Molecular Cell最新文献_第10页

Single-cell stimulus-response gene expression trajectories reveal the stimulus specificities of dynamic responses by single macrophages 单细胞刺激-反应基因表达轨迹揭示了单个巨噬细胞动态反应的刺激特异性

IF 16 1区生物学

Molecular Cell Pub Date : 2024-10-15 DOI: 10.1016/j.molcel.2024.09.023

Katherine M. Sheu, Aditya Pimplaskar, Alexander Hoffmann

{"title":"Single-cell stimulus-response gene expression trajectories reveal the stimulus specificities of dynamic responses by single macrophages","authors":"Katherine M. Sheu, Aditya Pimplaskar, Alexander Hoffmann","doi":"10.1016/j.molcel.2024.09.023","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.09.023","url":null,"abstract":"Macrophages induce the expression of hundreds of genes in response to immune threats. However, current technology limits our ability to capture single-cell inducible gene expression dynamics. Here, we generated high-resolution time series single-cell RNA sequencing (scRNA-seq) data from mouse macrophages responding to six stimuli, and imputed ensembles of real-time single-cell gene expression trajectories (scGETs). We found that dynamic information contained in scGETs substantially contributes to macrophage stimulus-response specificity (SRS). Dynamic information also identified correlations between immune response genes, indicating biological coordination. Furthermore, we showed that the microenvironmental context of polarizing cytokines profoundly affects scGETs, such that measuring response dynamics offered clearer discrimination of the polarization state of individual macrophage cells than single time-point measurements. Our findings highlight the important contribution of dynamic information contained in the single-cell expression responses of immune genes in characterizing the SRS and functional states of macrophages.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"83 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142436314","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Evidence of RNA polymerase III recruitment and transcription at protein-coding gene promoters RNA 聚合酶 III 招募和转录蛋白编码基因启动子的证据

IF 16 1区生物学

Molecular Cell Pub Date : 2024-10-10 DOI: 10.1016/j.molcel.2024.09.019

Rajendra K C, Ruiying Cheng, Sihang Zhou, Simon Lizarazo, Duncan J. Smith, Kevin Van Bortle

{"title":"Evidence of RNA polymerase III recruitment and transcription at protein-coding gene promoters","authors":"Rajendra K C, Ruiying Cheng, Sihang Zhou, Simon Lizarazo, Duncan J. Smith, Kevin Van Bortle","doi":"10.1016/j.molcel.2024.09.019","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.09.019","url":null,"abstract":"The transcriptional interplay of human RNA polymerase I (RNA Pol I), RNA Pol II, and RNA Pol III remains largely uncharacterized due to limited integrative genomic analyses for all three enzymes. To address this gap, we applied a uniform framework to quantify global RNA Pol I, RNA Pol II, and RNA Pol III occupancies and identify both canonical and noncanonical patterns of gene localization. Most notably, our survey captures unexpected RNA Pol III recruitment at promoters of specific protein-coding genes. We show that such RNA Pol III-occupied promoters are enriched for small nascent RNAs terminating in a run of 4 Ts—a hallmark of RNA Pol III termination indicative of constrained RNA Pol III transcription. Taken further, RNA Pol III disruption generally reduces the expression of RNA Pol III-occupied protein-coding genes, suggesting RNA Pol III recruitment and transcription enhance RNA Pol II activity. These findings resemble analogous patterns of RNA Pol II activity at RNA Pol III-transcribed genes, altogether uncovering a reciprocal form of crosstalk between RNA Pol II and RNA Pol III.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"38 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142398278","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

BRCA1 levels and DNA-damage response are controlled by the competitive binding of circHIPK3 or FMRP to the BRCA1 mRNA BRCA1水平和DNA损伤反应受控于circHIPK3或FMRP与BRCA1 mRNA的竞争性结合

IF 16 1区生物学

Molecular Cell Pub Date : 2024-10-09 DOI: 10.1016/j.molcel.2024.09.016

Chiara Grelloni, Raffaele Garraffo, Adriano Setti, Francesca Rossi, Giovanna Peruzzi, Mario Cinquanta, Maria Carmela Di Rosa, Marco Alessandro Pierotti, Manuel Beltran, Irene Bozzoni

{"title":"BRCA1 levels and DNA-damage response are controlled by the competitive binding of circHIPK3 or FMRP to the BRCA1 mRNA","authors":"Chiara Grelloni, Raffaele Garraffo, Adriano Setti, Francesca Rossi, Giovanna Peruzzi, Mario Cinquanta, Maria Carmela Di Rosa, Marco Alessandro Pierotti, Manuel Beltran, Irene Bozzoni","doi":"10.1016/j.molcel.2024.09.016","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.09.016","url":null,"abstract":"Circular RNAs (circRNAs) are covalently closed RNA molecules widely expressed in eukaryotes and deregulated in several pathologies, including cancer. Many studies point to their activity as microRNAs (miRNAs) and protein sponges; however, we propose a function based on circRNA-mRNA interaction to regulate mRNA fate. We show that the widely tumor-associated circHIPK3 directly interacts in vivo with the BRCA1 mRNA through the back-splicing region in human cancer cells. This interaction increases BRCA1 translation by competing for the binding of the fragile-X mental retardation 1 protein (FMRP) protein, which we identified as a BRCA1 translational repressor. CircHIPK3 depletion or disruption of the circRNA-mRNA interaction decreases BRCA1 protein levels and increases DNA damage, sensitizing several cancer cells to DNA-damage-inducing agents and rendering them susceptible to synthetic lethality. Additionally, blocking FMRP interaction with BRCA1 mRNA with locked nucleic acid (LNA) restores physiological protein levels in BRCA1 hemizygous breast cancer cells, underscoring the importance of this circRNA-mRNA interaction in regulating DNA-damage response.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"57 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142385959","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

HOXDeRNA activates a cancerous transcription program and super enhancers via genome-wide binding HOXDeRNA 通过全基因组结合激活癌症转录程序和超级增强子

IF 16 1区生物学

Molecular Cell Pub Date : 2024-10-08 DOI: 10.1016/j.molcel.2024.09.018

Evgeny Deforzh, Prakash Kharel, Yanhong Zhang, Anton Karelin, Abdellatif El Khayari, Pavel Ivanov, Anna M. Krichevsky

{"title":"HOXDeRNA activates a cancerous transcription program and super enhancers via genome-wide binding","authors":"Evgeny Deforzh, Prakash Kharel, Yanhong Zhang, Anton Karelin, Abdellatif El Khayari, Pavel Ivanov, Anna M. Krichevsky","doi":"10.1016/j.molcel.2024.09.018","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.09.018","url":null,"abstract":"The role of long non-coding RNAs (lncRNAs) in malignant cell transformation remains elusive. We previously identified an enhancer-associated lncRNA, LINC01116 (named HOXDeRNA), as a transformative factor converting human astrocytes into glioma-like cells. Employing a combination of CRISPR editing, chromatin isolation by RNA purification coupled with sequencing (ChIRP-seq), in situ mapping RNA-genome interactions (iMARGI), chromatin immunoprecipitation sequencing (ChIP-seq), HiC, and RNA/DNA FISH, we found that HOXDeRNA directly binds to CpG islands within the promoters of 35 glioma-specific transcription factors (TFs) distributed throughout the genome, including key stem cell TFs SOX2, OLIG2, POU3F2, and ASCL1, liberating them from PRC2 repression. This process requires a distinct RNA quadruplex structure and other segments of HOXDeRNA, interacting with EZH2 and CpGs, respectively. Subsequent transformation activates multiple oncogenes (e.g., EGFR, miR-21, and WEE1), driven by the SOX2- and OLIG2-dependent glioma-specific super enhancers. These results help reconstruct the sequence of events underlying the process of astrocyte transformation, highlighting HOXDeRNA’s central genome-wide activity and suggesting a shared RNA-dependent mechanism in otherwise heterogeneous and multifactorial gliomagenesis.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"51 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142384292","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Inactive Parp2 causes Tp53-dependent lethal anemia by blocking replication-associated nick ligation in erythroblasts 非活性 Parp2 通过阻断红细胞中与复制相关的缺口连接，导致 Tp53 依赖性致死性贫血

IF 16 1区生物学

Molecular Cell Pub Date : 2024-10-08 DOI: 10.1016/j.molcel.2024.09.020

Xiaohui Lin, Dipika Gupta, Alina Vaitsiankova, Seema Khattri Bhandari, Kay Sze Karina Leung, Demis Menolfi, Brian J. Lee, Helen R. Russell, Steven Gershik, Xiaoyu Huang, Wei Gu, Peter J. McKinnon, Françoise Dantzer, Eli Rothenberg, Alan E. Tomkinson, Shan Zha

{"title":"Inactive Parp2 causes Tp53-dependent lethal anemia by blocking replication-associated nick ligation in erythroblasts","authors":"Xiaohui Lin, Dipika Gupta, Alina Vaitsiankova, Seema Khattri Bhandari, Kay Sze Karina Leung, Demis Menolfi, Brian J. Lee, Helen R. Russell, Steven Gershik, Xiaoyu Huang, Wei Gu, Peter J. McKinnon, Françoise Dantzer, Eli Rothenberg, Alan E. Tomkinson, Shan Zha","doi":"10.1016/j.molcel.2024.09.020","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.09.020","url":null,"abstract":"Poly (ADP-ribose) polymerase (PARP) 1 and 2 enzymatic inhibitors (PARPi) are promising cancer treatments. But recently, their use has been hindered by unexplained severe anemia and treatment-related leukemia. In addition to enzymatic inhibition, PARPi also trap PARP1 and 2 at DNA lesions. Here we report that, unlike Parp2−/− mice, which develop normally, mice expressing catalytically inactive Parp2 (E534A and Parp2EA/EA) succumb to Tp53- and Chk2-dependent erythropoietic failure in utero, mirroring Lig1−/− mice. While DNA damage mainly activates PARP1, we demonstrate that DNA replication activates PARP2 robustly. PARP2 is selectively recruited and activated by 5′-phosphorylated nicks (5′p-nicks), including those between Okazaki fragments, resolved by ligase 1 (Lig1) and Lig3. Inactive PARP2, but not its active form or absence, impedes Lig1- and Lig3-mediated ligation, causing dose-dependent replication fork collapse, which is detrimental to erythroblasts with ultra-fast forks. This PARylation-dependent structural function of PARP2 at 5′p-nicks explains the detrimental effects of PARP2 inactivation on erythropoiesis, shedding light on PARPi-induced anemia and the selection for TP53/CHK2 loss.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"14 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142384289","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The H3.3K36M oncohistone disrupts the establishment of epigenetic memory through loss of DNA methylation H3.3K36M 同源组蛋白通过 DNA 甲基化的丧失破坏表观遗传记忆的建立

IF 16 1区生物学

Molecular Cell Pub Date : 2024-10-04 DOI: 10.1016/j.molcel.2024.09.015

Joydeb Sinha, Jan F. Nickels, Abby R. Thurm, Connor H. Ludwig, Bella N. Archibald, Michaela M. Hinks, Jun Wan, Dong Fang, Lacramioara Bintu

{"title":"The H3.3K36M oncohistone disrupts the establishment of epigenetic memory through loss of DNA methylation","authors":"Joydeb Sinha, Jan F. Nickels, Abby R. Thurm, Connor H. Ludwig, Bella N. Archibald, Michaela M. Hinks, Jun Wan, Dong Fang, Lacramioara Bintu","doi":"10.1016/j.molcel.2024.09.015","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.09.015","url":null,"abstract":"Histone H3.3 is frequently mutated in tumors, with the lysine 36 to methionine mutation (K36M) being a hallmark of chondroblastomas. While it is known that H3.3K36M changes the epigenetic landscape, its effects on gene expression dynamics remain unclear. Here, we use a synthetic reporter to measure the effects of H3.3K36M on silencing and epigenetic memory after recruitment of the ZNF10 Krüppel-associated box (KRAB) domain, part of the largest class of human repressors and associated with H3K9me3 deposition. We find that H3.3K36M, which decreases H3K36 methylation and increases histone acetylation, leads to a decrease in epigenetic memory and promoter methylation weeks after KRAB release. We propose a model for establishment and maintenance of epigenetic memory, where the H3K36 methylation pathway is necessary to maintain histone deacetylation and convert H3K9me3 domains into DNA methylation for stable epigenetic memory. Our quantitative model can inform oncogenic mechanisms and guide development of epigenetic editing tools.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"51 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142374104","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The structural landscape of Microprocessor-mediated processing of pri-let-7 miRNAs 微处理器介导的 pri-let-7 miRNA 处理结构图

IF 16 1区生物学

Molecular Cell Pub Date : 2024-10-04 DOI: 10.1016/j.molcel.2024.09.008

Ankur Garg, Renfu Shang, Todor Cvetanovic, Eric C. Lai, Leemor Joshua-Tor

{"title":"The structural landscape of Microprocessor-mediated processing of pri-let-7 miRNAs","authors":"Ankur Garg, Renfu Shang, Todor Cvetanovic, Eric C. Lai, Leemor Joshua-Tor","doi":"10.1016/j.molcel.2024.09.008","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.09.008","url":null,"abstract":"MicroRNA (miRNA) biogenesis is initiated upon cleavage of a primary miRNA (pri-miRNA) hairpin by the Microprocessor (MP), composed of the Drosha RNase III enzyme and its partner DGCR8. Multiple pri-miRNA sequence motifs affect MP recognition, fidelity, and efficiency. Here, we performed cryoelectron microscopy (cryo-EM) and biochemical studies of several let-7 family pri-miRNAs in complex with human MP. We show that MP has the structural plasticity to accommodate a range of pri-miRNAs. These structures revealed key features of the 5′ UG sequence motif, more comprehensively represented as the “flipped U with paired N” (fUN) motif. Our analysis explains how cleavage of class-II pri-let-7 members harboring a bulged nucleotide generates a non-canonical precursor with a 1-nt 3′ overhang. Finally, the MP-SRSF3-pri-let-7f1 structure reveals how SRSF3 contributes to MP fidelity by interacting with the CNNC motif and Drosha’s Piwi/Argonaute/Zwille (PAZ)-like domain. Overall, this study sheds light on the mechanisms for flexible recognition, accurate cleavage, and regulated processing of different pri-miRNAs by MP.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"9 8 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142374106","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Cell-cycle-dependent mRNA localization in P-bodies 细胞周期依赖的 mRNA 在 P 体内的定位

IF 16 1区生物学

Molecular Cell Pub Date : 2024-10-04 DOI: 10.1016/j.molcel.2024.09.011

Adham Safieddine, Marie-Noëlle Benassy, Thomas Bonte, Floric Slimani, Oriane Pourcelot, Michel Kress, Michèle Ernoult-Lange, Maïté Courel, Emeline Coleno, Arthur Imbert, Antoine Laine, Annie Munier Godebert, Angelique Vinit, Corinne Blugeon, Guillaume Chevreux, Daniel Gautheret, Thomas Walter, Edouard Bertrand, Marianne Bénard, Dominique Weil

{"title":"Cell-cycle-dependent mRNA localization in P-bodies","authors":"Adham Safieddine, Marie-Noëlle Benassy, Thomas Bonte, Floric Slimani, Oriane Pourcelot, Michel Kress, Michèle Ernoult-Lange, Maïté Courel, Emeline Coleno, Arthur Imbert, Antoine Laine, Annie Munier Godebert, Angelique Vinit, Corinne Blugeon, Guillaume Chevreux, Daniel Gautheret, Thomas Walter, Edouard Bertrand, Marianne Bénard, Dominique Weil","doi":"10.1016/j.molcel.2024.09.011","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.09.011","url":null,"abstract":"Understanding the dynamics of RNA targeting to membraneless organelles is essential to disentangle their functions. Here, we investigate how P-bodies (PBs) evolve during cell-cycle progression in HEK293 cells. PB purification across the cell cycle uncovers widespread changes in their RNA content, partly uncoupled from cell-cycle-dependent changes in RNA expression. Single-molecule fluorescence in situ hybridization (FISH) shows various mRNA localization patterns in PBs peaking in G1, S, or G2, with examples illustrating the timely capture of mRNAs in PBs when their encoded protein becomes dispensable. Rather than directly reflecting absence of translation, cyclic mRNA localization in PBs can be controlled by RBPs, such as HuR in G2, and by RNA features. Indeed, while PB mRNAs are AU rich at all cell-cycle phases, they are specifically longer in G1, possibly related to post-mitotic PB reassembly. Altogether, our study supports a model where PBs are more than a default location for excess untranslated mRNAs.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"207 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142374105","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The challenges of investigating RNA function 研究 RNA 功能面临的挑战

IF 16 1区生物学

Molecular Cell Pub Date : 2024-10-03 DOI: 10.1016/j.molcel.2024.08.019

Li Yang, Igor Ulitsky, Wendy V. Gilbert, Chengqi Yi, Jernej Ule, Maïwen Caudron-Herger

引用次数: 0

PRC2-RNA interactions: Viewpoint from Tom Cech, Chen Davidovich, and Richard Jenner PRC2-RNA 相互作用：Tom Cech、Chen Davidovich 和 Richard Jenner 的观点

IF 16 1区生物学

Molecular Cell Pub Date : 2024-10-03 DOI: 10.1016/j.molcel.2024.09.010

Thomas R. Cech, Chen Davidovich, Richard G. Jenner

引用次数: 0