Molecular Systems Biology最新文献_第4页

A new way of looking at transcription factor assays. 转录因子检测的新视角。

IF 8.5 1区生物学

Molecular Systems Biology Pub Date : 2024-07-01 Epub Date: 2024-06-07 DOI: 10.1038/s44320-024-00044-7

Alan F Rubin

引用次数: 0

Deep mutational scanning quantifies DNA binding and predicts clinical outcomes of PAX6 variants. 深度突变扫描可量化 DNA 结合并预测 PAX6 变体的临床结果。

IF 8.5 1区生物学

Molecular Systems Biology Pub Date : 2024-07-01 Epub Date: 2024-06-07 DOI: 10.1038/s44320-024-00043-8

Alexander F McDonnell, Marcin Plech, Benjamin J Livesey, Lukas Gerasimavicius, Liusaidh J Owen, Hildegard Nikki Hall, David R FitzPatrick, Joseph A Marsh, Grzegorz Kudla

{"title":"Deep mutational scanning quantifies DNA binding and predicts clinical outcomes of PAX6 variants.","authors":"Alexander F McDonnell, Marcin Plech, Benjamin J Livesey, Lukas Gerasimavicius, Liusaidh J Owen, Hildegard Nikki Hall, David R FitzPatrick, Joseph A Marsh, Grzegorz Kudla","doi":"10.1038/s44320-024-00043-8","DOIUrl":"10.1038/s44320-024-00043-8","url":null,"abstract":"Nonsense and missense mutations in the transcription factor PAX6 cause a wide range of eye development defects, including aniridia, microphthalmia and coloboma. To understand how changes of PAX6:DNA binding cause these phenotypes, we combined saturation mutagenesis of the paired domain of PAX6 with a yeast one-hybrid (Y1H) assay in which expression of a PAX6-GAL4 fusion gene drives antibiotic resistance. We quantified binding of more than 2700 single amino-acid variants to two DNA sequence elements. Mutations in DNA-facing residues of the N-terminal subdomain and linker region were most detrimental, as were mutations to prolines and to negatively charged residues. Many variants caused sequence-specific molecular gain-of-function effects, including variants in position 71 that increased binding to the LE9 enhancer but decreased binding to a SELEX-derived binding site. In the absence of antibiotic selection, variants that retained DNA binding slowed yeast growth, likely because such variants perturbed the yeast transcriptome. Benchmarking against known patient variants and applying ACMG/AMP guidelines to variant classification, we obtained supporting-to-moderate evidence that 977 variants are likely pathogenic and 1306 are likely benign. Our analysis shows that most pathogenic mutations in the paired domain of PAX6 can be explained simply by the effects of these mutations on PAX6:DNA association, and establishes Y1H as a generalisable assay for the interpretation of variant effects in transcription factors.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"825-844"},"PeriodicalIF":8.5,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11219921/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141288337","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A continuum of zinc finger transcription factor retention on native chromatin underlies dynamic genome organization. 锌指转录因子在原生染色质上的连续保留是动态基因组组织的基础。

IF 8.5 1区生物学

Molecular Systems Biology Pub Date : 2024-07-01 Epub Date: 2024-05-14 DOI: 10.1038/s44320-024-00038-5

Siling Hu, Yangying Liu, Qifan Zhang, Juan Bai, Chenhuan Xu

{"title":"A continuum of zinc finger transcription factor retention on native chromatin underlies dynamic genome organization.","authors":"Siling Hu, Yangying Liu, Qifan Zhang, Juan Bai, Chenhuan Xu","doi":"10.1038/s44320-024-00038-5","DOIUrl":"10.1038/s44320-024-00038-5","url":null,"abstract":"Transcription factor (TF) residence on chromatin translates into quantitative transcriptional or structural outcomes on genome. Commonly used formaldehyde crosslinking fixes TF-DNA interactions cumulatively and compromises the measured occupancy level. Here we mapped the occupancy level of global or individual zinc finger TFs like CTCF and MAZ, in the form of highly resolved footprints, on native chromatin. By incorporating reinforcing perturbation conditions, we established S-score, a quantitative metric to proxy the continuum of CTCF or MAZ retention across different motifs on native chromatin. The native chromatin-retained CTCF sites harbor sequence features within CTCF motifs better explained by S-score than the metrics obtained from other crosslinking or native assays. CTCF retention on native chromatin correlates with local SUMOylation level, and anti-correlates with transcriptional activity. The S-score successfully delineates the otherwise-masked differential stability of chromatin structures mediated by CTCF, or by MAZ independent of CTCF. Overall, our study established a paradigm continuum of TF retention across binding sites on native chromatin, explaining the dynamic genome organization.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"799-824"},"PeriodicalIF":8.5,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11220090/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140922704","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Uncovering the dynamics and consequences of RNA isoform changes during neuronal differentiation. 揭示神经元分化过程中 RNA 同工酶变化的动态及后果

IF 8.5 1区生物学

Molecular Systems Biology Pub Date : 2024-07-01 Epub Date: 2024-05-16 DOI: 10.1038/s44320-024-00039-4

Jelena Ulicevic, Zhihao Shao, Olga Jasnovidova, Annkatrin Bressin, Martyna Gajos, Alex Hm Ng, Siddharth Annaldasula, David Meierhofer, George M Church, Volker Busskamp, Andreas Mayer

{"title":"Uncovering the dynamics and consequences of RNA isoform changes during neuronal differentiation.","authors":"Jelena Ulicevic, Zhihao Shao, Olga Jasnovidova, Annkatrin Bressin, Martyna Gajos, Alex Hm Ng, Siddharth Annaldasula, David Meierhofer, George M Church, Volker Busskamp, Andreas Mayer","doi":"10.1038/s44320-024-00039-4","DOIUrl":"10.1038/s44320-024-00039-4","url":null,"abstract":"Static gene expression programs have been extensively characterized in stem cells and mature human cells. However, the dynamics of RNA isoform changes upon cell-state-transitions during cell differentiation, the determinants and functional consequences have largely remained unclear. Here, we established an improved model for human neurogenesis in vitro that is amenable for systems-wide analyses of gene expression. Our multi-omics analysis reveals that the pronounced alterations in cell morphology correlate strongly with widespread changes in RNA isoform expression. Our approach identifies thousands of new RNA isoforms that are expressed at distinct differentiation stages. RNA isoforms mainly arise from exon skipping and the alternative usage of transcription start and polyadenylation sites during human neurogenesis. The transcript isoform changes can remodel the identity and functions of protein isoforms. Finally, our study identifies a set of RNA binding proteins as a potential determinant of differentiation stage-specific global isoform changes. This work supports the view of regulated isoform changes that underlie state-transitions during neurogenesis.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"767-798"},"PeriodicalIF":8.5,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11219738/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140958457","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Building and analyzing metacells in single-cell genomics data. 在单细胞基因组学数据中构建和分析元胞。

IF 8.5 1区生物学

Molecular Systems Biology Pub Date : 2024-07-01 Epub Date: 2024-05-29 DOI: 10.1038/s44320-024-00045-6

Mariia Bilous, Léonard Hérault, Aurélie Ag Gabriel, Matei Teleman, David Gfeller

{"title":"Building and analyzing metacells in single-cell genomics data.","authors":"Mariia Bilous, Léonard Hérault, Aurélie Ag Gabriel, Matei Teleman, David Gfeller","doi":"10.1038/s44320-024-00045-6","DOIUrl":"10.1038/s44320-024-00045-6","url":null,"abstract":"The advent of high-throughput single-cell genomics technologies has fundamentally transformed biological sciences. Currently, millions of cells from complex biological tissues can be phenotypically profiled across multiple modalities. The scaling of computational methods to analyze and visualize such data is a constant challenge, and tools need to be regularly updated, if not redesigned, to cope with ever-growing numbers of cells. Over the last few years, metacells have been introduced to reduce the size and complexity of single-cell genomics data while preserving biologically relevant information and improving interpretability. Here, we review recent studies that capitalize on the concept of metacells-and the many variants in nomenclature that have been used. We further outline how and when metacells should (or should not) be used to analyze single-cell genomics data and what should be considered when analyzing such data at the metacell level. To facilitate the exploration of metacells, we provide a comprehensive tutorial on the construction and analysis of metacells from single-cell RNA-seq data ( https://github.com/GfellerLab/MetacellAnalysisTutorial ) as well as a fully integrated pipeline to rapidly build, visualize and evaluate metacells with different methods ( https://github.com/GfellerLab/MetacellAnalysisToolkit ).","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"744-766"},"PeriodicalIF":8.5,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11220014/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141176158","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Systematic identification of structure-specific protein-protein interactions. 系统识别结构特异的蛋白质-蛋白质相互作用。

IF 8.5 1区生物学

Molecular Systems Biology Pub Date : 2024-06-01 Epub Date: 2024-05-03 DOI: 10.1038/s44320-024-00037-6

Aleš Holfeld, Dina Schuster, Fabian Sesterhenn, Alison K Gillingham, Patrick Stalder, Walther Haenseler, Inigo Barrio-Hernandez, Dhiman Ghosh, Jane Vowles, Sally A Cowley, Luise Nagel, Basavraj Khanppnavar, Tetiana Serdiuk, Pedro Beltrao, Volodymyr M Korkhov, Sean Munro, Roland Riek, Natalie de Souza, Paola Picotti

{"title":"Systematic identification of structure-specific protein-protein interactions.","authors":"Aleš Holfeld, Dina Schuster, Fabian Sesterhenn, Alison K Gillingham, Patrick Stalder, Walther Haenseler, Inigo Barrio-Hernandez, Dhiman Ghosh, Jane Vowles, Sally A Cowley, Luise Nagel, Basavraj Khanppnavar, Tetiana Serdiuk, Pedro Beltrao, Volodymyr M Korkhov, Sean Munro, Roland Riek, Natalie de Souza, Paola Picotti","doi":"10.1038/s44320-024-00037-6","DOIUrl":"10.1038/s44320-024-00037-6","url":null,"abstract":"The physical interactome of a protein can be altered upon perturbation, modulating cell physiology and contributing to disease. Identifying interactome differences of normal and disease states of proteins could help understand disease mechanisms, but current methods do not pinpoint structure-specific PPIs and interaction interfaces proteome-wide. We used limited proteolysis-mass spectrometry (LiP-MS) to screen for structure-specific PPIs by probing for protease susceptibility changes of proteins in cellular extracts upon treatment with specific structural states of a protein. We first demonstrated that LiP-MS detects well-characterized PPIs, including antibody-target protein interactions and interactions with membrane proteins, and that it pinpoints interfaces, including epitopes. We then applied the approach to study conformation-specific interactors of the Parkinson's disease hallmark protein alpha-synuclein (aSyn). We identified known interactors of aSyn monomer and amyloid fibrils and provide a resource of novel putative conformation-specific aSyn interactors for validation in further studies. We also used our approach on GDP- and GTP-bound forms of two Rab GTPases, showing detection of differential candidate interactors of conformationally similar proteins. This approach is applicable to screen for structure-specific interactomes of any protein, including posttranslationally modified and unmodified, or metabolite-bound and unbound protein states.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"651-675"},"PeriodicalIF":8.5,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11148107/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140857211","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Genome-wide CRISPR screens identify novel regulators of wild-type and mutant p53 stability. 全基因组 CRISPR 筛选确定了野生型和突变型 p53 稳定性的新型调节器。

IF 9.9 1区生物学

Molecular Systems Biology Pub Date : 2024-06-01 Epub Date: 2024-04-05 DOI: 10.1038/s44320-024-00032-x

YiQing Lü, Tiffany Cho, Saptaparna Mukherjee, Carmen Florencia Suarez, Nicolas S Gonzalez-Foutel, Ahmad Malik, Sebastien Martinez, Dzana Dervovic, Robin Hyunseo Oh, Ellen Langille, Khalid N Al-Zahrani, Lisa Hoeg, Zhen Yuan Lin, Ricky Tsai, Geraldine Mbamalu, Varda Rotter, Patricia Ashton-Prolla, Jason Moffat, Lucia Beatriz Chemes, Anne-Claude Gingras, Moshe Oren, Daniel Durocher, Daniel Schramek

{"title":"Genome-wide CRISPR screens identify novel regulators of wild-type and mutant p53 stability.","authors":"YiQing Lü, Tiffany Cho, Saptaparna Mukherjee, Carmen Florencia Suarez, Nicolas S Gonzalez-Foutel, Ahmad Malik, Sebastien Martinez, Dzana Dervovic, Robin Hyunseo Oh, Ellen Langille, Khalid N Al-Zahrani, Lisa Hoeg, Zhen Yuan Lin, Ricky Tsai, Geraldine Mbamalu, Varda Rotter, Patricia Ashton-Prolla, Jason Moffat, Lucia Beatriz Chemes, Anne-Claude Gingras, Moshe Oren, Daniel Durocher, Daniel Schramek","doi":"10.1038/s44320-024-00032-x","DOIUrl":"10.1038/s44320-024-00032-x","url":null,"abstract":"Tumor suppressor p53 (TP53) is frequently mutated in cancer, often resulting not only in loss of its tumor-suppressive function but also acquisition of dominant-negative and even oncogenic gain-of-function traits. While wild-type p53 levels are tightly regulated, mutants are typically stabilized in tumors, which is crucial for their oncogenic properties. Here, we systematically profiled the factors that regulate protein stability of wild-type and mutant p53 using marker-based genome-wide CRISPR screens. Most regulators of wild-type p53 also regulate p53 mutants, except for p53 R337H regulators, which are largely private to this mutant. Mechanistically, FBXO42 emerged as a positive regulator for a subset of p53 mutants, working with CCDC6 to control USP28-mediated mutant p53 stabilization. Additionally, C16orf72/HAPSTR1 negatively regulates both wild-type p53 and all tested mutants. C16orf72/HAPSTR1 is commonly amplified in breast cancer, and its overexpression reduces p53 levels in mouse mammary epithelium leading to accelerated breast cancer. This study offers a network perspective on p53 stability regulation, potentially guiding strategies to reinforce wild-type p53 or target mutant p53 in cancer.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"719-740"},"PeriodicalIF":9.9,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11148184/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140869136","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Dietary fiber and gut bacteria shape infection susceptibility. 膳食纤维和肠道细菌影响感染易感性。

IF 9.9 1区生物学

Molecular Systems Biology Pub Date : 2024-06-01 Epub Date: 2024-05-23 DOI: 10.1038/s44320-024-00042-9

Aqsa Mohammed, Robert R Jenq

引用次数: 0

Diet-driven differential response of Akkermansia muciniphila modulates pathogen susceptibility. 饮食驱动的 Akkermansia muciniphila 不同反应调节了病原体的易感性。

IF 8.5 1区生物学

Molecular Systems Biology Pub Date : 2024-06-01 Epub Date: 2024-05-14 DOI: 10.1038/s44320-024-00036-7

Mathis Wolter, Erica T Grant, Marie Boudaud, Nicholas A Pudlo, Gabriel V Pereira, Kathryn A Eaton, Eric C Martens, Mahesh S Desai

{"title":"Diet-driven differential response of Akkermansia muciniphila modulates pathogen susceptibility.","authors":"Mathis Wolter, Erica T Grant, Marie Boudaud, Nicholas A Pudlo, Gabriel V Pereira, Kathryn A Eaton, Eric C Martens, Mahesh S Desai","doi":"10.1038/s44320-024-00036-7","DOIUrl":"10.1038/s44320-024-00036-7","url":null,"abstract":"The erosion of the colonic mucus layer by a dietary fiber-deprived gut microbiota results in heightened susceptibility to an attaching and effacing pathogen, Citrobacter rodentium. Nevertheless, the questions of whether and how specific mucolytic bacteria aid in the increased pathogen susceptibility remain unexplored. Here, we leverage a functionally characterized, 14-member synthetic human microbiota in gnotobiotic mice to deduce which bacteria and functions are responsible for the pathogen susceptibility. Using strain dropouts of mucolytic bacteria from the community, we show that Akkermansia muciniphila renders the host more vulnerable to the mucosal pathogen during fiber deprivation. However, the presence of A. muciniphila reduces pathogen load on a fiber-sufficient diet, highlighting the context-dependent beneficial effects of this mucin specialist. The enhanced pathogen susceptibility is not owing to altered host immune or pathogen responses, but is driven by a combination of increased mucus penetrability and altered activities of A. muciniphila and other community members. Our study provides novel insights into the mechanisms of how discrete functional responses of the same mucolytic bacterium either resist or enhance enteric pathogen susceptibility.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"596-625"},"PeriodicalIF":8.5,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11148096/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140922754","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

An integrative epigenome-based strategy for unbiased functional profiling of clinical kinase inhibitors. 基于表观基因组的综合策略，对临床激酶抑制剂进行无偏见的功能分析。

IF 9.9 1区生物学

Molecular Systems Biology Pub Date : 2024-06-01 Epub Date: 2024-05-09 DOI: 10.1038/s44320-024-00040-x

Francesco Gualdrini, Stefano Rizzieri, Sara Polletti, Francesco Pileri, Yinxiu Zhan, Alessandro Cuomo, Gioacchino Natoli

{"title":"An integrative epigenome-based strategy for unbiased functional profiling of clinical kinase inhibitors.","authors":"Francesco Gualdrini, Stefano Rizzieri, Sara Polletti, Francesco Pileri, Yinxiu Zhan, Alessandro Cuomo, Gioacchino Natoli","doi":"10.1038/s44320-024-00040-x","DOIUrl":"10.1038/s44320-024-00040-x","url":null,"abstract":"More than 500 kinases are implicated in the control of most cellular process in mammals, and deregulation of their activity is linked to cancer and inflammatory disorders. 80 clinical kinase inhibitors (CKIs) have been approved for clinical use and hundreds are in various stages of development. However, CKIs inhibit other kinases in addition to the intended target(s), causing both enhanced clinical effects and undesired side effects that are only partially predictable based on in vitro selectivity profiling. Here, we report an integrative approach grounded on the use of chromatin modifications as unbiased, information-rich readouts of the functional effects of CKIs on macrophage activation. This approach exceeded the performance of transcriptome-based approaches and allowed us to identify similarities and differences among CKIs with identical intended targets, to recognize novel CKI specificities and to pinpoint CKIs that may be repurposed to control inflammation, thus supporting the utility of this strategy to improve selection and use of CKIs in clinical settings.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"626-650"},"PeriodicalIF":9.9,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11148061/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140897948","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0