Pub Date : 2025-01-02DOI: 10.1016/j.molcel.2024.12.009
Yantao Hong, Xiaohua Shen
In a recent issue of Cell, Arribas et al.1 and Pasquesi et al.2 explore the phenomenon of transposable element (TE) exonization and its impact on proteomic and immune diversity, highlighting its potential role as a driver of evolutionary innovation.
{"title":"Transposon exonization generates new protein-coding sequences","authors":"Yantao Hong, Xiaohua Shen","doi":"10.1016/j.molcel.2024.12.009","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.12.009","url":null,"abstract":"In a recent issue of <em>Cell</em>, Arribas et al<em>.</em><span><span><sup>1</sup></span></span> and Pasquesi et al.<span><span><sup>2</sup></span></span> explore the phenomenon of transposable element (TE) exonization and its impact on proteomic and immune diversity, highlighting its potential role as a driver of evolutionary innovation.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"42 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142912156","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}
Pub Date : 2025-01-02DOI: 10.1016/j.molcel.2024.12.008
Tobias D. Williams, Ewa M. Michalak, Kirstyn.T. Carey, Enid Y.N. Lam, Ashley Anderson, Esther Griesbach, Yih-Chih Chan, Panagiotis Papasaikas, Vicky W.T. Tan, Linh Ngo, Laura MacPherson, Omer Gilan, Amber Rucinski, Anna Rutkowska-Klute, Nico Zinn, Paola Grandi, Marcus Bantscheff, Rab K. Prinjha, Sarah-Jane Dawson, Jeffrey A. Chao, Mark A. Dawson
Several transcription inhibitors have been developed as cancer therapies. However, they show modest clinical activity, highlighting that our understanding of the cellular response to transcriptional inhibition remains incomplete. Here we report that potent inhibitors of transcription not only impact mRNA output but also markedly impair mRNA transcript localization and nuclear export. We demonstrate that retention of newly transcribed mRNA in nuclear speckles is an adaptive response to chemically distinct transcriptional inhibitors. Retained transcripts are fully processed and accumulate in proportion to the expression level of the genes from which they emanate. The TREX mRNA export complex plays an integral role in directing nascent transcripts to nuclear speckles where they are bound to NXF1, protected from degradation, and poised for rapid export following re-initiation of transcription. Our findings provide new insights into the crosstalk between transcription and mRNA export with important implications for drugs aiming to inhibit transcription for therapeutic gain.
{"title":"mRNA export factors store nascent transcripts within nuclear speckles as an adaptive response to transient global inhibition of transcription","authors":"Tobias D. Williams, Ewa M. Michalak, Kirstyn.T. Carey, Enid Y.N. Lam, Ashley Anderson, Esther Griesbach, Yih-Chih Chan, Panagiotis Papasaikas, Vicky W.T. Tan, Linh Ngo, Laura MacPherson, Omer Gilan, Amber Rucinski, Anna Rutkowska-Klute, Nico Zinn, Paola Grandi, Marcus Bantscheff, Rab K. Prinjha, Sarah-Jane Dawson, Jeffrey A. Chao, Mark A. Dawson","doi":"10.1016/j.molcel.2024.12.008","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.12.008","url":null,"abstract":"Several transcription inhibitors have been developed as cancer therapies. However, they show modest clinical activity, highlighting that our understanding of the cellular response to transcriptional inhibition remains incomplete. Here we report that potent inhibitors of transcription not only impact mRNA output but also markedly impair mRNA transcript localization and nuclear export. We demonstrate that retention of newly transcribed mRNA in nuclear speckles is an adaptive response to chemically distinct transcriptional inhibitors. Retained transcripts are fully processed and accumulate in proportion to the expression level of the genes from which they emanate. The TREX mRNA export complex plays an integral role in directing nascent transcripts to nuclear speckles where they are bound to NXF1, protected from degradation, and poised for rapid export following re-initiation of transcription. Our findings provide new insights into the crosstalk between transcription and mRNA export with important implications for drugs aiming to inhibit transcription for therapeutic gain.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"34 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142912157","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}
Pub Date : 2025-01-02DOI: 10.1016/j.molcel.2024.12.006
Cody M. Rogers, Patrick Sung
In this issue of Molecular Cell, studies by Xu et al.,1 Kimble et al.,2 and Elango et al.3 examine how yeast and mammalian cells process DNA double-strand breaks that arise when the DNA replication machinery encounters a DNA nick.
{"title":"Deciphering the fate of replication-induced DNA double-strand breaks","authors":"Cody M. Rogers, Patrick Sung","doi":"10.1016/j.molcel.2024.12.006","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.12.006","url":null,"abstract":"In this issue of <em>Molecular Cell</em>, studies by Xu et al.,<span><span><sup>1</sup></span></span> Kimble et al.,<span><span><sup>2</sup></span></span> and Elango et al.<span><span><sup>3</sup></span></span> examine how yeast and mammalian cells process DNA double-strand breaks that arise when the DNA replication machinery encounters a DNA nick.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"20 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142912153","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}
Pub Date : 2025-01-02DOI: 10.1016/j.molcel.2024.12.003
William C. Merrick
While most of the regulation of translation initiation occurs in the cytosol predominantly through phosphorylation, Ly et al. have discovered the first instance of regulation via protein concentration due to disruption of the nuclear membrane at mitosis.1 Only eIF1 appears to be involved in this regulation, and its release at mitosis enhances translational accuracy of start codon recognition.
{"title":"A little protein makes big news in translation initiation","authors":"William C. Merrick","doi":"10.1016/j.molcel.2024.12.003","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.12.003","url":null,"abstract":"While most of the regulation of translation initiation occurs in the cytosol predominantly through phosphorylation, Ly et al. have discovered the first instance of regulation via protein concentration due to disruption of the nuclear membrane at mitosis.<span><span><sup>1</sup></span></span> Only eIF1 appears to be involved in this regulation, and its release at mitosis enhances translational accuracy of start codon recognition.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"4 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142912154","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}
Pub Date : 2024-12-31DOI: 10.1016/j.molcel.2024.12.004
Yajie Gu, Huan Li, Amar Deep, Eray Enustun, Dapeng Zhang, Kevin D. Corbett
Prokaryotes possess diverse anti-bacteriophage immune systems, including the single-protein Shedu nuclease. Here, we reveal the structural basis for activation of Bacillus cereus Shedu. Two cryoelectron microscopy structures of Shedu show that it switches between inactive and active states through conformational changes affecting active-site architecture, which are controlled by the protein’s N-terminal domain (NTD). We find that B. cereus Shedu cleaves near DNA ends with a 3′ single-stranded overhang, likely enabling it to specifically degrade the DNA injected by certain bacteriophages. Bioinformatic analysis of Shedu homologs reveals a conserved nuclease domain with remarkably diverse N-terminal regulatory domains: we identify 79 distinct NTD types falling into eight broad classes, including those with predicted nucleic acid binding, enzymatic, and other activities. Together, these data reveal Shedu as a broad family of immune nucleases with a common nuclease core regulated by diverse NTDs that likely respond to a range of signals.
{"title":"Bacterial Shedu immune nucleases share a common enzymatic core regulated by diverse sensor domains","authors":"Yajie Gu, Huan Li, Amar Deep, Eray Enustun, Dapeng Zhang, Kevin D. Corbett","doi":"10.1016/j.molcel.2024.12.004","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.12.004","url":null,"abstract":"Prokaryotes possess diverse anti-bacteriophage immune systems, including the single-protein Shedu nuclease. Here, we reveal the structural basis for activation of <em>Bacillus cereus</em> Shedu. Two cryoelectron microscopy structures of Shedu show that it switches between inactive and active states through conformational changes affecting active-site architecture, which are controlled by the protein’s N-terminal domain (NTD). We find that <em>B. cereus</em> Shedu cleaves near DNA ends with a 3′ single-stranded overhang, likely enabling it to specifically degrade the DNA injected by certain bacteriophages. Bioinformatic analysis of Shedu homologs reveals a conserved nuclease domain with remarkably diverse N-terminal regulatory domains: we identify 79 distinct NTD types falling into eight broad classes, including those with predicted nucleic acid binding, enzymatic, and other activities. Together, these data reveal Shedu as a broad family of immune nucleases with a common nuclease core regulated by diverse NTDs that likely respond to a range of signals.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"20 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142905040","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}
In multicellular organisms, very little is known about how Ca2+ transients on the ER outer surface elicited by autophagy stimuli are sustained and decoded to trigger autophagosome formation. Here, we show that Ca2+/calmodulin-dependent protein kinase II β (CaMKIIβ) integrates ER Ca2+ transients to trigger liquid-liquid phase separation (LLPS) of the autophagosome-initiating FIP200 complex. In response to ER Ca2+ transients, CaMKIIβ is recruited from actin filaments and forms condensates, which serve as sites for the emergence of or interaction with FIP200 puncta. CaMKIIβ phosphorylates FIP200 at Thr269, Thr1127, and Ser1484 to modulate LLPS and properties of the FIP200 complex, thereby controlling its function in autophagosome formation. CaMKIIβ also controls the amplitude, duration, and propagation of ER Ca2+ transients during autophagy induction. CaMKIIβ mutations identified in the neurodevelopmental disorder MRD54 affect the function of CaMKIIβ in autophagy. Our study reveals that CaMKIIβ is essential for sustaining and decoding ER Ca2+ transients to specify autophagosome formation in mammalian cells.
{"title":"Ca2+/calmodulin-dependent protein kinase II β decodes ER Ca2+ transients to trigger autophagosome formation","authors":"Qiaoxia Zheng, Huan Zhang, Hongyu Zhao, Yong Chen, Hongzhining Yang, Tingting Li, Qixu Cai, Yingyu Chen, Youjun Wang, Mingjie Zhang, Hong Zhang","doi":"10.1016/j.molcel.2024.12.005","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.12.005","url":null,"abstract":"In multicellular organisms, very little is known about how Ca<sup>2+</sup> transients on the ER outer surface elicited by autophagy stimuli are sustained and decoded to trigger autophagosome formation. Here, we show that Ca<sup>2+</sup>/calmodulin-dependent protein kinase II β (CaMKIIβ) integrates ER Ca<sup>2+</sup> transients to trigger liquid-liquid phase separation (LLPS) of the autophagosome-initiating FIP200 complex. In response to ER Ca<sup>2+</sup> transients, CaMKIIβ is recruited from actin filaments and forms condensates, which serve as sites for the emergence of or interaction with FIP200 puncta. CaMKIIβ phosphorylates FIP200 at Thr269, Thr1127, and Ser1484 to modulate LLPS and properties of the FIP200 complex, thereby controlling its function in autophagosome formation. CaMKIIβ also controls the amplitude, duration, and propagation of ER Ca<sup>2+</sup> transients during autophagy induction. CaMKIIβ mutations identified in the neurodevelopmental disorder MRD54 affect the function of CaMKIIβ in autophagy. Our study reveals that CaMKIIβ is essential for sustaining and decoding ER Ca<sup>2+</sup> transients to specify autophagosome formation in mammalian cells.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"26 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142905039","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}
Pub Date : 2024-12-27DOI: 10.1016/j.molcel.2024.12.002
Elana Bryan, Devisree Valsakumar, Nwamaka J. Idigo, Marie Warburton, Kimberly M. Webb, Katy A. McLaughlin, Christos Spanos, Simone Lenci, Viktoria Major, Christina Ambrosi, Simon Andrews, Tuncay Baubec, Juri Rappsilber, Philipp Voigt
Promoters of developmental genes in embryonic stem cells (ESCs) are marked by histone H3 lysine 4 trimethylation (H3K4me3) and H3K27me3 in an asymmetric nucleosomal conformation, with each sister histone H3 carrying only one of the two marks. These bivalent domains are thought to poise genes for timely activation upon differentiation. Here, we show that asymmetric bivalent nucleosomes recruit repressive H3K27me3 binders but fail to enrich activating H3K4me3 binders, thereby promoting a poised state. Strikingly, the bivalent mark combination further promotes recruitment of specific chromatin proteins that are not recruited by each mark individually, including the lysine acetyltransferase (KAT) complex KAT6B. Knockout of KAT6B blocks neuronal differentiation, demonstrating that KAT6B is critical for proper bivalent gene expression during ESC differentiation. These findings reveal how readout of the bivalent histone marks directly promotes a poised state at developmental genes while highlighting how nucleosomal asymmetry is critical for histone mark readout and function.
{"title":"Nucleosomal asymmetry shapes histone mark binding and promotes poising at bivalent domains","authors":"Elana Bryan, Devisree Valsakumar, Nwamaka J. Idigo, Marie Warburton, Kimberly M. Webb, Katy A. McLaughlin, Christos Spanos, Simone Lenci, Viktoria Major, Christina Ambrosi, Simon Andrews, Tuncay Baubec, Juri Rappsilber, Philipp Voigt","doi":"10.1016/j.molcel.2024.12.002","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.12.002","url":null,"abstract":"Promoters of developmental genes in embryonic stem cells (ESCs) are marked by histone H3 lysine 4 trimethylation (H3K4me3) and H3K27me3 in an asymmetric nucleosomal conformation, with each sister histone H3 carrying only one of the two marks. These bivalent domains are thought to poise genes for timely activation upon differentiation. Here, we show that asymmetric bivalent nucleosomes recruit repressive H3K27me3 binders but fail to enrich activating H3K4me3 binders, thereby promoting a poised state. Strikingly, the bivalent mark combination further promotes recruitment of specific chromatin proteins that are not recruited by each mark individually, including the lysine acetyltransferase (KAT) complex KAT6B. Knockout of KAT6B blocks neuronal differentiation, demonstrating that KAT6B is critical for proper bivalent gene expression during ESC differentiation. These findings reveal how readout of the bivalent histone marks directly promotes a poised state at developmental genes while highlighting how nucleosomal asymmetry is critical for histone mark readout and function.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"62 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142887880","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}
Pub Date : 2024-12-26DOI: 10.1016/j.molcel.2024.11.039
Irmela R.E.A. Trussina, Andreas Hartmann, Christine Desroches Altamirano, Janani Natarajan, Charlotte M. Fischer, Marta Aleksejczuk, Hannes Ausserwöger, Tuomas P.J. Knowles, Michael Schlierf, Titus M. Franzmann, Simon Alberti
Ribonucleoprotein (RNP) granules have been linked to translation regulation and disease, but their assembly and regulatory mechanisms are not well understood. Here, we show that the RNA-binding protein G3BP1 preferentially interacts with unfolded RNA, driving the assembly of RNP granule-like condensates that establish RNA-RNA interactions. These RNA-RNA interactions limit the mobility and translatability of sequestered mRNAs and stabilize the condensates. The DEAD-box RNA helicase DDX3X attenuates RNA-RNA interactions inside RNP granule-like condensates, rendering the condensates dynamic and enabling mRNA translation. Importantly, disease-associated and catalytically inactive DDX3X variants fail to resolve such RNA-RNA interactions. Inhibiting DDX3X in cultured cells accelerates RNP granule assembly and delays their disassembly, indicating that RNA-RNA interactions contribute to RNP granule stability in cells. Our findings reveal how RNP granules generate inhibitory RNA-RNA interactions that are modulated by DEAD-box RNA helicases to ensure RNA availability and translatability.
{"title":"G3BP-driven RNP granules promote inhibitory RNA-RNA interactions resolved by DDX3X to regulate mRNA translatability","authors":"Irmela R.E.A. Trussina, Andreas Hartmann, Christine Desroches Altamirano, Janani Natarajan, Charlotte M. Fischer, Marta Aleksejczuk, Hannes Ausserwöger, Tuomas P.J. Knowles, Michael Schlierf, Titus M. Franzmann, Simon Alberti","doi":"10.1016/j.molcel.2024.11.039","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.11.039","url":null,"abstract":"Ribonucleoprotein (RNP) granules have been linked to translation regulation and disease, but their assembly and regulatory mechanisms are not well understood. Here, we show that the RNA-binding protein G3BP1 preferentially interacts with unfolded RNA, driving the assembly of RNP granule-like condensates that establish RNA-RNA interactions. These RNA-RNA interactions limit the mobility and translatability of sequestered mRNAs and stabilize the condensates. The DEAD-box RNA helicase DDX3X attenuates RNA-RNA interactions inside RNP granule-like condensates, rendering the condensates dynamic and enabling mRNA translation. Importantly, disease-associated and catalytically inactive DDX3X variants fail to resolve such RNA-RNA interactions. Inhibiting DDX3X in cultured cells accelerates RNP granule assembly and delays their disassembly, indicating that RNA-RNA interactions contribute to RNP granule stability in cells. Our findings reveal how RNP granules generate inhibitory RNA-RNA interactions that are modulated by DEAD-box RNA helicases to ensure RNA availability and translatability.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"2 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142886695","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}
Pub Date : 2024-12-26DOI: 10.1016/j.molcel.2024.11.038
Patrick C. Hoffmann, Hyuntae Kim, Agnieszka Obarska-Kosinska, Jan Philipp Kreysing, Eli Andino-Frydman, Sergio Cruz-León, Erica Margiotta, Lenka Cernikova, Jan Kosinski, Beata Turoňová, Gerhard Hummer, Martin Beck
Changing environmental conditions necessitate rapid adaptation of cytoplasmic and nuclear volumes. We use the slime mold Dictyostelium discoideum, known for its ability to tolerate extreme changes in osmolarity, to assess which role nuclear pore complexes (NPCs) play in achieving nuclear volume adaptation and relieving mechanical stress. We capitalize on the unique properties of D. discoideum to quantify fluid flow across NPCs. D. discoideum has an elaborate NPC structure in situ. Its dilation state affects NPC permeability for nucleocytosolic flow. Based on mathematical concepts adapted from hydrodynamics, we conceptualize this phenomenon as porous flow across NPCs, which is distinct from canonically characterized modes of nucleocytoplasmic transport because of its dependence on pressure. Viral NPC blockage decreased nucleocytosolic flow. Our results may be relevant for any biological conditions that entail rapid nuclear size adaptation, including metastasizing cancer cells, migrating cells, or differentiating tissues.
{"title":"Nuclear pore permeability and fluid flow are modulated by its dilation state","authors":"Patrick C. Hoffmann, Hyuntae Kim, Agnieszka Obarska-Kosinska, Jan Philipp Kreysing, Eli Andino-Frydman, Sergio Cruz-León, Erica Margiotta, Lenka Cernikova, Jan Kosinski, Beata Turoňová, Gerhard Hummer, Martin Beck","doi":"10.1016/j.molcel.2024.11.038","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.11.038","url":null,"abstract":"Changing environmental conditions necessitate rapid adaptation of cytoplasmic and nuclear volumes. We use the slime mold <em>Dictyostelium discoideum</em>, known for its ability to tolerate extreme changes in osmolarity, to assess which role nuclear pore complexes (NPCs) play in achieving nuclear volume adaptation and relieving mechanical stress. We capitalize on the unique properties of <em>D. discoideum</em> to quantify fluid flow across NPCs. <em>D. discoideum</em> has an elaborate NPC structure <em>in situ</em>. Its dilation state affects NPC permeability for nucleocytosolic flow. Based on mathematical concepts adapted from hydrodynamics, we conceptualize this phenomenon as porous flow across NPCs, which is distinct from canonically characterized modes of nucleocytoplasmic transport because of its dependence on pressure. Viral NPC blockage decreased nucleocytosolic flow. Our results may be relevant for any biological conditions that entail rapid nuclear size adaptation, including metastasizing cancer cells, migrating cells, or differentiating tissues.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"32 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142886694","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}
Pub Date : 2024-12-24DOI: 10.1016/j.molcel.2024.11.037
Nicholas G. Aboreden, Jessica C. Lam, Viraat Y. Goel, Siqing Wang, Xiaokang Wang, Susannah C. Midla, Alma Quijano, Cheryl A. Keller, Belinda M. Giardine, Ross C. Hardison, Haoyue Zhang, Anders S. Hansen, Gerd A. Blobel
How specific enhancer-promoter pairing is established remains mostly unclear. Besides the CTCF/cohesin machinery, few nuclear factors have been studied for a direct role in physically connecting regulatory elements. Using a murine erythroid cell model, we show via acute degradation experiments that LDB1 directly and broadly promotes connectivity among regulatory elements. Most LDB1-mediated contacts, even those spanning hundreds of kb, can form in the absence of CTCF, cohesin, or YY1 as determined using multiple degron systems. Moreover, an engineered LDB1-driven chromatin loop is cohesin independent. Cohesin-driven loop extrusion does not stall at LDB1-occupied sites but aids the formation of a subset of LDB1-anchored loops. Leveraging the dynamic reorganization of nuclear architecture during the transition from mitosis to G1 phase, we observe that loop formation and de novo LDB1 occupancy correlate and can occur independently of structural loops. Tri-C and Region Capture Micro-C reveal that LDB1 organizes multi-enhancer networks to activate transcription. These findings establish LDB1 as a driver of spatial connectivity.
{"title":"LDB1 establishes multi-enhancer networks to regulate gene expression","authors":"Nicholas G. Aboreden, Jessica C. Lam, Viraat Y. Goel, Siqing Wang, Xiaokang Wang, Susannah C. Midla, Alma Quijano, Cheryl A. Keller, Belinda M. Giardine, Ross C. Hardison, Haoyue Zhang, Anders S. Hansen, Gerd A. Blobel","doi":"10.1016/j.molcel.2024.11.037","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.11.037","url":null,"abstract":"How specific enhancer-promoter pairing is established remains mostly unclear. Besides the CTCF/cohesin machinery, few nuclear factors have been studied for a direct role in physically connecting regulatory elements. Using a murine erythroid cell model, we show via acute degradation experiments that LDB1 directly and broadly promotes connectivity among regulatory elements. Most LDB1-mediated contacts, even those spanning hundreds of kb, can form in the absence of CTCF, cohesin, or YY1 as determined using multiple degron systems. Moreover, an engineered LDB1-driven chromatin loop is cohesin independent. Cohesin-driven loop extrusion does not stall at LDB1-occupied sites but aids the formation of a subset of LDB1-anchored loops. Leveraging the dynamic reorganization of nuclear architecture during the transition from mitosis to G1 phase, we observe that loop formation and <em>de novo</em> LDB1 occupancy correlate and can occur independently of structural loops. Tri-C and Region Capture Micro-C reveal that LDB1 organizes multi-enhancer networks to activate transcription. These findings establish LDB1 as a driver of spatial connectivity.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"137 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2024-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142880236","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}
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