nakayama","doi":"10.1111/gtc.13173","DOIUrl":"10.1111/gtc.13173","url":null,"abstract":"<p>The mammalian p57 protein is a member of the CIP/KIP family of cyclin-dependent kinase inhibitors and plays an essential role in the development of multiple tissues during embryogenesis as well as in the maintenance of tissue stem cells in adults. Although several transcription factors have been implicated in regulating the p57 gene, cis-elements such as enhancers that regulate its expression have remained ill-defined. Here we identify a candidate enhancer for the mouse p57 gene (<i>Cdkn1c</i>) within an intron of the <i>Kcnq1</i> locus by 4C-seq analysis in mouse embryonic stem cells (mESCs). Deletion of this putative enhancer region with the CRISPR-Cas9 system or its suppression by CRISPR interference resulted in a marked attenuation of <i>Cdkn1c</i> expression in differentiating mESCs. Our results thus suggest that this region may serve as an enhancer for the p57 gene during early mouse embryogenesis.</p>","PeriodicalId":12742,"journal":{"name":"Genes to Cells","volume":"29 12","pages":"1264-1274"},"PeriodicalIF":1.3,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/gtc.13173","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142463121","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Genes to CellsPub Date : 2024-10-08DOI: 10.1111/gtc.13172
Sema Bolkent
{"title":"Cellular and molecular mechanisms of asymmetric stem cell division in tissue homeostasis","authors":"Sema Bolkent","doi":"10.1111/gtc.13172","DOIUrl":"10.1111/gtc.13172","url":null,"abstract":"<p>The asymmetric cell division determines cell diversity and distinct sibling cell fates by mechanisms linked to mitosis. Many adult stem cells divide asymmetrically to balance self-renewal and differentiation. The process of asymmetric cell division involves an axis of polarity and, second, the localization of cell fate determinants at the cell poles. Asymmetric division of stem cells is achieved by intrinsic and extrinsic fate determinants such as signaling molecules, epigenetics factors, molecules regulating gene expression, and polarized organelles. At least some stem cells perform asymmetric and symmetric cell divisions during development. Asymmetric division ensures that the number of stem cells remains constant throughout life. The asymmetric division of stem cells plays an important role in biological events such as embryogenesis, tissue regeneration and carcinogenesis. This review summarizes recent advances in the regulation of asymmetric stem cell division in model organisms.</p>","PeriodicalId":12742,"journal":{"name":"Genes to Cells","volume":"29 12","pages":"1099-1110"},"PeriodicalIF":1.3,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/gtc.13172","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142389826","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"The scaffold protein IQGAP1 promotes reorientation of epithelial cell polarity at the two-cell stage for cystogenesis","authors":"Michihiro Horikawa, Junya Hayase, Sachiko Kamakura, Akira Kohda, Masafumi Nakamura, Hideki Sumimoto","doi":"10.1111/gtc.13169","DOIUrl":"10.1111/gtc.13169","url":null,"abstract":"<p>A single epithelial cell embedded in extracellular matrix (ECM) can proliferate to form an apical lumen-harboring cyst, whose formation is a fundamental step in epithelial organ development. At an early two-cell stage after cell division, the cell doublet typically displays “inverted” polarity, with apical and basolateral proteins being located to the ECM-facing and cell–cell-contacting plasma membranes, respectively. Correct cystogenesis requires polarity reorientation, a process containing apical protein endocytosis from the ECM-abutting periphery and subsequent apical vesicle delivery to a cell–cell contact site for lumen formation. Here, we show that downstream of the ECM-signal-transducer β1-integrin, Rac1, and its effector IQGAP1 promote apical protein endocytosis, contributing to polarity reorientation of mammalian epithelial Madin-Darby canine kidney (MDCK) cells at a later two-cell stage in three-dimensional culture. Rac1–GTP facilitates IQGAP1 interaction with the Rac-specific activator Tiam1, which also contributes to the endocytosis and enhances the effect of IQGAP1. These findings suggest that Tiam1 and IQGAP1 form a positive feedback loop to activate Rac1. With Rac1–GTP, IQGAP1 also binds to AP2α, an adaptor protein subunit for clathrin-mediated endocytosis; depletion of the AP2 complex impairs apical protein endocytosis in MDCK doublets. Thus, Rac1 likely participates in polarity reorientation at the two-cell stage via its interaction with IQGAP1.</p>","PeriodicalId":12742,"journal":{"name":"Genes to Cells","volume":"29 12","pages":"1154-1172"},"PeriodicalIF":1.3,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/gtc.13169","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142389828","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Evolution of the Cdk4/6–Cdkn2 system in invertebrates","authors":"Shiori Yuki, Shunsuke Sasaki, Yuta Yamamoto, Fumika Murakami, Kazumi Sakata, Isato Araki","doi":"10.1111/gtc.13165","DOIUrl":"10.1111/gtc.13165","url":null,"abstract":"<p>The cell cycle is driven by cyclin-dependent kinases (Cdks). The decision whether the cell cycle proceeds is made during G1 phase, when Cdk4/6 functions. Cyclin-dependent kinase inhibitor 2 (Cdkn2) is a specific inhibitor of Cdk4/6, and their interaction depends on D84 in Cdkn2 and R24/31 in Cdk4/6. This knowledge is based mainly on studies in mammalian cells. Here, we comprehensively analyzed <i>Cdk4/6</i> and <i>Cdkn2</i> in invertebrates and found that <i>Cdk4/6</i> was present in most of the investigated phyla, but the distribution of <i>Cdkn2</i> was rather uneven among and within the phyla. The positive charge of R24/R31 in Cdk4/6 was conserved in all analyzed species in phyla with Cdkn2. The presence of <i>Cdkn2</i> and the conservation of the positive charge were statistically correlated. We also found that <i>Cdkn2</i> has been tightly linked to <i>Fas associated factor 1</i> (<i>Faf1</i>) during evolution. We discuss potential interactions between Cdkn2 and Cdk4/6 in evolution and the possible cause of the strong conservation of the microsynteny.</p>","PeriodicalId":12742,"journal":{"name":"Genes to Cells","volume":"29 11","pages":"1037-1051"},"PeriodicalIF":1.3,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11555623/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142389827","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Roles of ZEB1 and ZEB2 in E-cadherin expression and cell aggressiveness in head and neck cancer","authors":"Arisa Kinouchi, Takahiro Jubashi, Rikito Tatsuno, Jiro Ichikawa, Kaname Sakamoto, Daiju Sakurai, Tomonori Kawasaki, Hiroki Ishii, Keiji Miyazawa, Masao Saitoh","doi":"10.1111/gtc.13167","DOIUrl":"10.1111/gtc.13167","url":null,"abstract":"<p>Zinc finger E-box binding homeobox 1 (ZEB1) has been identified as a key factor in cancer cell differentiation and metastasis, and has been well studied in the field of cancer cell biology. ZEB2 has a highly similar conformation to ZEB1, but its role in head and neck squamous cell carcinoma (HNSCC) cells is not fully understood. Here, we separately overexpressed ZEB1 and ZEB2 in C57BL/6 mouse oral cancer (MOC) cells and investigated their cellular characteristics, including E-cadherin levels, motile properties, chemoresistance, and metastatic ability in immunocompetent mice. Both ZEB1 and ZEB2 overexpression reduced epithelial traits and converted cells to an aggressive phenotype. Surprisingly, ZEB1 overexpression increased the endogenous level of ZEB2 in MOC cells, and vice versa. The molecular mechanisms underlying these findings remain unclear. However, the in vitro anchorage-independent growth of MOC cells overexpressing ZEB2 was considerably greater than that of MOC cells overexpressing ZEB1. These findings suggest that ZEB2, like ZEB1, has the ability to induce the differentiation of cancer cells into those with highly aggressive traits.</p>","PeriodicalId":12742,"journal":{"name":"Genes to Cells","volume":"29 12","pages":"1131-1143"},"PeriodicalIF":1.3,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/gtc.13167","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142371639","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Regular exercise suppresses steatosis-associated liver cancer development by degrading E2F1 and c-Myc via circadian gene upregulation","authors":"Vu Thuong Huyen, Kanae Echizen, Ryota Yamagishi, Miho Kumagai, Yoshiki Nonaka, Takahiro Kodama, Tatsuya Ando, Megumu Yano, Naoki Takada, Masaki Takasugi, Fumitaka Kamachi, Naoko Ohtani","doi":"10.1111/gtc.13161","DOIUrl":"10.1111/gtc.13161","url":null,"abstract":"<p>Regular exercise is believed to suppress cancer progression. However, the precise molecular mechanisms by which exercise prevents cancer development remain unclear. In this study, using a steatosis-associated liver cancer mouse model, we found that regular exercise at a speed of 18 m/min for 20 min daily suppressed liver cancer development. To explore the underlying mechanisms, we examined the gene expression profiles in the livers of the exercise and non-exercise groups. The expressions of circadian genes, such as Per1 and Cry2, were upregulated in the exercise group. As circadian rhythm disruption is known to cause various diseases, including cancer, improving circadian rhythm through exercise could contribute to cancer prevention. We further found that the expression of a series of E2F1 and c-Myc target genes that directly affect the proliferation of cancer cells was downregulated in the exercise group. However, the expression of E2F1 and c-Myc was transcriptionally unchanged but degraded at the post-translational level by exercise. Cry2, which is regulated by the Skp1-Cul1-FBXL3 (SCF<sup>FBXL3</sup>) ubiquitin ligase complex by binding to FBXL3, can form a complex with E2F1 and c-Myc, which we think is the mechanism to degrade them. Our study revealed a previously unknown mechanism by which exercise prevents cancer development.</p>","PeriodicalId":12742,"journal":{"name":"Genes to Cells","volume":"29 11","pages":"1012-1025"},"PeriodicalIF":1.3,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142365047","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Genes to CellsPub Date : 2024-09-30DOI: 10.1111/gtc.13168
Sora Ishikawa, Sae Tanaka, Kazuharu Arakawa
{"title":"Search for putative gene regulatory motifs in CAHS3, linked to anhydrobiosis in a tardigrade Ramazzottius varieornatus, in vivo and in silico","authors":"Sora Ishikawa, Sae Tanaka, Kazuharu Arakawa","doi":"10.1111/gtc.13168","DOIUrl":"10.1111/gtc.13168","url":null,"abstract":"<p>Tardigrades possess the ability to enter an almost completely dehydrated state, anhydrobiosis. The CAHS (cytosolic abundant heat-soluble) protein family has been identified as one of the anhydrobiosis-related proteins. In particular, CAHS3 protein from an anhydrobiotic tardigrade, <i>Ramazzottius varieornatus</i>, shows heat-solubility and reversible condensation and is one of the most highly expressed among the CAHS paralogs. A recently developed tardigrade-specific vector showed tissue-specific expression of RvCAHS3 most pronounced in the epidermis in vivo, contrary to the idea that anhydrobiotic genes are uniformly expressed in all tardigrade cells. In this study, we investigated the regulation of RvCAHS3 gene expression through in vivo expression experiments using tardigrade vectors with a series of truncated upstream regions coupled with in silico analysis to identify the anhydrobiosis-related genes that are expressed under the same regulatory system as RvCAHS3. As a result, the 300–350 bp region upstream of RvCAHS3 is critical for regulating gene expression in tardigrade vector experiments, and three motifs conserved between two species of anhydrobiotic tardigrades were identified within a 500 bp region directly upstream of RvCAHS3 start codon. These motifs, which have also been identified upstream of other CAHS genes, could be associated with the regulatory system of anhydrobiosis-related genes in tardigrades.</p>","PeriodicalId":12742,"journal":{"name":"Genes to Cells","volume":"29 12","pages":"1144-1153"},"PeriodicalIF":1.3,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/gtc.13168","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142345083","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Meta-analysis of gonadal transcriptome provides novel insights into sex change mechanism across protogynous fishes","authors":"Ryo Nozu, Mitsutaka Kadota, Masaru Nakamura, Shigehiro Kuraku, Hidemasa Bono","doi":"10.1111/gtc.13166","DOIUrl":"10.1111/gtc.13166","url":null,"abstract":"<p>Protogyny, being capable of changing from female to male during their lifetime, is prevalent in 20 families of teleosts but is believed to have evolved within specific evolutionary lineages. Therefore, shared regulatory factors governing the sex change process are expected to be conserved across protogynous fishes. However, a comprehensive understanding of this mechanism remains elusive. To identify these factors, we conducted a meta-analysis using gonadal transcriptome data from seven species. We curated data pairs of ovarian tissue and transitional gonad, and employed ratios of expression level as a unified criterion for differential expression, enabling a meta-analysis across species. Our approach revealed that classical sex change-related genes exhibited differential expression levels between the ovary and transitional gonads, consistent with previous reports. These results validate our methodology's robustness. Additionally, we identified novel genes not previously linked to gonadal sex change in fish. Notably, changes in the expression levels of acetoacetyl-CoA synthetase and apolipoprotein Eb, which are involved in cholesterol synthesis and transport, respectively, suggest that the levels of cholesterol, a precursor of steroid hormones crucial for sex change, are decreased upon sex change onset in the gonads. This implies a potential universal influence of cholesterol dynamics on gonadal transformation in protogyny.</p>","PeriodicalId":12742,"journal":{"name":"Genes to Cells","volume":"29 11","pages":"1052-1068"},"PeriodicalIF":1.3,"publicationDate":"2024-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11555629/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142345082","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Genes to CellsPub Date : 2024-09-23DOI: 10.1111/gtc.13164
Tatsuya Ikuta, Riko Suzuki, Asuka Inoue
{"title":"The repertoire of G-protein-coupled receptor variations in the Japanese population 54KJPN","authors":"Tatsuya Ikuta, Riko Suzuki, Asuka Inoue","doi":"10.1111/gtc.13164","DOIUrl":"10.1111/gtc.13164","url":null,"abstract":"<p>G-protein-coupled receptors (GPCRs) are the largest superfamily in the human genome and the major targets for the market drugs. Recent massive genomics studies revealed numerous natural variations in the general population. 54KJPN is the most extensive Japanese population genomics study, curating the whole genome sequences from about 54,000 individuals. Here, by analyzing 390 non-olfactory GPCR genes in the 54KJPN dataset, we annotated 25,443 missense single-nucleotide variations. Among them, we found 120 major variations that appear with an allele frequency greater than 0.5, including variations that occurred on posttranslational modification sites. Structural alignment of GPCRs using the generic numbering system in the GPCRdb reveals enrichment of alterations in the conserved arginine residue within the DRY motif, which contributes to downstream G-protein signaling. A comparison with the worldwide 1000 Genomes Project (1KGP) dataset found 23 variations that were present exclusively in the 54KJPN dataset. This study will be the basis for future pharmacogenomics studies for the Japanese population.</p>","PeriodicalId":12742,"journal":{"name":"Genes to Cells","volume":"29 11","pages":"1026-1036"},"PeriodicalIF":1.3,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142284369","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}