Pub Date : 2024-10-25DOI: 10.1016/j.molcel.2024.09.032
Jing Fan, Yimin Wang, Miaomiao Wen, Deng Tong, Kai Wu, Kunming Yan, Peixuan Jia, Yi Zhu, Qinyu Liu, Hecun Zou, Peng Zhao, Falong Lu, Caihong Yun, Yuanchao Xue, Yu Zhou, Hong Cheng
The export and degradation pathways compete to sort nuclear RNAs, yet the default pathway remains unclear. Sorting of mature RNAs to degradation, facilitated by the exosome co-factor poly(A) exosome targeting (PAXT), is particularly challenging for their resemblance to mRNAs intended for translation. Here, we unveil that ZFC3H1, a core PAXT component, is co-transcriptionally loaded onto the first exon/intron of RNA precursors (pre-RNAs). Interestingly, this initial loading does not lead to pre-RNA degradation, as ZFC3H1 adopts a “closed” conformation, effectively blocking exosome recruitment. As processing progresses, RNA fate can be reshaped. Longer RNAs with more exons are allowed for nuclear export. By contrast, short RNAs with fewer exons preferentially recruit transient PAXT components ZC3H3 and RBM26/27 to the 3′ end, triggering ZFC3H1 “opening” and subsequent exosomal degradation. Together, the decoupled loading and activation of ZFC3H1 pre-configures RNA fate for decay while still allowing a switch to nuclear export, depending on mature RNA features.
{"title":"Dual modes of ZFC3H1 confer selectivity in nuclear RNA sorting","authors":"Jing Fan, Yimin Wang, Miaomiao Wen, Deng Tong, Kai Wu, Kunming Yan, Peixuan Jia, Yi Zhu, Qinyu Liu, Hecun Zou, Peng Zhao, Falong Lu, Caihong Yun, Yuanchao Xue, Yu Zhou, Hong Cheng","doi":"10.1016/j.molcel.2024.09.032","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.09.032","url":null,"abstract":"The export and degradation pathways compete to sort nuclear RNAs, yet the default pathway remains unclear. Sorting of mature RNAs to degradation, facilitated by the exosome co-factor poly(A) exosome targeting (PAXT), is particularly challenging for their resemblance to mRNAs intended for translation. Here, we unveil that ZFC3H1, a core PAXT component, is co-transcriptionally loaded onto the first exon/intron of RNA precursors (pre-RNAs). Interestingly, this initial loading does not lead to pre-RNA degradation, as ZFC3H1 adopts a “closed” conformation, effectively blocking exosome recruitment. As processing progresses, RNA fate can be reshaped. Longer RNAs with more exons are allowed for nuclear export. By contrast, short RNAs with fewer exons preferentially recruit transient PAXT components ZC3H3 and RBM26/27 to the 3′ end, triggering ZFC3H1 “opening” and subsequent exosomal degradation. Together, the decoupled loading and activation of ZFC3H1 pre-configures RNA fate for decay while still allowing a switch to nuclear export, depending on mature RNA features.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"97 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142489627","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 : 2024-10-25DOI: 10.1016/j.molcel.2024.10.001
Qiqi Li, Gang Yang, Bingbing Ren, Xu Liu, Li-Qin Tang, Qinghua Shi, Ge Shan, Xiaolin Wang
Circular RNAs (circRNAs) are natural outputs of eukaryotic transcription and RNA processing and have emerged as critical regulators in physiology and diseases. Although multiple cis-elements and trans-factors are reported to modulate the backsplicing of circRNA biogenesis, most of these regulations play roles in flanking introns of circRNAs. Here, using a genome-wide CRISPR knockout screen, we have identified an evolutionarily conserved RNA-binding protein ZC3H14 in regulating circRNA biogenesis. ZC3H14 binds to 3′ and 5′ exon-intron boundaries and 3′ UTRs of cognate mRNAs to promote circRNA biogenesis through dimerization and the association with spliceosome. Yeast knockout of the ZC3H14 ortholog Nab2 has significantly lower levels of circRNAs. Zc3h14−/− mice exhibit disrupted spermatogenesis and reduced testicular circRNA levels. Additionally, expression levels of human ZC3H14 are associated with non-obstructive azoospermia. Our findings reveal a conserved requirement for ZC3H14 in the modulation of backsplicing and link ZC3H14 and circRNA biogenesis to male fertility.
{"title":"ZC3H14 facilitates backsplicing by binding to exon-intron boundary and 3′ UTR","authors":"Qiqi Li, Gang Yang, Bingbing Ren, Xu Liu, Li-Qin Tang, Qinghua Shi, Ge Shan, Xiaolin Wang","doi":"10.1016/j.molcel.2024.10.001","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.10.001","url":null,"abstract":"Circular RNAs (circRNAs) are natural outputs of eukaryotic transcription and RNA processing and have emerged as critical regulators in physiology and diseases. Although multiple <em>cis</em>-elements and <em>trans</em>-factors are reported to modulate the backsplicing of circRNA biogenesis, most of these regulations play roles in flanking introns of circRNAs. Here, using a genome-wide CRISPR knockout screen, we have identified an evolutionarily conserved RNA-binding protein ZC3H14 in regulating circRNA biogenesis. ZC3H14 binds to 3′ and 5′ exon-intron boundaries and 3′ UTRs of cognate mRNAs to promote circRNA biogenesis through dimerization and the association with spliceosome. Yeast knockout of the ZC3H14 ortholog Nab2 has significantly lower levels of circRNAs. <em>Zc3h14</em><sup>−/−</sup> mice exhibit disrupted spermatogenesis and reduced testicular circRNA levels. Additionally, expression levels of human ZC3H14 are associated with non-obstructive azoospermia. Our findings reveal a conserved requirement for ZC3H14 in the modulation of backsplicing and link ZC3H14 and circRNA biogenesis to male fertility.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"42 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142489587","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 : 2024-10-24DOI: 10.1016/j.molcel.2024.09.030
Ballachanda N. Devaiah, Amit Kumar Singh, Jie Mu, Qingrong Chen, Daoud Meerzaman, Dinah S. Singer
Bromodomain 4 (BRD4), a key regulator with pleiotropic functions, plays crucial roles in cancers and cellular stress responses. It exhibits dual functionality: chromatin-bound BRD4 regulates remodeling through its histone acetyltransferase (HAT) activity, while promoter-associated BRD4 regulates transcription through its kinase activity. Notably, chromatin-bound BRD4 lacks kinase activity, and RNA polymerase II (RNA Pol II)-bound BRD4 exhibits no HAT activity. This study unveils one mechanism underlying BRD4’s functional switch. In response to diverse stimuli, c-Jun N-terminal kinase (JNK)-mediated phosphorylation of human BRD4 at Thr1186 and Thr1212 triggers its transient release from chromatin, disrupting its HAT activity and potentiating its kinase activity. Released BRD4 directly interacts with and phosphorylates RNA Pol II, PTEFb, and c-Myc, thereby promoting transcription of target genes involved in immune and inflammatory responses. JNK-mediated BRD4 functional switching induces CD8 expression in thymocytes and epithelial-to-mesenchymal transition (EMT) in prostate cancer cells. These findings elucidate the mechanism by which BRD4 transitions from a chromatin regulator to a transcriptional activator.
溴结构域 4（BRD4）是一种具有多种功能的关键调控因子，在癌症和细胞应激反应中发挥着至关重要的作用。它具有双重功能：染色质结合的 BRD4 通过其组蛋白乙酰转移酶（HAT）活性调节重塑，而启动子相关的 BRD4 则通过其激酶活性调节转录。值得注意的是，与染色质结合的BRD4缺乏激酶活性，与RNA聚合酶II（RNA Pol II）结合的BRD4没有HAT活性。这项研究揭示了BRD4功能转换的一种机制。在各种刺激下，c-Jun N-末端激酶（JNK）介导的人类 BRD4 在 Thr1186 和 Thr1212 处的磷酸化会引发其从染色质中的短暂释放，从而破坏其 HAT 活性并增强其激酶活性。释放的 BRD4 直接与 RNA Pol II、PTEFb 和 c-Myc 相互作用并使其磷酸化，从而促进参与免疫和炎症反应的靶基因的转录。JNK 介导的 BRD4 功能转换可诱导胸腺细胞中 CD8 的表达和前列腺癌细胞中上皮细胞向间质转化（EMT）。这些发现阐明了BRD4从染色质调节剂转变为转录激活剂的机制。
{"title":"Phosphorylation by JNK switches BRD4 functions","authors":"Ballachanda N. Devaiah, Amit Kumar Singh, Jie Mu, Qingrong Chen, Daoud Meerzaman, Dinah S. Singer","doi":"10.1016/j.molcel.2024.09.030","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.09.030","url":null,"abstract":"Bromodomain 4 (BRD4), a key regulator with pleiotropic functions, plays crucial roles in cancers and cellular stress responses. It exhibits dual functionality: chromatin-bound BRD4 regulates remodeling through its histone acetyltransferase (HAT) activity, while promoter-associated BRD4 regulates transcription through its kinase activity. Notably, chromatin-bound BRD4 lacks kinase activity, and RNA polymerase II (RNA Pol II)-bound BRD4 exhibits no HAT activity. This study unveils one mechanism underlying BRD4’s functional switch. In response to diverse stimuli, c-Jun N-terminal kinase (JNK)-mediated phosphorylation of human BRD4 at Thr1186 and Thr1212 triggers its transient release from chromatin, disrupting its HAT activity and potentiating its kinase activity. Released BRD4 directly interacts with and phosphorylates RNA Pol II, PTEFb, and c-Myc, thereby promoting transcription of target genes involved in immune and inflammatory responses. JNK-mediated BRD4 functional switching induces CD8 expression in thymocytes and epithelial-to-mesenchymal transition (EMT) in prostate cancer cells. These findings elucidate the mechanism by which BRD4 transitions from a chromatin regulator to a transcriptional activator.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"109 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142489217","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 : 2024-10-17DOI: 10.1016/j.molcel.2024.09.027
Jung Seung Nam, Maya S. Dixon, Iok In Christine Chio
Hydrogen sulfide (H2S) can regulate biological processes by post-translational persulfidation of proteins at select cysteine residues. In this issue of Molecular Cell, Zheng et al.1 identify the enzyme SAHH as an H2S substrate, which upon persulfidation disrupts homocysteine metabolism and sensitizes lung cancer cells to ferroptosis.
{"title":"Hydrogen sulfide: A whiff of trouble for cancer cell survival","authors":"Jung Seung Nam, Maya S. Dixon, Iok In Christine Chio","doi":"10.1016/j.molcel.2024.09.027","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.09.027","url":null,"abstract":"Hydrogen sulfide (H<sub>2</sub>S) can regulate biological processes by post-translational persulfidation of proteins at select cysteine residues. In this issue of <em>Molecular Cell</em>, Zheng et al.<span><span><sup>1</sup></span></span> identify the enzyme SAHH as an H<sub>2</sub>S substrate, which upon persulfidation disrupts homocysteine metabolism and sensitizes lung cancer cells to ferroptosis.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"35 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142444068","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 : 2024-10-17DOI: 10.1016/j.molcel.2024.09.029
Adam Kosti, Gary J. Bassell
In this issue of Molecular Cell, Lee et al.1 report that alternative translation initiation can generate new proteoforms with distinct localization patterns in a neuronal activity-dependent manner.
{"title":"Where to start? Activity-dependent alternative translation initiation generates multifunctional proteoforms in the brain","authors":"Adam Kosti, Gary J. Bassell","doi":"10.1016/j.molcel.2024.09.029","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.09.029","url":null,"abstract":"In this issue of <em>Molecular Cell</em>, Lee et al.<span><span><sup>1</sup></span></span> report that alternative translation initiation can generate new proteoforms with distinct localization patterns in a neuronal activity-dependent manner.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"31 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142444071","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 : 2024-10-17DOI: 10.1016/j.molcel.2024.09.026
Sadaaki Nishimura, Juan F. Linares, Antoine L’Hermitte, Angeles Duran, Tania Cid-Diaz, Anxo Martinez-Ordoñez, Marc Ruiz-Martinez, Yotaro Kudo, Antonio Marzio, Mathias Heikenwalder, Lewis R. Roberts, Maria T. Diaz-Meco, Jorge Moscat
Hepatocellular carcinoma (HCC) emerges from chronic inflammation, to which activation of hepatic stellate cells (HSCs) contributes by shaping a pro-tumorigenic microenvironment. Key to this process is p62, whose inactivation leads to enhanced hepatocarcinogenesis. Here, we show that p62 activates the interferon (IFN) cascade by promoting STING ubiquitination by tripartite motif protein 32 (TRIM32) in HSCs. p62, binding neighbor of BRCA1 gene 1 (NBR1) and STING, triggers the IFN cascade by displacing NBR1, which normally prevents the interaction of TRIM32 with STING and its subsequent activation. Furthermore, NBR1 also antagonizes STING by promoting its trafficking to the endosome-lysosomal compartment for degradation independent of autophagy. Of functional relevance, NBR1 deletion completely reverts the tumor-promoting function of p62-deficient HSCs by rescuing the inhibited STING-IFN pathway, thus enhancing anti-tumor responses mediated by CD8+ T cells. Therefore, NBR1 emerges as a synthetic vulnerability of p62 deficiency in HSCs by promoting the STING/IFN pathway, which boosts anti-tumor CD8+ T cell responses to restrain HCC progression.
{"title":"Opposing regulation of the STING pathway in hepatic stellate cells by NBR1 and p62 determines the progression of hepatocellular carcinoma","authors":"Sadaaki Nishimura, Juan F. Linares, Antoine L’Hermitte, Angeles Duran, Tania Cid-Diaz, Anxo Martinez-Ordoñez, Marc Ruiz-Martinez, Yotaro Kudo, Antonio Marzio, Mathias Heikenwalder, Lewis R. Roberts, Maria T. Diaz-Meco, Jorge Moscat","doi":"10.1016/j.molcel.2024.09.026","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.09.026","url":null,"abstract":"Hepatocellular carcinoma (HCC) emerges from chronic inflammation, to which activation of hepatic stellate cells (HSCs) contributes by shaping a pro-tumorigenic microenvironment. Key to this process is p62, whose inactivation leads to enhanced hepatocarcinogenesis. Here, we show that p62 activates the interferon (IFN) cascade by promoting STING ubiquitination by tripartite motif protein 32 (TRIM32) in HSCs. p62, binding neighbor of BRCA1 gene 1 (NBR1) and STING, triggers the IFN cascade by displacing NBR1, which normally prevents the interaction of TRIM32 with STING and its subsequent activation. Furthermore, NBR1 also antagonizes STING by promoting its trafficking to the endosome-lysosomal compartment for degradation independent of autophagy. Of functional relevance, NBR1 deletion completely reverts the tumor-promoting function of p62-deficient HSCs by rescuing the inhibited STING-IFN pathway, thus enhancing anti-tumor responses mediated by CD8<sup>+</sup> T cells. Therefore, NBR1 emerges as a synthetic vulnerability of p62 deficiency in HSCs by promoting the STING/IFN pathway, which boosts anti-tumor CD8<sup>+</sup> T cell responses to restrain HCC progression.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"7 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142444066","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 : 2024-10-17DOI: 10.1016/j.molcel.2024.09.021
Sangin Kim, Roger A. Greenberg
In a recent study in Cell, Lascaux et al.1 implicate TEX264 in the autophagy-driven resolution of nuclear topoisomerase 1 cleavage complexes (TOP1cc) in lysosomes, altering current concepts on the mechanism of action for clinically relevant doses of TOP1 inhibitors.
{"title":"Crossing the border: Replication fork adducts move to lysosomes for autophagic repair","authors":"Sangin Kim, Roger A. Greenberg","doi":"10.1016/j.molcel.2024.09.021","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.09.021","url":null,"abstract":"In a recent study in <em>Cell</em>, Lascaux et al.<span><span><sup>1</sup></span></span> implicate TEX264 in the autophagy-driven resolution of nuclear topoisomerase 1 cleavage complexes (TOP1cc) in lysosomes, altering current concepts on the mechanism of action for clinically relevant doses of TOP1 inhibitors.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"231 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142444069","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 : 2024-10-17DOI: 10.1016/j.molcel.2024.09.028
Sara R. Wasserman, Nathaniel A. Hathaway
In this issue, Sinha et al.1 use cellular chromatin reporter assays along with CRISPR gene editing to reveal that the histone H3.3K36M oncohistone mutation disrupts epigenetic memory and stability of H3K9me3 domains by blocking transitions into a stably repressed state.
{"title":"Stalling out chromatin machinery—Oncohistone mutation disrupts heterochromatin memory","authors":"Sara R. Wasserman, Nathaniel A. Hathaway","doi":"10.1016/j.molcel.2024.09.028","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.09.028","url":null,"abstract":"In this issue, Sinha et al.<span><span><sup>1</sup></span></span> use cellular chromatin reporter assays along with CRISPR gene editing to reveal that the histone H3.3K36M oncohistone mutation disrupts epigenetic memory and stability of H3K9me3 domains by blocking transitions into a stably repressed state.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"1 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142444067","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 : 2024-10-15DOI: 10.1016/j.molcel.2024.09.022
Kaustubh Wagh, Diana A. Stavreva, Gordon L. Hager
Single-molecule tracking (SMT) has emerged as the dominant technology to investigate the dynamics of chromatin-transcription factor (TF) interactions. How long a TF needs to bind to a regulatory site to elicit a transcriptional response is a fundamentally important question. However, highly divergent estimates of TF binding have been presented in the literature, stemming from differences in photobleaching correction and data analysis. TF movement is often interpreted as specific or non-specific association with chromatin, yet the dynamic nature of the chromatin polymer is often overlooked. In this perspective, we highlight how recent SMT studies have reshaped our understanding of TF dynamics, chromatin mobility, and genome organization in the mammalian nucleus, focusing on the technical details and biological implications of these approaches. In a remarkable convergence of fixed and live-cell imaging, we show how super-resolution and SMT studies of chromatin have dovetailed to provide a convincing nanoscale view of genome organization.
{"title":"Transcription dynamics and genome organization in the mammalian nucleus: Recent advances","authors":"Kaustubh Wagh, Diana A. Stavreva, Gordon L. Hager","doi":"10.1016/j.molcel.2024.09.022","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.09.022","url":null,"abstract":"Single-molecule tracking (SMT) has emerged as the dominant technology to investigate the dynamics of chromatin-transcription factor (TF) interactions. How long a TF needs to bind to a regulatory site to elicit a transcriptional response is a fundamentally important question. However, highly divergent estimates of TF binding have been presented in the literature, stemming from differences in photobleaching correction and data analysis. TF movement is often interpreted as specific or non-specific association with chromatin, yet the dynamic nature of the chromatin polymer is often overlooked. In this perspective, we highlight how recent SMT studies have reshaped our understanding of TF dynamics, chromatin mobility, and genome organization in the mammalian nucleus, focusing on the technical details and biological implications of these approaches. In a remarkable convergence of fixed and live-cell imaging, we show how super-resolution and SMT studies of chromatin have dovetailed to provide a convincing nanoscale view of genome organization.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"32 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142436317","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 : 2024-10-15DOI: 10.1016/j.molcel.2024.09.024
Sang Joon Won, Yuxiang Zhang, Christopher J. Reinhardt, Lauren M. Hargis, Nicole S. MacRae, Kristen E. DeMeester, Evert Njomen, Jarrett R. Remsberg, Bruno Melillo, Benjamin F. Cravatt, Michael A. Erb
Pioneer transcription factors (TFs) bind to and open closed chromatin, facilitating engagement by other regulatory factors involved in gene activation or repression. Chemical probes are lacking for pioneer TFs, which has hindered their mechanistic investigation in cells. Here, we report the chemical proteomic discovery of electrophilic compounds that stereoselectively and site-specifically bind the pioneer TF forkhead box protein A1 (FOXA1) at a cysteine (C258) within the forkhead DNA-binding domain. We show that these covalent ligands react with FOXA1 in a DNA-dependent manner and rapidly remodel its pioneer activity in prostate cancer cells reflected in redistribution of FOXA1 binding across the genome and directionally correlated changes in chromatin accessibility. Motif analysis supports a mechanism where the ligands relax the canonical DNA-binding preference of FOXA1 by strengthening interactions with suboptimal sequences in predicted proximity to C258. Our findings reveal a striking plasticity underpinning the pioneering function of FOXA1 that can be controlled by small molecules.
先驱转录因子（TFs）与封闭的染色质结合并打开染色质，促进参与基因激活或抑制的其他调控因子的参与。先锋转录因子缺乏化学探针，这阻碍了它们在细胞中的机理研究。在这里，我们报告了化学蛋白质组学发现的亲电化合物，它们能在叉头 DNA 结合域内的半胱氨酸（C258）上立体选择性地结合先锋 TF 叉头盒蛋白 A1（FOXA1）。我们的研究表明，这些共价配体以一种 DNA 依赖性方式与 FOXA1 发生反应，并迅速重塑其在前列腺癌细胞中的先锋活性，这反映在 FOXA1 结合在整个基因组中的重新分布以及染色质可及性中方向相关的变化。基元分析支持一种机制，即配体通过加强与预测的靠近 C258 的次优序列的相互作用来放松 FOXA1 的典型 DNA 结合偏好。我们的研究结果揭示了 FOXA1 先驱功能所具有的惊人的可塑性，这种功能可以由小分子控制。
{"title":"Redirecting the pioneering function of FOXA1 with covalent small molecules","authors":"Sang Joon Won, Yuxiang Zhang, Christopher J. Reinhardt, Lauren M. Hargis, Nicole S. MacRae, Kristen E. DeMeester, Evert Njomen, Jarrett R. Remsberg, Bruno Melillo, Benjamin F. Cravatt, Michael A. Erb","doi":"10.1016/j.molcel.2024.09.024","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.09.024","url":null,"abstract":"Pioneer transcription factors (TFs) bind to and open closed chromatin, facilitating engagement by other regulatory factors involved in gene activation or repression. Chemical probes are lacking for pioneer TFs, which has hindered their mechanistic investigation in cells. Here, we report the chemical proteomic discovery of electrophilic compounds that stereoselectively and site-specifically bind the pioneer TF forkhead box protein A1 (FOXA1) at a cysteine (C258) within the forkhead DNA-binding domain. We show that these covalent ligands react with FOXA1 in a DNA-dependent manner and rapidly remodel its pioneer activity in prostate cancer cells reflected in redistribution of FOXA1 binding across the genome and directionally correlated changes in chromatin accessibility. Motif analysis supports a mechanism where the ligands relax the canonical DNA-binding preference of FOXA1 by strengthening interactions with suboptimal sequences in predicted proximity to C258. Our findings reveal a striking plasticity underpinning the pioneering function of FOXA1 that can be controlled by small molecules.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"65 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142436311","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}
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：