综合性期刊最新文献

{"title":"Zscan4 mediates ubiquitination and degradation of the corepressor complex to promote chromatin accessibility in 2C-like cells","authors":"Jiao Yang, Jiameng Dan, Nannan Zhao, Linlin Liu, Huasong Wang, Qiangqiang Liu, Lingling Wang, Jie Li, Yiwei Wu, Feilong Chen, Weilun Fu, Fei Liu, Meiqi Lin, Weiyu Zhang, Fuquan Chen, Xinqi Liu, Xinyi Lu, Quan Chen, Xudong Wu, Yuyu Niu, Na Yang, Yushan Zhu, Jiafu Long, Lin Liu","doi":"10.1073/pnas.2407490121","DOIUrl":"https://doi.org/10.1073/pnas.2407490121","url":null,"abstract":"Zygotic genome activation occurs in two-cell (2C) embryos, and a 2C-like state is also activated in sporadic (~1%) naïve embryonic stem cells in mice. Elevated chromatin accessibility is critical for the 2C-like state to occur, yet the underlying molecular mechanisms remain elusive. Zscan4 exhibits burst expression in 2C embryos and 2C-like cells. Here, we show that Zscan4 mediates chromatin remodeling to promote the chromatin accessibility for achieving the 2C-like state. Through coimmunoprecipitation/mass spectrometry, we identified that Zscan4 interacts with the corepressors Kap1/Trim28, Lsd1, and Hdac1, also with H3K9me3 modifiers Suv39h1/2, to transiently form a repressive chromatin complex. Then, Zscan4 mediates the degradation of these chromatin repressors by recruiting Trim25 as an E3 ligase, enabling the ubiquitination of Lsd1, Hdac1, and Suv39h1/2. Degradation of the chromatin repressors promotes the chromatin accessibility for activation of the 2C-like state. These findings reveal the molecular insights into the roles of Zscan4 in promoting full activation of the 2C-like state.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"269 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142867594","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nuclear microRNA 9 mediates G-quadruplex formation and 3D genome organization during TGF-β-induced transcription","authors":"Julio Cordero, Guruprasadh Swaminathan, Diana G. Rogel-Ayala, Karla Rubio, Adel Elsherbiny, Samina Mahmood, Witold Szymanski, Johannes Graumann, Thomas Braun, Stefan Günther, Gergana Dobreva, Guillermo Barreto","doi":"10.1038/s41467-024-54740-x","DOIUrl":"https://doi.org/10.1038/s41467-024-54740-x","url":null,"abstract":"<p>The dynamics of three-dimensional (3D) genome organization are essential to transcriptional regulation. While enhancers regulate spatiotemporal gene expression, chromatin looping is a means for enhancer-promoter interactions yielding cell-type-specific gene expression. Further, non-canonical DNA secondary structures, such as G-quadruplexes (G4s), are related to increased gene expression. However, the role of G4s in promoter-distal regulatory elements, such as super-enhancers (SE), and in chromatin looping has remained elusive. Here we show that mature microRNA 9 (<i>miR-9</i>) is enriched at promoters and SE of genes that are inducible by transforming growth factor beta 1 (TGFB1) signaling. Moreover, we find that <i>miR-9</i> is required for formation of G4s, promoter-super-enhancer looping and broad domains of the euchromatin histone mark H3K4me3 at TGFB1-responsive genes. Our study places <i>miR-9</i> in the same functional context with G4s and promoter-enhancer interactions during 3D genome organization and transcriptional activation induced by TGFB1 signaling, a critical signaling pathway in cancer and fibrosis.</p>","PeriodicalId":19066,"journal":{"name":"Nature Communications","volume":"31 1","pages":""},"PeriodicalIF":16.6,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142857868","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"FDA should consider drug-therapy regimens.","authors":"Eero Castrén, Claus Normann","doi":"10.1126/science.adt1480","DOIUrl":"https://doi.org/10.1126/science.adt1480","url":null,"abstract":"","PeriodicalId":21678,"journal":{"name":"Science","volume":"386 6728","pages":"1356-1357"},"PeriodicalIF":44.7,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142865447","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Biocatalytic C-H oxidation meets radical cross-coupling: Simplifying complex piperidine synthesis.","authors":"Jiayan He, Kenta Yokoi, Breanna Wixted, Benxiang Zhang, Yu Kawamata, Hans Renata, Phil S Baran","doi":"10.1126/science.adr9368","DOIUrl":"https://doi.org/10.1126/science.adr9368","url":null,"abstract":"<p><p>Modern medicinal chemists are targeting more complex molecules to address challenging biological targets, which leads to synthesizing structures with higher sp³ character (Fsp³) to enhance specificity as well as physiochemical properties. Although traditional flat, high-fraction sp² molecules, such as pyridine, can be decorated through electrophilic aromatic substitution and palladium (Pd)-based cross-couplings, general strategies to derivatize three-dimensional (3D) saturated molecules are far less developed. In this work, we present an approach for the rapid, modular, enantiospecific, and diastereoselective functionalization of piperidine (saturated analog of pyridine), combining robust biocatalytic carbon-hydrogen oxidation with radical cross-coupling. This combination is directly analogous to electrophilic aromatic substitution followed by Pd-couplings for flat molecules, streamlining synthesis of 3D molecules. This study offers a generalizable strategy for accessing complex architectures, appealing to both medicinal and process chemists.</p>","PeriodicalId":21678,"journal":{"name":"Science","volume":"386 6728","pages":"1421-1427"},"PeriodicalIF":44.7,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142865477","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Absence of gut microbiota alleviates iron overload-induced colitis by modulating ferroptosis in mice","authors":"Ke Gu, Aimin Wu, Chen Liu, Bing Yu, Jun He, Xin Lai, Junzhou Chen, Yuheng Luo, Hui Yan, Ping Zheng, Junqiu Luo, Junning Pu, Quyuan Wang, Huifen Wang, Daiwen Chen","doi":"10.1016/j.jare.2024.12.030","DOIUrl":"https://doi.org/10.1016/j.jare.2024.12.030","url":null,"abstract":"<h3>Introduction</h3>Iron overload disrupts gut microbiota and induces ferroptosis, contributing to colitis. However, whether gut microbiota directly drives iron overload-induced colitis and its underlying mechanism remain unclear.<h3>Objectives</h3>The study aimed to explore whether gut microbiota can directly regulate iron overload-induced colitis and its underling mechanism.<h3>Methods</h3>Male C57BL/6N mice were fed with ferrous sulfate to establish an iron overload model. Antibiotics and DSS were used to create germ-free and colitis models, respectively.<h3>Results</h3>Results showed that iron overload caused disruption of systemic iron homeostasis via activating pro-inflammation response, which caused induction of ferroptosis and eventually resulted in colitis in mice. Notably, iron overload inhibited System Xc- and activated the nuclear factor E2-related factor 2/heme oxygenase-1 pathway, driving ferroptosis and colitis progression. Similar results were observed in mouse colon epithelial cells, which were treated with high doses ferric ammonium citrate. Additionally, iron overload exacerbated DSS-induced colitis by activating the ferroptosis and increasing harmful bacteria (e.g., <em>Mucispirillum</em>) abundance. Interestingly, eliminating gut microbiota attenuated iron overload-induced colitis, without affecting systemic inflammation through inhibiting ferroptosis of mice. Depletion of the gut microbiota partially mitigated the exacerbating effect of iron overload on DSS-induced colitis through inhibiting ferroptosis of mice.<h3>Conclusion</h3>Iron overload activates ferroptosis in colonic cells, increases the relative abundance of harmful bacteria, and exacerbates DSS-induced colitis in mice. Iron overload exacerbates DSS-induced ferroptosis and colitis in a microbiota-dependent manner. Targeting gut microbiota may offer new strategies for managing iron overload-induced colitis.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"27 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142867557","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SKA2 enhances stress-related glucocorticoid receptor signaling through FKBP4–FKBP5 interactions in neurons","authors":"Jakob Hartmann, Claudia Klengel, Larissa J. Dillmann, Erin E. Hisey, Kathrin Hafner, Rammohan Shukla, Marina Soliva Estruch, Thomas Bajaj, Tim Ebert, Katharine G. Mabbott, Luise Rostin, Alexandra Philipsen, William A. Carlezon, Barbara Gisabella, Robert E. McCullumsmith, John M. Vergis, Torsten Klengel, Sabina Berretta, Nikolaos P. Daskalakis, Harry Pantazopoulos, Nils C. Gassen, Kerry J. Ressler","doi":"10.1073/pnas.2417728121","DOIUrl":"https://doi.org/10.1073/pnas.2417728121","url":null,"abstract":"Genes involved in regulating the hypothalamic–pituitary–adrenal (HPA) axis, including the glucocorticoid receptor (GR), are linked to various stress-related psychopathologies including bipolar disorder as well as other mood and trauma-related disorders. The protein product of the cell cycle gene, <jats:italic>SKA2,</jats:italic> is a GR interaction partner in peripheral cells. However, the precise roles of SKA2 in stress and GR signaling in the brain, specifically in nonreplicating postmitotic neurons, and its involvement in HPA axis regulation remain unclear. Here, we demonstrate, using diverse in vitro cell assays, a mechanism by which SKA2 promotes GR signaling through enhancing GR–FKBP4 interaction leading to dissociation of FK506-bindingprotein 51 (FKBP5) from the complex. FKBP4 and FKBP5 are cochaperones known to regulate GR function in opposite directions. Notably in mice, SKA2 in <jats:italic>Crh</jats:italic> <jats:sup>+</jats:sup> neurons of the paraventricular nucleus of the hypothalamus is crucial for HPA axis responsiveness and for maintaining the negative feedback loop underlying allostasis. Moreover, we show that SKA2 expression is increased in postmortem human hippocampus and amygdala from individuals with BD. Our study highlights a critical role of SKA2 in HPA axis function, adds to the understanding of the molecular basis of stress-related psychiatric disorders, and points to potential targets for intervention.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"89 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142867593","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Is political interference causing faculty brain drain in the southern United States?","authors":"","doi":"10.1038/d41586-024-04070-1","DOIUrl":"https://doi.org/10.1038/d41586-024-04070-1","url":null,"abstract":"Faculty members say academic freedom is under fire, and many are seeking work outside the region.","PeriodicalId":18787,"journal":{"name":"Nature","volume":"12 1","pages":""},"PeriodicalIF":64.8,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142857878","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hydrogenotrophic methanogens overwrite isotope signals of subsurface methane.","authors":"Daisuke Mayumi, Hideyuki Tamaki, Souichiro Kato, Kensuke Igarashi, Ellen Lalk, Yasunori Nishikawa, Hideki Minagawa, Tomoyuki Sato, Shuhei Ono, Yoichi Kamagata, Susumu Sakata","doi":"10.1126/science.ado0126","DOIUrl":"https://doi.org/10.1126/science.ado0126","url":null,"abstract":"<p><p>Methane, a greenhouse gas and energy source, is commonly studied using stable isotope signals as proxies for its formation processes. In subsurface environments, methane often exhibits equilibrium isotopic signals, but the equilibration process has never been demonstrated in the laboratory. We cocultured a hydrogenotrophic methanogen with an H₂-producing bacterium under conditions (55°C, 10 megapascals) simulating a methane-bearing subsurface. This resulted in near-complete reversibility of methanogenesis, leading to equilibria for both hydrogen and carbon isotopes. The methanogen not only equilibrated kinetic isotope signals of initially produced methane but also modified the isotope signals of amended thermogenic methane. These findings suggest that hydrogenotrophic methanogenesis can overwrite the isotope signals of subsurface methane, distorting proxies for its origin and formation temperature-insights crucial for natural gas exploration.</p>","PeriodicalId":21678,"journal":{"name":"Science","volume":"386 6728","pages":"1372-1376"},"PeriodicalIF":44.7,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142865488","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tolerance on trial.","authors":"H Holden Thorp","doi":"10.1126/science.adv2874","DOIUrl":"https://doi.org/10.1126/science.adv2874","url":null,"abstract":"<p><p>Next year will mark the 100th anniversary of the Scopes trial, a 1925 court case in the US state of Tennessee on the teaching of evolution in public schools. John Scopes was tried for violating the Butler Act, a state rule that declared unlawful any teaching that denied the creation of man according to the Bible. The highly publicized event put an intense spotlight on William Jennings Bryan, a populist presidential candidate and religious fundamentalist who was counsel for the government, and on Clarence Darrow, a liberal agnostic and social justice advocate who defended Scopes. Scopes was found guilty, a verdict that was later overturned on a technicality. The trial was one of the first to be dubbed the \"trial of the century\" and has since been discussed, taught, and reflected on in books, plays, and movies (most notably, it was fictionalized in <i>Inherit the Wind</i>). A century later, the politics and sociology of that moment are still relevant, with implications for tolerance in today's world.</p>","PeriodicalId":21678,"journal":{"name":"Science","volume":"386 6728","pages":"1325"},"PeriodicalIF":44.7,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142865507","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Platform influencers-host RNA control of antiviral immunity.","authors":"Sonja M Best, Adam Hage","doi":"10.1126/science.adu4928","DOIUrl":"https://doi.org/10.1126/science.adu4928","url":null,"abstract":"<p><p>Cellular RNAs directly regulate the activity of an antiviral immune signaling complex.</p>","PeriodicalId":21678,"journal":{"name":"Science","volume":"386 6728","pages":"1346-1347"},"PeriodicalIF":44.7,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142865542","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}