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Nutrient control of growth and metabolism through mTORC1 regulation of mRNA splicing 营养物质通过 mTORC1 对 mRNA 剪接的调控控制生长和新陈代谢
IF 16 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-11-20 DOI: 10.1016/j.molcel.2024.10.037
Takafumi Ogawa, Meltem Isik, Ziyun Wu, Kiran Kurmi, Jin Meng, Sungyun Cho, Gina Lee, L. Paulette Fernandez-Cardenas, Masaki Mizunuma, John Blenis, Marcia C. Haigis, T. Keith Blackwell
Cellular growth and organismal development are remarkably complex processes that require the nutrient-responsive kinase mechanistic target of rapamycin complex 1 (mTORC1). Anticipating that important mTORC1 functions remained to be identified, we employed genetic and bioinformatic screening in C. elegans to uncover mechanisms of mTORC1 action. Here, we show that during larval growth, nutrients induce an extensive reprogramming of gene expression and alternative mRNA splicing by acting through mTORC1. mTORC1 regulates mRNA splicing and the production of protein-coding mRNA isoforms largely independently of its target p70 S6 kinase (S6K) by increasing the activity of the serine/arginine-rich (SR) protein RSP-6 (SRSF3/7) and other splicing factors. mTORC1-mediated mRNA splicing regulation is critical for growth; mediates nutrient control of mechanisms that include energy, nucleotide, amino acid, and other metabolic pathways; and may be conserved in humans. Although mTORC1 inhibition delays aging, mTORC1-induced mRNA splicing promotes longevity, suggesting that when mTORC1 is inhibited, enhancement of this splicing might provide additional anti-aging benefits.
细胞生长和生物体发育是非常复杂的过程,需要雷帕霉素复合体 1(mTORC1)的营养响应激酶机制靶标。考虑到 mTORC1 的重要功能仍有待确定,我们在秀丽隐杆线虫中采用了遗传和生物信息学筛选方法来揭示 mTORC1 的作用机制。在这里,我们发现在幼虫生长过程中,营养物质通过mTORC1的作用诱导基因表达和mRNA剪接的广泛重编程。mTORC1通过增加丝氨酸/精氨酸丰富(SR)蛋白RSP-6(SRSF3/7)和其他剪接因子的活性,在很大程度上独立于其目标p70 S6激酶(S6K)来调节mRNA剪接和编码蛋白的mRNA异构体的产生。mTORC1 介导的 mRNA 剪接调控对生长至关重要;介导包括能量、核苷酸、氨基酸和其他代谢途径在内的营养控制机制;并且可能在人类中保守。虽然抑制 mTORC1 会延缓衰老,但 mTORC1 诱导的 mRNA 剪接会促进长寿,这表明当 mTORC1 受到抑制时,加强这种剪接可能会带来额外的抗衰老益处。
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引用次数: 0
A genome-wide screen identifies silencers with distinct chromatin properties and mechanisms of repression 全基因组筛选确定了具有不同染色质特性和抑制机制的沉默子
IF 16 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-11-20 DOI: 10.1016/j.molcel.2024.10.041
Lorena Hofbauer, Lisa-Marie Pleyer, Franziska Reiter, Alexander Schleiffer, Anna Vlasova, Leonid Serebreni, Annie Huang, Alexander Stark
Differential gene transcription enables development and homeostasis in all animals and is regulated by two major classes of distal cis-regulatory DNA elements (CREs): enhancers and silencers. Although enhancers have been thoroughly characterized, the properties and mechanisms of silencers remain largely unknown. By an unbiased genome-wide functional screen in Drosophila melanogaster S2 cells, we discover a class of silencers that bind one of three transcription factors (TFs) and are generally not included in chromatin-defined CRE catalogs as they mostly lack detectable DNA accessibility. The silencer-binding TF CG11247, which we term Saft, safeguards cell fate decisions in vivo and functions via a highly conserved domain we term zinc-finger-associated C-terminal (ZAC) and the corepressor G9a, independently of G9a’s H3K9-methyltransferase activity. Overall, our identification of silencers with unexpected properties and mechanisms has important implications for the understanding and future study of repressive CREs, as well as the functional annotation of animal genomes.
差异基因转录能促进所有动物的发育和体内平衡,并受到两大类远端顺式 DNA 调控元件(CRE)的调控:增强子和沉默子。虽然增强子的特征已被彻底描述,但沉默子的特性和机制在很大程度上仍不为人所知。通过在黑腹果蝇 S2 细胞中进行无偏见的全基因组功能筛选,我们发现了一类与三种转录因子(TFs)中的一种结合的沉默子,由于它们大多缺乏可检测到的 DNA 可及性,因此通常不包括在染色质定义的 CRE 目录中。与沉默子结合的 TF CG11247(我们称其为 Saft)可保障体内细胞命运的决定,它通过一个高度保守的结构域(我们称其为锌指相关 C-末端(ZAC))和核心抑制因子 G9a 发挥作用,与 G9a 的 H3K9-甲基转移酶活性无关。总之,我们发现的沉默子具有意想不到的特性和机制,对于理解和未来研究抑制性 CREs 以及动物基因组的功能注释具有重要意义。
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引用次数: 0
EMF1 functions as a 3D chromatin modulator in Arabidopsis EMF1 在拟南芥中发挥三维染色质调节器的功能
IF 16 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-11-19 DOI: 10.1016/j.molcel.2024.10.031
Jiayue Shu, Linhua Sun, Dingyue Wang, Xiaochang Yin, Minqi Yang, Zhijia Yang, Zheng Gao, Yuehui He, Myriam Calonje, Jinsheng Lai, Xing Wang Deng, Hang He, Yue Zhou
It is well known that genome organizers, like mammalian CCCTC-binding factor (CTCF) or Drosophila architectural proteins CP190 and BEAF-32, contribute to the three-dimensional (3D) organization of the genome and ensure normal gene transcription. However, bona fide genome organizers have not been identified in plants. Here, we show that EMBRYONIC FLOWER1 (EMF1) functions as a genome modulator in Arabidopsis. EMF1 interacts with the cohesin component SISTER CHROMATIN COHESION3 (SCC3), and both proteins are enriched at compartment domain (CD) boundaries. Accordingly, emf1 and scc3 show a strength decrease at the CD boundary in which these proteins colocalize. EMF1 maintains CD boundary strength, either independently or in cooperation with histone modifications. Moreover, EMF1 is required to maintain gene-resolution interactions and to block long-range aberrant chromatin loops. These data unveil a key role of EMF1 in regulating 3D chromatin structure.
众所周知,基因组组织者,如哺乳动物的 CCCTC 结合因子(CTCF)或果蝇的结构蛋白 CP190 和 BEAF-32,有助于基因组的三维(3D)组织,并确保基因的正常转录。然而,在植物中尚未发现真正的基因组组织者。在这里,我们发现 EMBRYONIC FLOWER1(EMF1)在拟南芥中具有基因组调节器的功能。EMF1 与凝聚素成分 SISTER CHROMATIN COHESION3(SCC3)相互作用,这两种蛋白都富集在区室结构域(CD)边界。因此,emf1 和 scc3 在这些蛋白共定位的 CD 边界处显示出强度下降。EMF1 可独立或与组蛋白修饰共同维持 CD 边界强度。此外,EMF1还是维持基因分辨率相互作用和阻断长程异常染色质环路的必要条件。这些数据揭示了EMF1在调节三维染色质结构中的关键作用。
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引用次数: 0
Multiprotein bridging factor 1 is required for robust activation of the integrated stress response on collided ribosomes 碰撞核糖体上的综合应激反应需要多蛋白桥接因子1的强力激活
IF 16 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-11-19 DOI: 10.1016/j.molcel.2024.10.029
Kyusik Q. Kim, Jeffrey J. Li, Ankanahalli N. Nanjaraj Urs, Miguel E. Pacheco, Victor Lasehinde, Timo Denk, Petr Tesina, Shota Tomomatsu, Yoshitaka Matsuo, Elesa McDonald, Roland Beckmann, Toshifumi Inada, Rachel Green, Hani S. Zaher
In yeast, multiprotein bridging factor 1 (Mbf1) has been proposed to function in the integrated stress response (ISR) as a transcriptional coactivator by mediating a direct interaction between general transcription machinery and the process’s key effector, Gcn4. However, mounting evidence has demonstrated that Mbf1 (and its human homolog EDF1) is recruited to collided ribosomes, a known activator of the ISR. In this study, we connect these otherwise seemingly disparate functions of Mbf1. Our biochemical and structural analyses reveal that Mbf1 functions as a core ISR factor by interacting with collided ribosomes to mediate Gcn2 activation. We further show that Mbf1 serves no role as a transcriptional coactivator of Gcn4. Instead, Mbf1 is required for optimal stress-induced eukaryotic initiation factor 2α (eIF2α) phosphorylation and downstream de-repression of GCN4 translation. Collectively, our data establish that Mbf1 functions in ISR signaling by acting as a direct sensor of stress-induced ribosome collisions.
在酵母中,多蛋白桥接因子 1(Mbf1)通过介导一般转录机制与该过程的关键效应物 Gcn4 之间的直接相互作用,被认为在综合应激反应(ISR)中起着转录辅激活剂的作用。然而,越来越多的证据表明,Mbf1(及其人类同源物 EDF1)被招募到碰撞核糖体上,而核糖体是 ISR 的已知激活因子。在本研究中,我们将 Mbf1 这些看似不同的功能联系起来。我们的生化和结构分析表明,Mbf1 通过与碰撞核糖体相互作用来介导 Gcn2 激活,从而发挥 ISR 核心因子的功能。我们进一步发现,Mbf1 并不充当 Gcn4 的转录辅激活因子。相反,Mbf1 是压力诱导的真核启动因子 2α(eIF2α)最佳磷酸化和 GCN4 翻译下游去抑制所必需的。总之,我们的数据证实了 Mbf1 在 ISR 信号转导中的功能,它是应激诱导的核糖体碰撞的直接传感器。
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引用次数: 0
DNA nicks in both leading and lagging strand templates can trigger break-induced replication 前向链和滞后链模板上的 DNA 缺口都能引发断裂诱导复制
IF 16 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-11-18 DOI: 10.1016/j.molcel.2024.10.026
Yuanlin Xu, Carl A. Morrow, Yassine Laksir, Orla M. Holt, Kezia Taylor, Costas Tsiappourdhi, Patrick Collins, Su Jia, Christos Andreadis, Matthew C. Whitby
Encounters between replication forks and unrepaired DNA single-strand breaks (SSBs) can generate both single-ended and double-ended double-strand breaks (seDSBs and deDSBs). seDSBs can be repaired by break-induced replication (BIR), which is a highly mutagenic pathway that is thought to be responsible for many of the mutations and genome rearrangements that drive cancer development. However, the frequency of BIR’s deployment and its ability to be triggered by both leading and lagging template strand SSBs were unclear. Using site- and strand-specific SSBs generated by nicking enzymes, including CRISPR-Cas9 nickase (Cas9n), we demonstrate that leading and lagging template strand SSBs in fission yeast are typically converted into deDSBs that are repaired by homologous recombination. However, both types of SSBs can also trigger BIR, and the frequency of these events increases when fork convergence is delayed and the non-homologous end joining protein Ku70 is deleted.
复制叉与未修复的DNA单链断裂(SSB)相遇可产生单端和双端双链断裂(seDSB和deDSB)。seDSB可通过断裂诱导复制(BIR)修复,BIR是一种高度致突变的途径,被认为是导致癌症发生的许多突变和基因组重排的原因。然而,BIR 的部署频率及其由前导和滞后模板链 SSB 触发的能力尚不清楚。利用由包括CRISPR-Cas9缺口酶(Cas9n)在内的缺口酶产生的位点和链特异性SSB,我们证明裂殖酵母中的前导和滞后模板链SSB通常会转化为deDSB,并通过同源重组进行修复。然而,这两种类型的 SSB 也能引发 BIR,而且当叉汇聚延迟和非同源末端连接蛋白 Ku70 被删除时,这些事件的发生频率会增加。
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引用次数: 0
RNA polymerases reshape chromatin architecture and couple transcription on individual fibers. RNA 聚合酶重塑染色质结构,并将转录耦合到单个纤维上。
IF 14.5 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-05 Epub Date: 2024-08-26 DOI: 10.1016/j.molcel.2024.08.013
Thomas W Tullius, R Stefan Isaac, Danilo Dubocanin, Jane Ranchalis, L Stirling Churchman, Andrew B Stergachis

RNA polymerases must initiate and pause within a complex chromatin environment, surrounded by nucleosomes and other transcriptional machinery. This environment creates a spatial arrangement along individual chromatin fibers ripe for both competition and coordination, yet these relationships remain largely unknown owing to the inherent limitations of traditional structural and sequencing methodologies. To address this, we employed long-read chromatin fiber sequencing (Fiber-seq) in Drosophila to visualize RNA polymerase (Pol) within its native chromatin context with single-molecule precision along up to 30 kb fibers. We demonstrate that Fiber-seq enables the identification of individual Pol II, nucleosome, and transcription factor footprints, revealing Pol II pausing-driven destabilization of downstream nucleosomes. Furthermore, we demonstrate pervasive direct distance-dependent transcriptional coupling between nearby Pol II genes, Pol III genes, and transcribed enhancers, modulated by local chromatin architecture. Overall, transcription initiation reshapes surrounding nucleosome architecture and couples nearby transcriptional machinery along individual chromatin fibers.

RNA 聚合酶必须在复杂的染色质环境中启动和暂停,周围环绕着核糖体和其他转录机制。这种环境形成了沿染色质纤维的空间排列,竞争和协调的条件已经成熟,但由于传统结构和测序方法的固有局限性,这些关系在很大程度上仍不为人所知。为了解决这个问题,我们在果蝇中采用了长线程染色质纤维测序(Fiber-seq)技术,以单分子精度沿长达30 kb的纤维观察RNA聚合酶(Pol)在其原生染色质环境中的情况。我们证明了纤维-质谱能够识别单个 Pol II、核小体和转录因子的足迹,揭示了 Pol II 暂停驱动的下游核小体失稳。此外,我们还证明了附近的 Pol II 基因、Pol III 基因和转录增强子之间普遍存在直接的距离依赖性转录耦合,并受局部染色质结构的调节。总之,转录起始重塑了周围的核小体结构,并使附近的转录机制沿着单个染色质纤维耦合。
{"title":"RNA polymerases reshape chromatin architecture and couple transcription on individual fibers.","authors":"Thomas W Tullius, R Stefan Isaac, Danilo Dubocanin, Jane Ranchalis, L Stirling Churchman, Andrew B Stergachis","doi":"10.1016/j.molcel.2024.08.013","DOIUrl":"10.1016/j.molcel.2024.08.013","url":null,"abstract":"<p><p>RNA polymerases must initiate and pause within a complex chromatin environment, surrounded by nucleosomes and other transcriptional machinery. This environment creates a spatial arrangement along individual chromatin fibers ripe for both competition and coordination, yet these relationships remain largely unknown owing to the inherent limitations of traditional structural and sequencing methodologies. To address this, we employed long-read chromatin fiber sequencing (Fiber-seq) in Drosophila to visualize RNA polymerase (Pol) within its native chromatin context with single-molecule precision along up to 30 kb fibers. We demonstrate that Fiber-seq enables the identification of individual Pol II, nucleosome, and transcription factor footprints, revealing Pol II pausing-driven destabilization of downstream nucleosomes. Furthermore, we demonstrate pervasive direct distance-dependent transcriptional coupling between nearby Pol II genes, Pol III genes, and transcribed enhancers, modulated by local chromatin architecture. Overall, transcription initiation reshapes surrounding nucleosome architecture and couples nearby transcriptional machinery along individual chromatin fibers.</p>","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":" ","pages":"3209-3222.e5"},"PeriodicalIF":14.5,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11500009/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142080926","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
eIF4F is a thermo-sensing regulatory node in the translational heat shock response. eIF4F 是翻译热休克反应中的热感应调节节点。
IF 16 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-05-02 Epub Date: 2024-03-27 DOI: 10.1016/j.molcel.2024.02.038
Christine Desroches Altamirano, Moo-Koo Kang, Mareike A Jordan, Tom Borianne, Irem Dilmen, Maren Gnädig, Alexander von Appen, Alf Honigmann, Titus M Franzmann, Simon Alberti

Heat-shocked cells prioritize the translation of heat shock (HS) mRNAs, but the underlying mechanism is unclear. We report that HS in budding yeast induces the disassembly of the eIF4F complex, where eIF4G and eIF4E assemble into translationally arrested mRNA ribonucleoprotein particles (mRNPs) and HS granules (HSGs), whereas eIF4A promotes HS translation. Using in vitro reconstitution biochemistry, we show that a conformational rearrangement of the thermo-sensing eIF4A-binding domain of eIF4G dissociates eIF4A and promotes the assembly with mRNA into HS-mRNPs, which recruit additional translation factors, including Pab1p and eIF4E, to form multi-component condensates. Using extracts and cellular experiments, we demonstrate that HS-mRNPs and condensates repress the translation of associated mRNA and deplete translation factors that are required for housekeeping translation, whereas HS mRNAs can be efficiently translated by eIF4A. We conclude that the eIF4F complex is a thermo-sensing node that regulates translation during HS.

热休克细胞优先翻译热休克(HS)mRNA,但其潜在机制尚不清楚。我们报告说,芽殖酵母中的热休克诱导 eIF4F 复合物解体,其中 eIF4G 和 eIF4E 组装成翻译受阻的 mRNA 核糖核蛋白颗粒(mRNPs)和热休克颗粒(HSGs),而 eIF4A 则促进热休克翻译。我们利用体外重组生物化学方法表明,eIF4G 的热感应 eIF4A 结合域的构象重排会解离 eIF4A 并促进其与 mRNA 组装成 HS-mRNPs,后者会招募其他翻译因子(包括 Pab1p 和 eIF4E)以形成多组分凝聚体。我们利用提取物和细胞实验证明,HS-mRNPs 和凝聚体抑制了相关 mRNA 的翻译,并耗尽了维持翻译所需的翻译因子,而 HS mRNA 可通过 eIF4A 进行高效翻译。我们的结论是,eIF4F 复合物是在 HS 期间调节翻译的热感应节点。
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引用次数: 0
Modularity of PRC1 composition and chromatin interaction define condensate properties. PRC1 的模块化组成和染色质相互作用决定了凝聚态的特性。
IF 14.5 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-05-02 Epub Date: 2024-03-22 DOI: 10.1016/j.molcel.2024.03.001
Stefan Niekamp, Sharon K Marr, Theresa A Oei, Radhika Subramanian, Robert E Kingston

Polycomb repressive complexes (PRCs) play a key role in gene repression and are indispensable for proper development. Canonical PRC1 forms condensates in vitro and in cells that are proposed to contribute to the maintenance of repression. However, how chromatin and the various subunits of PRC1 contribute to condensation is largely unexplored. Using a reconstitution approach and single-molecule imaging, we demonstrate that nucleosomal arrays and PRC1 act synergistically, reducing the critical concentration required for condensation by more than 20-fold. We find that the exact combination of PHC and CBX subunits determines condensate initiation, morphology, stability, and dynamics. Particularly, PHC2's polymerization activity influences condensate dynamics by promoting the formation of distinct domains that adhere to each other but do not coalesce. Live-cell imaging confirms CBX's role in condensate initiation and highlights PHC's importance for condensate stability. We propose that PRC1 composition can modulate condensate properties, providing crucial regulatory flexibility across developmental stages.

多角体抑制复合体(PRCs)在基因抑制中发挥着关键作用,是正常发育不可或缺的因素。典型的 PRC1 在体外和细胞内形成凝聚体,被认为有助于抑制的维持。然而,染色质和 PRC1 的各种亚基是如何促成凝集的在很大程度上还没有被研究。我们利用重组方法和单分子成像技术证明,核糖体阵列和 PRC1 具有协同作用,可将凝集所需的临界浓度降低 20 倍以上。我们发现,PHC 和 CBX 亚基的确切组合决定了凝聚体的启动、形态、稳定性和动力学。特别是,PHC2 的聚合活性通过促进形成相互粘附但不凝聚的不同结构域来影响凝聚态的动力学。活细胞成像证实了 CBX 在凝集物启动过程中的作用,并强调了 PHC 对凝集物稳定性的重要性。我们提出,PRC1 的组成可以调节凝聚态的特性,从而在不同发育阶段提供至关重要的调控灵活性。
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引用次数: 0
FAM86A methylation of eEF2 links mRNA translation elongation to tumorigenesis. eEF2 的 FAM86A 甲基化将 mRNA 翻译延长与肿瘤发生联系起来。
IF 16 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-05-02 Epub Date: 2024-03-19 DOI: 10.1016/j.molcel.2024.02.037
Joel William Francis, Simone Hausmann, Sabeen Ikram, Kunlun Yin, Robert Mealey-Farr, Natasha Mahealani Flores, Annie Truc Trinh, Tourkian Chasan, Julia Thompson, Pawel Karol Mazur, Or Gozani

eEF2 post-translational modifications (PTMs) can profoundly affect mRNA translation dynamics. However, the physiologic function of eEF2K525 trimethylation (eEF2K525me3), a PTM catalyzed by the enzyme FAM86A, is unknown. Here, we find that FAM86A methylation of eEF2 regulates nascent elongation to promote protein synthesis and lung adenocarcinoma (LUAD) pathogenesis. The principal physiologic substrate of FAM86A is eEF2, with K525me3 modeled to facilitate productive eEF2-ribosome engagement during translocation. FAM86A depletion in LUAD cells causes 80S monosome accumulation and mRNA translation inhibition. FAM86A is overexpressed in LUAD and eEF2K525me3 levels increase through advancing LUAD disease stages. FAM86A knockdown attenuates LUAD cell proliferation and suppression of the FAM86A-eEF2K525me3 axis inhibits cancer cell and patient-derived LUAD xenograft growth in vivo. Finally, FAM86A ablation strongly attenuates tumor growth and extends survival in KRASG12C-driven LUAD mouse models. Thus, our work uncovers an eEF2 methylation-mediated mRNA translation elongation regulatory node and nominates FAM86A as an etiologic agent in LUAD.

eEF2 翻译后修饰(PTM)可对 mRNA 翻译动态产生深远影响。然而,eEF2K525 三甲基化(eEF2K525me3)这种由 FAM86A 酶催化的 PTM 的生理功能尚不清楚。在这里,我们发现 eEF2 的 FAM86A 甲基化调节新生伸长,从而促进蛋白质合成和肺腺癌(LUAD)的发病。FAM86A 的主要生理底物是 eEF2,其中 K525me3 的作用是促进 eEF2 核糖体在转位过程中的高效参与。LUAD 细胞中 FAM86A 的耗竭会导致 80S 单体积累和 mRNA 翻译抑制。FAM86A 在 LUAD 中过表达,eEF2K525me3 水平随着 LUAD 疾病阶段的进展而增加。敲除 FAM86A 可抑制 LUAD 细胞增殖,抑制 FAM86A-eEF2K525me3 轴可抑制癌细胞和源自患者的 LUAD 异种移植的体内生长。最后,在 KRASG12C 驱动的 LUAD 小鼠模型中,FAM86A 消融可显著抑制肿瘤生长并延长存活期。因此,我们的研究发现了一个由 eEF2 甲基化介导的 mRNA 翻译延长调控节点,并将 FAM86A 命名为 LUAD 的致病因子。
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引用次数: 0
H3K4me1 facilitates promoter-enhancer interactions and gene activation during embryonic stem cell differentiation. 在胚胎干细胞分化过程中,H3K4me1 可促进启动子与增强子之间的相互作用和基因激活。
IF 14.5 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-05-02 Epub Date: 2024-03-20 DOI: 10.1016/j.molcel.2024.02.030
Naoki Kubo, Poshen B Chen, Rong Hu, Zhen Ye, Hiroyuki Sasaki, Bing Ren

Histone H3 lysine 4 mono-methylation (H3K4me1) marks poised or active enhancers. KMT2C (MLL3) and KMT2D (MLL4) catalyze H3K4me1, but their histone methyltransferase activities are largely dispensable for transcription during early embryogenesis in mammals. To better understand the role of H3K4me1 in enhancer function, we analyze dynamic enhancer-promoter (E-P) interactions and gene expression during neural differentiation of the mouse embryonic stem cells. We found that KMT2C/D catalytic activities were only required for H3K4me1 and E-P contacts at a subset of candidate enhancers, induced upon neural differentiation. By contrast, a majority of enhancers retained H3K4me1 in KMT2C/D catalytic mutant cells. Surprisingly, H3K4me1 signals at these KMT2C/D-independent sites were reduced after acute depletion of KMT2B, resulting in aggravated transcriptional defects. Our observations therefore implicate KMT2B in the catalysis of H3K4me1 at enhancers and provide additional support for an active role of H3K4me1 in enhancer-promoter interactions and transcription in mammalian cells.

组蛋白 H3 赖氨酸 4 单甲基化(H3K4me1)可标记出蓄势待发或活跃的增强子。KMT2C(MLL3)和KMT2D(MLL4)能催化H3K4me1,但它们的组蛋白甲基转移酶活性对哺乳动物早期胚胎发生过程中的转录基本不起作用。为了更好地理解H3K4me1在增强子功能中的作用,我们分析了小鼠胚胎干细胞神经分化过程中增强子-启动子(E-P)的动态相互作用和基因表达。我们发现,只有在神经分化过程中诱导的一部分候选增强子中,H3K4me1和E-P接触才需要KMT2C/D的催化活性。相比之下,大多数增强子在KMT2C/D催化突变细胞中保留了H3K4me1。令人惊讶的是,在急性消耗 KMT2B 后,这些 KMT2C/D 不依赖位点的 H3K4me1 信号减少,导致转录缺陷加剧。因此,我们的观察结果表明,KMT2B参与了增强子上H3K4me1的催化,并为H3K4me1在哺乳动物细胞中增强子-启动子相互作用和转录中的积极作用提供了更多支持。
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引用次数: 0
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