{"title":"Mrc1Claspin is essential for heterochromatin maintenance in Schizosaccharomyces pombe","authors":"Kei Kawakami, Yukari Ueno, Nao Hayama, Katsunori Tanaka","doi":"10.1111/gtc.13175","DOIUrl":"10.1111/gtc.13175","url":null,"abstract":"<p>In eukaryotes, maintenance of heterochromatin structure that represses gene expression during cell proliferation is essential for guaranteeing cell identity. However, how heterochromatin is maintained and transmitted to the daughter cells remains elusive. In this study, we constructed a reporter system to study the maintenance of heterochromatin in the subtelomeric region of the fission yeast, <i>Schizosaccharomyces pombe</i>. We demonstrated that once subtelomeric heterochromatin was established, it tended to be maintained as a metastable structure through cell proliferation. Using this system, we screened an <i>S. pombe</i> genome-wide gene deletion library for subtelomeric heterochromatin maintenance factors and identified 57 genes related to various cellular processes, in addition to well-characterized heterochromatin factors. We focused on Mrc1<sup>Claspin</sup>, a mediator of DNA replication checkpoint. We found that Mrc1 maintains heterochromatin structure not only at the subtelomeres but also at the pericentromeres and mating-type regions. Furthermore, we showed that Mrc1 is required for the localization of Snf2/Hdac-containing Repressor Complex (SHREC) and the maintenance of hypoacetylation state of histone H3K14. This study complements the recent discoveries that Mrc1 functions as a histone H3-H4 chaperone in heterochromatin maintenance.</p>","PeriodicalId":12742,"journal":{"name":"Genes to Cells","volume":"29 12","pages":"1207-1224"},"PeriodicalIF":1.3,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142545062","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}
{"title":"Pathogen challenge in Arabidopsis cotyledons induces enhanced disease resistance at newly formed rosette leaves via sustained upregulation of WRKY70","authors":"Kanoknipa Sukaoun, Tokuji Tsuchiya, Hiroshi Uchiyama","doi":"10.1111/gtc.13179","DOIUrl":"10.1111/gtc.13179","url":null,"abstract":"<p>Pathogenic microorganisms often target seedlings shortly after germination. If plants exhibit resistance or resilience to pathogens, those exposed to pathogen challenge may grow further and form new unchallenged leaves. The purpose of this study was to examine disease resistance in the newly formed leaves of plants subjected to pathogen challenge. We used <i>Arabidopsis thaliana</i> and the oomycete pathogen <i>Hyaloperonospora arabidopsidis</i> (<i>Hpa</i>) as the model pathosystem. We found that Arabidopsis seedlings primarily challenged with the avirulent isolate <i>Hpa</i> exhibited enhanced disease resistance against the virulent isolate <i>Hpa</i> in newly formed rosette leaves (NFRLs). Our observations indicated that the transcript levels of the transcription factor gene <i>WRKY70</i>, which is essential for full resistance to the virulent isolate <i>Hpa</i>Noco2, were elevated and maintained at high levels in the NFRLs. In contrast, the transcript levels of the salicylic acid marker gene <i>PR1</i> and systemic acquired resistance-related genes did not exhibit sustained elevation. The maintenance of increased transcript levels of <i>WRKY70</i> operated independently of non-expressor of pathogenesis-related gene 1. These findings suggest that prolonged upregulation of <i>WRKY70</i> represents a defensive state synchronized with plant development to ensure survival against subsequent infections.</p>","PeriodicalId":12742,"journal":{"name":"Genes to Cells","volume":"29 12","pages":"1236-1250"},"PeriodicalIF":1.3,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142521735","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}
{"title":"Notch signaling pathway suppresses mRNA expression of hexokinase 2 under nutrient-poor conditions in U87-MG glioma cells","authors":"Shuhei Kuwabara, Takamasa Mizoguchi, Jiawei Ma, Tohgo Kanoh, Yuki Ohta, Motoyuki Itoh","doi":"10.1111/gtc.13176","DOIUrl":"10.1111/gtc.13176","url":null,"abstract":"<p>Control of nutrient homeostasis plays a central role in cell proliferation/survival during embryonic development and tumor growth. Activation of the Notch signaling pathway, a major contributor to cell–cell interactions, is a potential mechanism for cell adaptation to nutrient-poor conditions. Our previous study also demonstrated that during embryogenesis when nutrients such as glutamine and growth factors are potentially maintained at lower levels, Notch signaling suppresses mRNA expression of <i>hexokinase 2</i> (<i>hk2</i>), which is a glycolysis-associated gene, in the central nervous system. However, whether and how the genetic regulation of <i>HK2</i> via Notch signaling contributes to cellular adaptability to nutrient-poor environments remains unknown. In this study, we performed gene expression analysis using a U87-MG human glioma cell line and revealed that under conditions where both glutamine and serum were absent, Notch signaling was activated and <i>HK2</i> expression was downregulated by Notch signaling. We also found that Notch-mediated <i>HK2</i> suppression was triggered in a Notch ligand-selective manner. Furthermore, <i>HK2</i> was shown to inhibit cell proliferation of U87-MG gliomas, which might depend on Notch signaling activity. Together, our findings suggest the involvement of Notch-mediated <i>HK2</i> suppression in an adaptive mechanism of U87-MG glioma cells to nutrient-poor conditions.</p>","PeriodicalId":12742,"journal":{"name":"Genes to Cells","volume":"29 12","pages":"1225-1235"},"PeriodicalIF":1.3,"publicationDate":"2024-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142499089","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}
{"title":"Roles of Pbp1, Mkt1, and Dhh1 in the regulation of gene expression in the medium containing non-fermentative carbon sources","authors":"Yurika Himeno, Nozomi Endo, Varsha Rana, Natsu Akitake, Tomomi Suda, Yasuyuki Suda, Tomoaki Mizuno, Kenji Irie","doi":"10.1111/gtc.13174","DOIUrl":"10.1111/gtc.13174","url":null,"abstract":"<p>Pbp1, a yeast ortholog of human ataxin-2, is important for cell growth in the medium containing non-fermentable carbon sources. We had reported that Pbp1 regulates expression of genes related to glycogenesis via transcriptional regulation and genes related to mitochondrial function through mRNA stability control. To further analyze the role of Pbp1 in gene expression, we first examined the time course of gene expression after transfer from YPD medium containing glucose to YPGlyLac medium containing glycerol and lactate. At 12 h after transfer to YPGlyLac medium, the <i>pbp1∆</i> mutant showed decreased expression of genes related to mitochondrial function but no decrease in expression of glycogenesis-related genes. We also examined a role of the Pbp1-binding factor, Mkt1. The <i>mkt1∆</i> mutant, like the <i>pbp1∆</i> mutant, showed slow growth on YPGlyLac plate and reduced expression of genes related to mitochondrial function. Furthermore, we found that mutation of <i>DHH1</i> gene encoding a decapping activator exacerbated the growth of the <i>pbp1∆</i> mutant on YPGlyLac plate. The <i>dhh1∆</i> mutant showed reduced expression of genes related to mitochondrial function. These results indicate that Pbp1 and Mkt1 regulate the expression of genes related to mitochondrial function and that the decapping activator Dhh1 also regulates the expression of those genes.</p>","PeriodicalId":12742,"journal":{"name":"Genes to Cells","volume":"29 12","pages":"1190-1206"},"PeriodicalIF":1.3,"publicationDate":"2024-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142499090","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}
{"title":"Investigation of exon skipping therapy in kidney organoids from Alport syndrome patients derived iPSCs","authors":"Kensuke Yabuuchi, Tomoko Horinouchi, Tomohiko Yamamura, Kandai Nozu, Minoru Takasato","doi":"10.1111/gtc.13170","DOIUrl":"10.1111/gtc.13170","url":null,"abstract":"<p>Alport syndrome (AS) is a hereditary disease caused by mutations in the <i>COL4A5</i> gene and leads to chronic kidney disease. Currently, no specific treatment has been developed. However, a recent study using AS-model mice demonstrated that the exon skipping method could partially rescue the symptoms. In this study, we evaluated the effects of the exon skipping method using kidney organoids generated from AS-patient-derived induced pluripotent stem cells (AS-iPSCs). We generated kidney organoids from AS-iPSCs, which exhibited nephron structures. As expected, the C-terminus of COL4A5 was not expressed in AS-organoids. Interestingly, anti-sense oligonucleotides restored the expression of the C-terminus of COL4A5 in vitro. Next, we transplanted AS-organoids into mice and evaluated glomerular basement membrane formation in vivo. We found that AS-organoids formed a lower slit diaphragm ratio compared to control organoids. Finally, we assessed the effects of exon skipping on transplanted organoids but observed minimum effects. These studies suggest that AS-iPSCs can generate kidney organoids lacking the C-terminus of COL4A5, and that exon skipping can induce its expression in vitro.</p>","PeriodicalId":12742,"journal":{"name":"Genes to Cells","volume":"29 12","pages":"1118-1130"},"PeriodicalIF":1.3,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/gtc.13170","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142463122","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":"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}