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C2H2-zinc-finger transcription factors bind RNA and function in diverse post-transcriptional regulatory processes C2H2-锌指转录因子与 RNA 结合并在多种转录后调控过程中发挥作用
IF 16 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-19 DOI: 10.1016/j.molcel.2024.08.037
Syed Nabeel-Shah, Shuye Pu, James D. Burns, Ulrich Braunschweig, Nujhat Ahmed, Giovanni L. Burke, Hyunmin Lee, Ernest Radovani, Guoqing Zhong, Hua Tang, Edyta Marcon, Zhaolei Zhang, Timothy R. Hughes, Benjamin J. Blencowe, Jack F. Greenblatt

Cys2-His2 zinc-finger proteins (C2H2-ZNFs) constitute the largest class of DNA-binding transcription factors (TFs) yet remain largely uncharacterized. Although certain family members, e.g., GTF3A, have been shown to bind both DNA and RNA, the extent to which C2H2-ZNFs interact with—and regulate—RNA-associated processes is not known. Using UV crosslinking and immunoprecipitation (CLIP), we observe that 148 of 150 analyzed C2H2-ZNFs bind directly to RNA in human cells. By integrating CLIP sequencing (CLIP-seq) RNA-binding maps for 50 of these C2H2-ZNFs with data from chromatin immunoprecipitation sequencing (ChIP-seq), protein-protein interaction assays, and transcriptome profiling experiments, we observe that the RNA-binding profiles of C2H2-ZNFs are generally distinct from their DNA-binding preferences and that they regulate a variety of post-transcriptional processes, including pre-mRNA splicing, cleavage and polyadenylation, and m6A modification of mRNA. Our results thus define a substantially expanded repertoire of C2H2-ZNFs that bind RNA and provide an important resource for elucidating post-transcriptional regulatory programs.

Cys2-His2锌指蛋白(C2H2-ZNFs)构成了 DNA 结合转录因子(TFs)中最大的一类,但大部分尚未定性。虽然某些家族成员(如 GTF3A)已被证明能同时结合 DNA 和 RNA,但 C2H2-ZNFs 与 RNA 相关过程的相互作用和调控程度尚不清楚。利用紫外交联和免疫沉淀(CLIP)技术,我们观察到 150 个被分析的 C2H2-ZNFs 中有 148 个直接与人体细胞中的 RNA 结合。通过将其中 50 个 C2H2-ZNFs 的 CLIP 测序(CLIP-seq)RNA 结合图谱与染色质免疫沉淀测序(ChIP-seq)、蛋白质-蛋白质相互作用测定和转录组图谱分析实验的数据进行整合、我们观察到,C2H2-ZNFs 的 RNA 结合特征通常不同于它们的 DNA 结合偏好,而且它们能调控多种转录后过程,包括 mRNA 的前剪接、裂解和多聚腺苷酸化,以及 mRNA 的 m6A 修饰。因此,我们的研究结果确定了可与 RNA 结合的 C2H2-ZNFs 种类,为阐明转录后调控程序提供了重要资源。
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引用次数: 0
Transcription regulation through selective partitioning: Weak interactions with a strong foundation 通过选择性分区进行转录调控:基础牢固的弱相互作用
IF 16 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-19 DOI: 10.1016/j.molcel.2024.08.029
Megan Palacio, Dylan J. Taatjes

In this issue of Molecular Cell, De La Cruz, Pradhan, Veettil et al.1 examine how selective partitioning of proteins via low-affinity IDR-dependent interactions may help regulate RNA polymerase II (RNA Pol II) function and identify sequence features that drive partitioning in cells.

在本期《分子细胞》(Molecular Cell)杂志上,De La Cruz、Pradhan、Veettil 等人1 研究了蛋白质通过低亲和性 IDR 依赖性相互作用进行选择性分区如何有助于调节 RNA 聚合酶 II(RNA Pol II)的功能,并确定了细胞中驱动分区的序列特征。
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引用次数: 0
Integrated multi-omics analysis of zinc-finger proteins uncovers roles in RNA regulation 锌指蛋白的多组学综合分析揭示其在 RNA 调控中的作用
IF 16 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-19 DOI: 10.1016/j.molcel.2024.08.010
Maya L. Gosztyla, Lijun Zhan, Sara Olson, Xintao Wei, Jack Naritomi, Grady Nguyen, Lena Street, Grant A. Goda, Francisco F. Cavazos, Jonathan C. Schmok, Manya Jain, Easin Uddin Syed, Eunjeong Kwon, Wenhao Jin, Eric Kofman, Alexandra T. Tankka, Allison Li, Valerie Gonzalez, Eric Lécuyer, Daniel Dominguez, Gene W. Yeo

RNA interactome studies have revealed that hundreds of zinc-finger proteins (ZFPs) are candidate RNA-binding proteins (RBPs), yet their RNA substrates and functional significance remain largely uncharacterized. Here, we present a systematic multi-omics analysis of the DNA- and RNA-binding targets and regulatory roles of more than 100 ZFPs representing 37 zinc-finger families. We show that multiple ZFPs are previously unknown regulators of RNA splicing, alternative polyadenylation, stability, or translation. The examined ZFPs show widespread sequence-specific RNA binding and preferentially bind proximal to transcription start sites. Additionally, several ZFPs associate with their targets at both the DNA and RNA levels. We highlight ZNF277, a C2H2 ZFP that binds thousands of RNA targets and acts as a multi-functional RBP. We also show that ZNF473 is a DNA/RNA-associated protein that regulates the expression and splicing of cell cycle genes. Our results reveal diverse roles for ZFPs in transcriptional and post-transcriptional gene regulation.

RNA相互作用组研究发现,数百种锌指蛋白(ZFPs)是候选的 RNA 结合蛋白(RBPs),但它们的 RNA 底物和功能意义在很大程度上仍未得到表征。在这里,我们对代表 37 个锌指家族的 100 多个 ZFPs 的 DNA 和 RNA 结合靶标及调控作用进行了系统的多组学分析。我们发现多个 ZFPs 是以前未知的 RNA 剪接、替代多腺苷酸化、稳定性或翻译的调控因子。所研究的 ZFPs 显示出广泛的序列特异性 RNA 结合,并优先结合到转录起始位点附近。此外,有几种 ZFP 在 DNA 和 RNA 水平上与它们的靶标结合。我们重点介绍了 ZNF277,它是一种 C2H2 ZFP,能与数千个 RNA 靶标结合,是一种多功能 RBP。我们还发现 ZNF473 是一种 DNA/RNA 相关蛋白,可调节细胞周期基因的表达和剪接。我们的研究结果揭示了 ZFP 在转录和转录后基因调控中的多种作用。
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引用次数: 0
Ubiquitylation: Sword and shield in the bacterial arsenal 泛素化:细菌武库中的剑与盾
IF 16 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-19 DOI: 10.1016/j.molcel.2024.08.034
Jonathan N. Pruneda, Felix Randow

In two recent studies in Nature, Hör et al.1 and Chambers et al.2 report that ubiquitin-like conjugation in bacteria antagonizes phage replication.

最近在《自然》杂志上发表的两项研究中,Hör 等人1 和 Chambers 等人2 报告说,细菌中的泛素类连接能拮抗噬菌体的复制。
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引用次数: 0
Finish the unfinished: Chd1 resolving hexasome-nucleosome complex with FACT 完成未完成的工作Chd1 与 FACT 一起解析六聚体-核小体复合物
IF 16 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-19 DOI: 10.1016/j.molcel.2024.08.031
Hongxin Yin, Yang Liu

In this issue of Molecular Cell, Engeholm et al.1 present cryo-EM structures of the chromatin remodeler Chd1 bound to a hexasome-nucleosome complex, an intermediate state during transcription either with or without FACT to restore the missing H2A-H2B dimer. These two binding modes reveal how Chd1 and FACT cooperate in nucleosome re-establishment during transcription.

在本期的《分子细胞》(Molecular Cell)杂志上,Engeholm 等人1 展示了染色质重塑者 Chd1 与六聚体-核小体复合物结合的冷冻电镜结构,六聚体-核小体复合物是转录过程中的中间状态,可与 FACT 结合或不与 FACT 结合,以恢复缺失的 H2A-H2B 二聚体。这两种结合模式揭示了 Chd1 和 FACT 如何在转录过程中合作重建核小体。
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引用次数: 0
Coming in out of the cold: Rho-dependent termination contributes to adaptation to cold shock 从寒冷中走来依赖 Rho 的终止有助于适应冷休克
IF 16 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-19 DOI: 10.1016/j.molcel.2024.08.033
Teppei Morita, Susan Gottesman

During cold shock, bacteria shut down translation of all but a set of cold-shock proteins critical for recovery; in this issue of Molecular Cell, Delaleau et al.1 show that Rho-dependent transcription termination plays an important role in cold adaptation, via temperature-regulated termination of the cold-shock protein mRNAs.

在本期《分子细胞》杂志上,Delaleau 等人1 通过温度调节冷休克蛋白 mRNA 的终止,证明 Rho 依赖性转录终止在冷适应中发挥着重要作用。
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引用次数: 0
A TBK1-independent primordial function of STING in lysosomal biogenesis STING 在溶酶体生物发生过程中的原始功能与 TBK1 无关
IF 16 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-19 DOI: 10.1016/j.molcel.2024.08.026
Bo Lv, William A. Dion, Haoxiang Yang, Jinrui Xun, Do-Hyung Kim, Bokai Zhu, Jay Xiaojun Tan

Stimulator of interferon genes (STING) is activated in many pathophysiological conditions, leading to TBK1-dependent interferon production in higher organisms. However, primordial functions of STING independent of TBK1 are poorly understood. Here, through proteomics and bioinformatics approaches, we identify lysosomal biogenesis as an unexpected function of STING. Transcription factor EB (TFEB), an evolutionarily conserved regulator of lysosomal biogenesis and host defense, is activated by STING from multiple species, including humans, mice, and frogs. STING-mediated TFEB activation is independent of TBK1, but it requires STING trafficking and its conserved proton channel. GABARAP lipidation, stimulated by the channel of STING, is key for STING-dependent TFEB activation. STING stimulates global upregulation of TFEB-target genes, mediating lysosomal biogenesis and autophagy. TFEB supports cell survival during chronic sterile STING activation, a common condition in aging and age-related diseases. These results reveal a primordial function of STING in the biogenesis of lysosomes, essential organelles in immunity and cellular stress resistance.

干扰素基因刺激器(STING)在许多病理生理条件下被激活,导致高等生物产生依赖于 TBK1 的干扰素。然而,人们对 STING 独立于 TBK1 的原始功能知之甚少。在这里,通过蛋白质组学和生物信息学方法,我们发现溶酶体生物生成是 STING 的一项意想不到的功能。转录因子 EB(TFEB)是溶酶体生物生成和宿主防御的进化保守调节因子,它被包括人类、小鼠和青蛙在内的多个物种的 STING 激活。STING 介导的 TFEB 激活与 TBK1 无关,但需要 STING 的贩运及其保守的质子通道。由 STING 通道刺激的 GABARAP 脂化是 STING 依赖性 TFEB 激活的关键。STING 可刺激 TFEB 靶基因的全面上调,介导溶酶体的生物生成和自噬。在慢性无菌 STING 激活过程中,TFEB 支持细胞存活,这是衰老和与年龄相关疾病的常见情况。这些结果揭示了 STING 在溶酶体生物发生过程中的基本功能,而溶酶体是免疫和细胞抗应激的重要细胞器。
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引用次数: 0
Spatial omics advances for in situ RNA biology 空间全息技术在原位 RNA 生物学方面的进展
IF 16 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-12 DOI: 10.1016/j.molcel.2024.08.002
Jingyi Ren, Shuchen Luo, Hailing Shi, Xiao Wang

Spatial regulation of RNA plays a critical role in gene expression regulation and cellular function. Understanding spatially resolved RNA dynamics and translation is vital for bringing new insights into biological processes such as embryonic development, neurobiology, and disease pathology. This review explores past studies in subcellular, cellular, and tissue-level spatial RNA biology driven by diverse methodologies, ranging from cell fractionation, in situ and proximity labeling, imaging, spatially indexed next-generation sequencing (NGS) approaches, and spatially informed computational modeling. Particularly, recent advances have been made for near-genome-scale profiling of RNA and multimodal biomolecules at high spatial resolution. These methods enabled new discoveries into RNA’s spatiotemporal kinetics, RNA processing, translation status, and RNA-protein interactions in cells and tissues. The evolving landscape of experimental and computational strategies reveals the complexity and heterogeneity of spatial RNA biology with subcellular resolution, heralding new avenues for RNA biology research.

RNA 的空间调控在基因表达调控和细胞功能中起着至关重要的作用。了解空间解析的 RNA 动态和翻译对于深入了解胚胎发育、神经生物学和疾病病理学等生物过程至关重要。本综述探讨了过去在亚细胞、细胞和组织级空间 RNA 生物学方面的研究,这些研究采用了多种方法,包括细胞分馏、原位和近距离标记、成像、空间索引下一代测序(NGS)方法和空间知情计算建模。特别是最近在高空间分辨率下对 RNA 和多模态生物大分子进行近基因组尺度剖析方面取得了进展。这些方法使人们对 RNA 的时空动力学、RNA 加工、翻译状态以及细胞和组织中 RNA 蛋白相互作用有了新的发现。不断发展的实验和计算策略揭示了亚细胞分辨率空间 RNA 生物学的复杂性和异质性,预示着 RNA 生物学研究的新途径。
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引用次数: 0
Resolution of transcription-induced hexasome-nucleosome complexes by Chd1 and FACT 通过 Chd1 和 FACT 分解转录诱导的六聚体-核小体复合物
IF 16 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-12 DOI: 10.1016/j.molcel.2024.08.022
Maik Engeholm, Johann J. Roske, Elisa Oberbeckmann, Christian Dienemann, Michael Lidschreiber, Patrick Cramer, Lucas Farnung

To maintain the nucleosome organization of transcribed genes, ATP-dependent chromatin remodelers collaborate with histone chaperones. Here, we show that at the 5′ ends of yeast genes, RNA polymerase II (RNAPII) generates hexasomes that occur directly adjacent to nucleosomes. The resulting hexasome-nucleosome complexes are then resolved by Chd1. We present two cryoelectron microscopy (cryo-EM) structures of Chd1 bound to a hexasome-nucleosome complex before and after restoration of the missing inner H2A/H2B dimer by FACT. Chd1 uniquely interacts with the complex, positioning its ATPase domain to shift the hexasome away from the nucleosome. In the absence of the inner H2A/H2B dimer, its DNA-binding domain (DBD) packs against the ATPase domain, suggesting an inhibited state. Restoration of the dimer by FACT triggers a rearrangement that displaces the DBD and stimulates Chd1 remodeling. Our results demonstrate how chromatin remodelers interact with a complex nucleosome assembly and suggest how Chd1 and FACT jointly support transcription by RNAPII.

为了维持转录基因的核小体组织,依赖 ATP 的染色质重塑者与组蛋白伴侣合作。在这里,我们发现在酵母基因的 5′末端,RNA 聚合酶 II(RNAPII)会产生直接毗邻核小体的六聚体。产生的六聚体-核小体复合物随后被 Chd1 分解。我们展示了 Chd1 与六聚体-核小体复合物结合的两种冷冻电子显微镜(cryo-EM)结构,分别发生在通过 FACT 恢复缺失的内部 H2A/H2B 二聚体之前和之后。Chd1 与复合物独特地相互作用,定位其 ATPase 结构域,使六聚体远离核糖体。在缺乏内部 H2A/H2B 二聚体的情况下,其 DNA 结合结构域 (DBD) 会与 ATPase 结构域相抵触,这表明它处于抑制状态。通过 FACT 恢复二聚体会引发重排,从而移位 DBD 并刺激 Chd1 重塑。我们的研究结果证明了染色质重塑者如何与复杂的核小体组装相互作用,并表明 Chd1 和 FACT 如何共同支持 RNAPII 的转录。
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引用次数: 0
RAPIDASH: Tag-free enrichment of ribosome-associated proteins reveals composition dynamics in embryonic tissue, cancer cells, and macrophages RAPIDASH:无标记核糖体相关蛋白富集揭示胚胎组织、癌细胞和巨噬细胞中的组成动态
IF 16 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-10 DOI: 10.1016/j.molcel.2024.08.023
Teodorus Theo Susanto, Victoria Hung, Andrew G. Levine, Yuxiang Chen, Craig H. Kerr, Yongjin Yoo, Juan A. Oses-Prieto, Lisa Fromm, Zijian Zhang, Travis C. Lantz, Kotaro Fujii, Marius Wernig, Alma L. Burlingame, Davide Ruggero, Maria Barna

Ribosomes are emerging as direct regulators of gene expression, with ribosome-associated proteins (RAPs) allowing ribosomes to modulate translation. Nevertheless, a lack of technologies to enrich RAPs across sample types has prevented systematic analysis of RAP identities, dynamics, and functions. We have developed a label-free methodology called RAPIDASH to enrich ribosomes and RAPs from any sample. We applied RAPIDASH to mouse embryonic tissues and identified hundreds of potential RAPs, including Dhx30 and Llph, two forebrain RAPs important for neurodevelopment. We identified a critical role of LLPH in neural development linked to the translation of genes with long coding sequences. In addition, we showed that RAPIDASH can identify ribosome changes in cancer cells. Finally, we characterized ribosome composition remodeling during immune cell activation and observed extensive changes post-stimulation. RAPIDASH has therefore enabled the discovery of RAPs in multiple cell types, tissues, and stimuli and is adaptable to characterize ribosome remodeling in several contexts.

核糖体正在成为基因表达的直接调节器,核糖体相关蛋白(RAPs)使核糖体能够调节翻译。然而,由于缺乏在不同样本类型中富集 RAPs 的技术,因此无法对 RAP 的特性、动态和功能进行系统分析。我们开发了一种名为 RAPIDASH 的无标记方法,可从任何样本中富集核糖体和 RAPs。我们将 RAPIDASH 应用于小鼠胚胎组织,发现了数百个潜在的 RAPs,包括 Dhx30 和 Llph 这两个对神经发育很重要的前脑 RAPs。我们确定了 LLPH 在神经发育中的关键作用,它与长编码序列基因的翻译有关。此外,我们还发现 RAPIDASH 可以识别癌细胞中核糖体的变化。最后,我们描述了免疫细胞活化过程中核糖体组成重塑的特点,并观察到刺激后的广泛变化。因此,RAPIDASH 能够发现多种细胞类型、组织和刺激下的 RAPs,并能适应多种情况下核糖体重塑的特征。
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引用次数: 0
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Molecular Cell
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