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Interleukin-2-mediated NF-κB-dependent mRNA splicing modulates interferon gamma protein production. 白细胞介素-2 介导的 NF-κB 依赖性 mRNA 剪接调节干扰素γ 蛋白的产生。
IF 6.5 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-11-22 DOI: 10.1038/s44319-024-00324-1
Rachel D Van Gelder, Nandan S Gokhale, Emmanuelle Genoyer, Dylan S Omelia, Stephen K Anderson, Howard A Young, Ram Savan

Interferon-gamma (IFNγ) is a pleiotropic cytokine produced by natural killer (NK) cells during the early infection response. IFNγ expression is tightly regulated to mount sterilizing immunity while preventing tissue pathology. Several post-transcriptional effectors dampen IFNγ expression through IFNG mRNA degradation. In this study, we identify mRNA splicing as a positive regulator of IFNγ production. While treatment with the combination of IL-12 and IL-2 causes synergistic induction of IFNG mRNA and protein, defying transcription-translation kinetics, we observe that NK cells treated with IL-12 alone transcribe IFNG with introns intact. When NK cells are treated with both IL-2 and IL-12, IFNG transcript is spliced to form mature mRNA with a concomitant increase in IFNγ protein. We find that IL-2-mediated intron splicing occurs independently of nascent transcription but relies upon NF-κB signaling. We propose that while IL-12 transcriptionally induces IFNG mRNA, IL-2 signaling stabilizes IFNG mRNA by splicing detained introns, allowing for rapid IFNγ protein production. This study uncovers a novel role for cytokine-induced splicing in regulating IFNγ through a mechanism potentially applicable to other inflammatory mediators.

γ干扰素(IFNγ)是自然杀伤(NK)细胞在早期感染反应中产生的一种多效细胞因子。IFNγ 的表达受到严格调控,以产生杀菌免疫,同时防止组织病变。一些转录后效应因子通过 IFNG mRNA 降解抑制 IFNγ 的表达。在本研究中,我们发现 mRNA 剪接是 IFNγ 生成的正向调节因子。IL-12和IL-2联合处理会协同诱导IFNG mRNA和蛋白质,从而违背转录-翻译动力学,但我们观察到,仅用IL-12处理的NK细胞会在内含子完整的情况下转录IFNG。当 NK 细胞同时接受 IL-2 和 IL-12 处理时,IFNG 转录本会剪接形成成熟的 mRNA,IFNγ 蛋白也会随之增加。我们发现,IL-2 介导的内含子剪接与新生转录无关,而是依赖于 NF-κB 信号转导。我们认为,IL-12 通过转录诱导 IFNG mRNA,而 IL-2 信号则通过剪接内含子来稳定 IFNG mRNA,从而快速产生 IFNγ 蛋白。这项研究通过一种可能适用于其他炎症介质的机制,发现了细胞因子诱导的剪接在调节 IFNγ 中的新作用。
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引用次数: 0
The DNA demethylase TET1 modifies the impact of maternal folic acid status on embryonic brain development. DNA 去甲基化酶 TET1 可改变母体叶酸状况对胚胎大脑发育的影响。
IF 6.5 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-11-22 DOI: 10.1038/s44319-024-00316-1
Lehua Chen, Bernard K van der Veer, Qiuying Chen, Spyridon Champeris Tsaniras, Wannes Brangers, Harm H M Kwak, Rita Khoueiry, Yunping Lei, Robert Cabrera, Steven S Gross, Richard H Finnell, Kian Peng Koh

Folic acid (FA) is well known to prevent neural tube defects (NTDs), but we do not know why many human NTD cases still remain refractory to FA supplementation. Here, we investigate how the DNA demethylase TET1 interacts with maternal FA status to regulate mouse embryonic brain development. We determined that cranial NTDs display higher penetrance in non-inbred than in inbred Tet1-/- embryos and are resistant to FA supplementation across strains. Maternal diets that are either too rich or deficient in FA are linked to an increased incidence of cranial deformities in wild type and Tet1+/- offspring and to altered DNA hypermethylation in Tet1-/- embryos, primarily at neurodevelopmental loci. Excess FA in Tet1-/- embryos results in phospholipid metabolite loss and reduced expression of multiple membrane solute carriers, including a FA transporter gene that exhibits increased promoter DNA methylation and thereby mimics FA deficiency. Moreover, FA deficiency reveals that Tet1 haploinsufficiency can contribute to DNA hypermethylation and susceptibility to NTDs. Overall, our study suggests that epigenetic dysregulation may underlie NTD development despite FA supplementation.

众所周知,叶酸(FA)可以预防神经管畸形(NTD),但我们不知道为什么许多人类NTD病例仍然对补充叶酸难以奏效。在这里,我们研究了DNA去甲基化酶TET1如何与母体的叶酸状态相互作用来调节小鼠胚胎大脑发育。我们发现,颅脑 NTD 在非近亲繁殖的小鼠胚胎中比近亲繁殖的 Tet1-/- 胚胎具有更高的穿透性,而且不同品系的小鼠胚胎对补充足量脂肪酸都有抵抗力。富含或缺乏脂肪酸的母体饮食与野生型和Tet1+/-后代颅骨畸形发生率增加有关,也与Tet1-/-胚胎DNA超甲基化改变有关,主要是在神经发育位点。Tet1-/- 胚胎中过量的 FA 会导致磷脂代谢物的损失和多种膜溶质载体的表达减少,其中包括一种 FA 转运体基因,该基因的启动子 DNA 甲基化增加,从而模拟 FA 缺乏。此外,FA 缺乏症揭示了 Tet1 单倍体缺乏可导致 DNA 高甲基化和 NTD 易感性。总之,我们的研究表明,尽管补充了 FA,但表观遗传失调可能是 NTD 发生的基础。
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引用次数: 0
Soul Men and Women-what must science do to regain public trust? 灵魂男女--科学必须做些什么才能重新赢得公众的信任?
IF 6.5 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-11-20 DOI: 10.1038/s44319-024-00325-0
Arthur Caplan
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引用次数: 0
KMT5C leverages disorder to optimize cooperation with HP1 for heterochromatin retention. KMT5C 利用紊乱来优化与 HP1 的合作,以保持异染色质。
IF 6.5 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-11-19 DOI: 10.1038/s44319-024-00320-5
Justin W Knechtel, Hilmar Strickfaden, Kristal Missiaen, Joanne D Hadfield, Michael J Hendzel, D Alan Underhill

A defining feature of constitutive heterochromatin compartments is the heterochromatin protein-1 (HP1) family, whose members display fast internal mobility and rapid exchange with the surrounding nucleoplasm. Here, we describe a paradoxical state for the lysine methyltransferase KMT5C characterized by rapid internal diffusion but minimal nucleoplasmic exchange. This retentive behavior is conferred by sparse sequence features that constitute two modules tethered by an intrinsically disordered linker. While both modules harbor variant HP1 interaction motifs, the first comprises adjacent sequences that increase affinity using avidity. The second motif increases HP1 effective concentration to further enhance affinity in a context-dependent manner, which is evident using distinct heterochromatin recruitment strategies and heterologous linkers with defined conformational ensembles. Despite the linker sequence being highly divergent, it is under evolutionary constraint for functional length, suggesting conformational buffering can support cooperativity between modules across distant orthologs. Overall, we show that KMT5C has evolved a robust tethering strategy that uses minimal sequence determinants to harness highly dynamic HP1 proteins for retention within heterochromatin compartments.

组成型异染色质区室的一个决定性特征是异染色质蛋白-1(HP1)家族,其成员显示出快速的内部流动性和与周围核质的快速交换。在这里,我们描述了赖氨酸甲基转移酶 KMT5C 的一种自相矛盾的状态,其特点是快速的内部扩散和最小的核质交换。这种保持行为是由稀疏的序列特征赋予的,这些序列特征构成了由一个内在无序连接体拴住的两个模块。虽然这两个模块都含有变异的 HP1 相互作用基序,但第一个基序由相邻的序列组成,能利用亲和力增加亲和力。第二个基序增加了 HP1 的有效浓度,从而以依赖于上下文的方式进一步提高了亲和力,这在使用不同的异染色质招募策略和具有确定构象组合的异源连接子时是显而易见的。尽管连接子序列差异很大,但它的功能长度却受到进化的限制,这表明构象缓冲作用可以支持远缘直向同源物模块之间的合作。总之,我们发现 KMT5C 已经进化出了一种稳健的系留策略,它利用最小的序列决定因素来利用高度动态的 HP1 蛋白,使其保留在异染色质区室中。
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引用次数: 0
Regulating translation in aging: from global to gene-specific mechanisms. 衰老过程中的翻译调控:从全球机制到基因特异性机制。
IF 6.5 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-11-19 DOI: 10.1038/s44319-024-00315-2
Mathilde Solyga, Amitabha Majumdar, Florence Besse

Aging is characterized by a decline in various biological functions that is associated with changes in gene expression programs. Recent transcriptome-wide integrative studies in diverse organisms and tissues have revealed a gradual uncoupling between RNA and protein levels with aging, which highlights the importance of post-transcriptional regulatory processes. Here, we provide an overview of multi-omics analyses that show the progressive uncorrelation of transcriptomes and proteomes during the course of healthy aging. We then describe the molecular changes leading to global downregulation of protein synthesis with age and review recent work dissecting the mechanisms involved in gene-specific translational regulation in complementary model organisms. These mechanisms include the recognition of regulated mRNAs by trans-acting factors such as miRNA and RNA-binding proteins, the condensation of mRNAs into repressive cytoplasmic RNP granules, and the pausing of ribosomes at specific residues. Lastly, we mention future challenges of this emerging field, possible buffering functions as well as potential links with disease.

衰老的特征是各种生物功能的下降,这与基因表达程序的变化有关。最近在不同生物体和组织中进行的全转录组整合研究发现,随着年龄的增长,RNA 和蛋白质水平逐渐脱钩,这凸显了转录后调控过程的重要性。在这里,我们概述了多组学分析,这些分析表明转录组和蛋白质组在健康衰老过程中逐渐失去相关性。然后,我们描述了导致蛋白质合成随年龄增长而全面下调的分子变化,并回顾了最近在互补模式生物中剖析基因特异性翻译调控机制的工作。这些机制包括 miRNA 和 RNA 结合蛋白等反式作用因子识别受调控的 mRNA、将 mRNA 凝聚成抑制性细胞质 RNP 颗粒以及核糖体在特定残基处暂停。最后,我们提到了这一新兴领域未来的挑战、可能的缓冲功能以及与疾病的潜在联系。
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引用次数: 0
Interplay between the brain and adipose tissue: a metabolic conversation. 大脑与脂肪组织之间的相互作用:新陈代谢的对话。
IF 6.5 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-11-18 DOI: 10.1038/s44319-024-00321-4
Francisco Díaz-Castro, Eugenia Morselli, Marc Claret

The central nervous system and adipose tissue interact through complex communication. This bidirectional signaling regulates metabolic functions. The hypothalamus, a key homeostatic brain region, integrates exteroceptive and interoceptive signals to control appetite, energy expenditure, glucose, and lipid metabolism. This regulation is partly achieved via the nervous modulation of white (WAT) and brown (BAT) adipose tissue. In this review, we highlight the roles of sympathetic and parasympathetic innervation in regulating WAT and BAT activities, such as lipolysis and thermogenesis. Adipose tissue, in turn, plays a dual role as an energy reservoir and an endocrine organ, secreting hormones that influence brain function and metabolic health. In addition, this review focuses on recently uncovered communication pathways, including extracellular vesicles and neuro-mesenchymal units, which add new layers of regulation and complexity to the brain-adipose tissue interaction. Finally, we also examine the consequences of disrupted communication between the brain and adipose tissue in metabolic disorders like obesity and type-2 diabetes, emphasizing the potential for new therapeutic strategies targeting these pathways to improve metabolic health.

中枢神经系统和脂肪组织通过复杂的交流相互作用。这种双向信号调节着新陈代谢功能。下丘脑是一个关键的平衡脑区,它整合外部感觉和内部感觉信号,控制食欲、能量消耗、葡萄糖和脂质代谢。这种调节部分是通过神经调节白色(WAT)和棕色(BAT)脂肪组织来实现的。在这篇综述中,我们将重点介绍交感神经和副交感神经在调节脂肪组织和棕色脂肪组织活动(如脂肪分解和产热)中的作用。反过来,脂肪组织又扮演着能量储备和内分泌器官的双重角色,它分泌的激素会影响大脑功能和代谢健康。此外,本综述还重点探讨了最近发现的沟通途径,包括细胞外囊泡和神经-间质单元,它们为大脑与脂肪组织的相互作用增加了新的调节层次和复杂性。最后,我们还探讨了大脑与脂肪组织之间的交流中断在肥胖和 2 型糖尿病等代谢性疾病中造成的后果,强调了针对这些途径的新治疗策略在改善代谢健康方面的潜力。
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引用次数: 0
Novel integrated multiomics analysis reveals a key role for integrin beta-like 1 in wound scarring. 新颖的多组学综合分析揭示了整合素 beta 样 1 在伤口瘢痕形成中的关键作用。
IF 6.5 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-11-18 DOI: 10.1038/s44319-024-00322-3
Sang-Eun Kim, Ryota Noda, Yu-Chen Liu, Yukari Nakajima, Shoichiro Kameoka, Daisuke Motooka, Seiya Mizuno, Satoru Takahashi, Kento Takaya, Takehiko Murase, Kazuya Ikematsu, Katsiaryna Tratsiakova, Takahiro Motoyama, Masahiro Nakashima, Kazuo Kishi, Paul Martin, Shigeto Seno, Daisuke Okuzaki, Ryoichi Mori

Exacerbation of scarring can originate from a minority fibroblast population that has undergone inflammatory-mediated genetic changes within the wound microenvironment. The fundamental relationship between molecular and spatial organization of the repair process at the single-cell level remains unclear. We have developed a novel, high-resolution spatial multiomics method that integrates spatial transcriptomics with scRNA-Seq; we identified new characteristic features of cell-cell communication and signaling during the repair process. Data from PU.1-/- mice, which lack an inflammatory response, combined with scRNA-Seq and Visium transcriptomics, led to the identification of nine genes potentially involved in inflammation-related scarring, including integrin beta-like 1 (Itgbl1). Transgenic mouse experiments confirmed that Itgbl1-expressing fibroblasts are required for granulation tissue formation and drive fibrogenesis during skin repair. Additionally, we detected a minority population of Acta2high-expressing myofibroblasts with apparent involvement in scarring, in conjunction with Itgbl1 expression. IL1β signaling inhibited Itgbl1 expression in TGFβ1-treated primary fibroblasts from humans and mice. Our novel methodology reveal molecular mechanisms underlying fibroblast-inflammatory cell interactions that initiate wound scarring.

瘢痕的加重可能源于少数成纤维细胞群,它们在伤口微环境中经历了炎症介导的基因变化。单细胞水平上修复过程的分子和空间组织之间的基本关系仍不清楚。我们开发了一种新颖的高分辨率空间多组学方法,它将空间转录组学与 scRNA-Seq 整合在一起;我们发现了修复过程中细胞-细胞通讯和信号传导的新特征。来自缺乏炎症反应的 PU.1-/- 小鼠的数据与 scRNA-Seq 和 Visium 转录组学相结合,确定了九个可能参与炎症相关瘢痕形成的基因,其中包括整合素 beta 样 1 (Itgbl1)。转基因小鼠实验证实,表达Itgbl1的成纤维细胞是肉芽组织形成所必需的,并在皮肤修复过程中驱动纤维生成。此外,我们还检测到少数Acta2高表达的肌成纤维细胞,它们与Itgbl1的表达一起明显参与了瘢痕形成。在经 TGFβ1 处理的人类和小鼠原代成纤维细胞中,IL1β 信号抑制了 Itgbl1 的表达。我们的新方法揭示了成纤维细胞与炎症细胞相互作用导致伤口瘢痕形成的分子机制。
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引用次数: 0
The Dystrophin-Dystroglycan complex ensures cytokinesis efficiency in Drosophila epithelia. Dystrophin-Dystroglycan复合体可确保果蝇上皮细胞的细胞分裂效率。
IF 6.5 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-11-15 DOI: 10.1038/s44319-024-00319-y
Margarida Gonçalves, Catarina Lopes, Hervé Alégot, Mariana Osswald, Floris Bosveld, Carolina Ramos, Graziella Richard, Yohanns Bellaiche, Vincent Mirouse, Eurico Morais-de-Sá

Cytokinesis physically separates daughter cells at the end of cell division. This step is particularly challenging for epithelial cells, which are connected to their neighbors and to the extracellular matrix by transmembrane protein complexes. To systematically evaluate the impact of the cell adhesion machinery on epithelial cytokinesis efficiency, we performed an RNAi-based modifier screen in the Drosophila follicular epithelium. Strikingly, this unveiled adhesion molecules and transmembrane receptors that facilitate cytokinesis completion. Among these is Dystroglycan, which connects the extracellular matrix to the cytoskeleton via Dystrophin. Live imaging revealed that Dystrophin and Dystroglycan become enriched in the ingressing membrane, below the cytokinetic ring, during and after ring constriction. Using multiple alleles, including Dystrophin isoform-specific mutants, we show that Dystrophin/Dystroglycan localization is linked with unanticipated roles in regulating cytokinetic ring contraction and in preventing membrane regression during the abscission period. Altogether, we provide evidence that, rather than opposing cytokinesis completion, the machinery involved in cell-cell and cell-matrix interactions has also evolved functions to ensure cytokinesis efficiency in epithelial tissues.

细胞分裂是在细胞分裂结束时物理分离子细胞。上皮细胞通过跨膜蛋白复合物与邻近细胞和细胞外基质相连,因此这一步骤对于上皮细胞来说尤其具有挑战性。为了系统评估细胞粘附机制对上皮细胞分裂效率的影响,我们在果蝇滤泡上皮细胞中进行了基于 RNAi 的修饰物筛选。令人震惊的是,我们发现了能促进细胞分裂完成的粘附分子和跨膜受体。其中的Dystroglycan通过Dystrophin连接细胞外基质和细胞骨架。实时成像显示,在细胞运动环收缩期间和之后,Dystrophin 和 Dystroglycan 在细胞运动环下方的摄入膜中富集。利用多种等位基因(包括 Dystrophin 同工酶特异性突变体),我们发现 Dystrophin/Dystroglycan 的定位在调节细胞分裂环收缩和防止脱落期膜退缩方面发挥了意想不到的作用。总之,我们提供的证据表明,参与细胞-细胞和细胞-基质相互作用的机制不仅反对细胞分裂的完成,而且还进化出了确保上皮组织细胞分裂效率的功能。
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引用次数: 0
Cultivating the next generation of leaders : How postdocs, principal investigators and institutes can nurture and select for leadership competencies. 培养下一代领导者:博士后、主要研究人员和研究机构如何培养和选拔领导能力。
IF 6.5 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-11-12 DOI: 10.1038/s44319-024-00308-1
James W Bryson, Ülkü Uzun, Victor O Oria, Jamie Y Auxillos, Iman Safari, Alexia M Lopresti, Agnieszka Krzyzanowska, Katrine Sonne-Hansen
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引用次数: 0
The winter holidays are glorious-except when they're not. 寒假是灿烂的--除了不灿烂的时候。
IF 6.5 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-11-11 DOI: 10.1038/s44319-024-00318-z
Shina Caroline Lynn Kamerlin
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引用次数: 0
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