【Cell】2024年7月论文导读（187卷，14期）
期刊介绍：
Cell是Cell Press细胞出版社旗下的旗舰刊，创办于1974年，由Elsevier公司出版发行。这是一本多学科期刊，包括但不限于细胞生物学、分子生物学、神经科学、免疫学、病毒学和微生物学、癌症、人类遗传学、系统生物学、信号传导和疾病机制和疾病治疗。该期刊为双周刊，影响因子为45.5。
2024年7月11日，Volume 187（Issue 14）：p3461-3786
2024年7月11日，共发表26篇文章，其中包括1篇Story，3篇Previews，13篇Articles,1篇Resource，6篇Corrections,1篇Retraction。
1.Temporal dynamics of woolly mammoth genome erosion prior to extinction
猛犸象灭绝前基因组侵蚀的时间动态
Summary
A number of species have recently recovered from near-extinction. Although these species have avoided the immediate extinction threat, their long-term viability remains precarious due to the potential genetic consequences of population declines, which are poorly understood on a timescale beyond a few generations. Woolly mammoths (Mammuthus primigenius) became isolated on Wrangel Island around 10,000 years ago and persisted for over 200 generations before becoming extinct around 4,000 years ago. To study the evolutionary processes leading up to the mammoths’ extinction, we analyzed 21 Siberian woolly mammoth genomes. Our results show that the population recovered quickly from a severe bottleneck and remained demographically stable during the ensuing six millennia. We find that mildly deleterious mutations gradually accumulated, whereas highly deleterious mutations were purged, suggesting ongoing inbreeding depression that lasted for hundreds of generations. The time-lag between demographic and genetic recovery has wide-ranging implications for conservation management of recently bottlenecked populations.
摘要：
近年来，一些物种已从濒临灭绝的状态恢复过来。尽管这些物种避免了立即灭绝的威胁，但由于种群数量下降可能带来的遗传后果，它们的长期生存能力仍然很弱，而这种后果在几代人以上的时间尺度上尚未得到充分认识。大约1万年前，长毛猛犸象（Mammuthus primigenius）在弗兰格尔岛（Wrangel Island）上被孤立起来，并在那里延续了200多代，于4000年前灭绝。为了研究导致猛犸象灭绝的进化过程，该研究分析了21个西伯利亚长毛猛犸象基因组。研究结果显示，该种群从严重的种群瓶颈中迅速恢复过来，并在随后的6000年里保持了稳定的种群数量增长。该研究发现，轻微有害的突变逐渐积累，而高度有害的突变则被清除，这表明近亲繁殖衰退持续了数百代。种群数量和基因恢复之间的时间差对最近经历了种群瓶颈的物种的保护管理具有广泛的影响。
2. Three-dimensional genome architecture persists in a 52,000-year-old woolly mammoth skin sample
一个52000年前的长毛象皮肤样本中仍然存在三维基因组结构
Summary
Analyses of ancient DNA typically involve sequencing the surviving short oligonucleotides and aligning to genome assemblies from related, modern species. Here, we report that skin from a female woolly mammoth (†Mammuthus primigenius) that died 52,000 years ago retained its ancient genome architecture. We use PaleoHi-C to map chromatin contacts and assemble its genome, yielding 28 chromosome-length scaffolds. Chromosome territories, compartments, loops, Barr bodies, and inactive X chromosome (Xi) superdomains persist. The active and inactive genome compartments in mammoth skin more closely resemble Asian elephant skin than other elephant tissues. Our analyses uncover new biology. Differences in compartmentalization reveal genes whose transcription was potentially altered in mammoths vs. elephants. Mammoth Xi has a tetradic architecture, not bipartite like human and mouse. We hypothesize that, shortly after this mammoth’s death, the sample spontaneously freeze-dried in the Siberian cold, leading to a glass transition that preserved subfossils of ancient chromosomes at nanometer scale.
摘要：
古DNA的分析通常涉及对存留的短寡核苷酸进行测序，并将其与现代相关物种的基因组组装进行比对。该研究报告了一只52,000年前死亡的雌性猛犸象（†Mammuthus primigenius）的皮肤保留了其古老的基因组结构。该研究使用古染色质捕获技术（PaleoHi-C）来绘制染色质接触图谱，并组装其基因组，得到了28条染色体长度的支架。染色体领域、区域隔室、环状结构、巴氏小体和失活X染色体（Xi）超域仍然存在。猛犸象皮肤中的活性和非活性基因组区域更接近亚洲象皮肤，而非其他象类组织。该研究的分析揭示了新的生物学信息。区域化的差异揭示了在猛犸象与象类之间可能发生转录改变的基因。猛犸象的Xi染色体具有四部分结构，而不像人类和小鼠那样是二分的。该研究推测，在这只猛犸象死亡后不久，样本在西伯利亚的寒冷中自发冷冻干燥，导致玻璃化转变，从而在纳米尺度上保留了古染色体的亚化石。
3. The genomic and cellular basis of biosynthetic innovation in rove beetles
隐翅虫生物合成创新的基因组和细胞基础
Summary
How evolution at the cellular level potentiates macroevolutionary change is central to understanding biological diversification. The >66,000 rove beetle species (Staphylinidae) form the largest metazoan family. Combining genomic and cell type transcriptomic insights spanning the largest clade, Aleocharinae, we retrace evolution of two cell types comprising a defensive gland—a putative catalyst behind staphylinid megadiversity. We identify molecular evolutionary steps leading to benzoquinone production by one cell type via a mechanism convergent with plant toxin release systems, and synthesis by the second cell type of a solvent that weaponizes the total secretion. This cooperative system has been conserved since the Early Cretaceous as Aleocharinae radiated into tens of thousands of lineages. Reprogramming each cell type yielded biochemical novelties enabling ecological specialization—most dramatically in symbionts that infiltrate social insect colonies via host-manipulating secretions. Our findings uncover cell type evolutionary processes underlying the origin and evolvability of a beetle chemical innovation.
摘要：
细胞层面的进化如何促进宏观进化变化，是理解生物多样性的核心问题。拥有超过66,000种类的隐翅虫科（Staphylinidae），是节肢动物中最大的家族。该研究结合了基因组学和细胞类型转录组学的见解，深入研究了隐翅虫科中最大的支系——隐翅亚科（Aleocharinae），追溯了构成防御腺体的两种细胞类型的进化历程，这可能是隐翅虫科物种极度丰富背后的潜在催化剂。该研究确定了分子进化的步骤，这些步骤导致了一种细胞类型通过一种与植物毒素释放系统趋同的机制产生苯醌，而另一种细胞类型则合成了一种溶剂，使整体分泌物具有攻击性。自白垩纪早期以来，这一协同系统随着隐翅亚科的辐射分化而被保留下来，形成了成千上万的谱系。每种细胞类型的重新编程产生了生物化学上的新奇性，从而实现了生态特化——尤其是在通过操纵宿主的分泌物渗入社会性昆虫群体的共生体中表现得最为显著。该研究的发现揭示了甲虫化学创新起源和可进化性背后的细胞类型进化过程。
4. A pseudoautosomal glycosylation disorder prompts the revision of dolichol biosynthesis
一种假性常染色体糖基化紊乱促使多萜醇生物合成途径的修正
Summary
Dolichol is a lipid critical for N-glycosylation as a carrier for activated sugars and nascent oligosaccharides. It is commonly thought to be directly produced from polyprenol by the enzyme SRD5A3. Instead, we found that dolichol synthesis requires a three-step detour involving additional metabolites, where SRD5A3 catalyzes only the second reaction. The first and third steps are performed by DHRSX, whose gene resides on the pseudoautosomal regions of the X and Y chromosomes. Accordingly, we report a pseudoautosomal-recessive disease presenting as a congenital disorder of glycosylation in patients with missense variants in DHRSX (DHRSX-CDG). Of note, DHRSX has a unique dual substrate and cofactor specificity, allowing it to act as a NAD+-dependent dehydrogenase and as a NADPH-dependent reductase in two non-consecutive steps. Thus, our work reveals unexpected complexity in the terminal steps of dolichol biosynthesis. Furthermore, we provide insights into the mechanism by which dolichol metabolism defects contribute to disease.
摘要：
多萜醇是一种对于N-糖基化过程至关重要的脂质，可作为活化糖和初级寡糖的载体。通常认为它是由SRD5A3酶直接催化聚戊烯醇而产生。然而，该研究发现多萜醇的合成需要经过一个涉及额外代谢物的三步路线，其中SRD5A3仅催化第二步反应。第一步和第三步由DHRSX酶催化，其基因位于X和Y染色体的假性常染色体区域。因此，该研究报道了一种假性常染色体隐性遗传病，表现为糖基化先天性障碍，患者中的DHRSX基因存在错义突变（DHRSX-CDG）。值得注意的是，DHRSX具有独特的双底物和辅因子特异性，在两个非连续的步骤中分别作为NAD+依赖性脱氢酶和NADPH依赖性还原酶。因此，该研究的工作揭示了多萜醇生物合成末端步骤中意想不到的复杂性。此外，该研究提供了有关多萜醇代谢缺陷如何导致疾病的机制的见解。
5. De novo and salvage purine synthesis pathways across tissues and tumors
组织和肿瘤中的从头合成和补救合成嘌呤途径
Summary
Purine nucleotides are vital for RNA and DNA synthesis, signaling, metabolism, and energy homeostasis. To synthesize purines, cells use two principal routes: the de novo and salvage pathways. Traditionally, it is believed that proliferating cells predominantly rely on de novo synthesis, whereas differentiated tissues favor the salvage pathway. Unexpectedly, we find that adenine and inosine are the most effective circulating precursors for supplying purine nucleotides to tissues and tumors, while hypoxanthine is rapidly catabolized and poorly salvaged in vivo. Quantitative metabolic analysis demonstrates comparative contribution from de novo synthesis and salvage pathways in maintaining purine nucleotide pools in tumors. Notably, feeding mice nucleotides accelerates tumor growth, while inhibiting purine salvage slows down tumor progression, revealing a crucial role of the salvage pathway in tumor metabolism. These findings provide fundamental insights into how normal tissues and tumors maintain purine nucleotides and highlight the significance of purine salvage in cancer.
摘要：
嘌呤核苷酸对于RNA和DNA的合成、信号传导、代谢和能量稳态至关重要。细胞采用两条主要途径合成嘌呤核苷酸：从头合成途径和补救合成途径。传统上认为，增殖细胞主要依赖从头合成途径，而分化组织则更偏向于补救合成途径。然而，意外的是，该研究发现腺嘌呤和肌苷是给组织和肿瘤供应嘌呤核苷酸的最有效循环前体，而次黄嘌呤在体内迅速被分解且补救效率低下。定量代谢分析显示，在肿瘤中，从头合成途径和补救合成途径对维持嘌呤核苷酸库的贡献相当。值得注意的是，给小鼠补充核苷酸加速了肿瘤生长，而抑制嘌呤补救合成则减缓了肿瘤进展，揭示了补救合成途径在肿瘤代谢中的关键作用。这些发现为正常组织和肿瘤如何维持嘌呤核苷酸提供了基础见解，并突显了嘌呤补救合成在癌症中的重要性。
6. MTFP1 controls mitochondrial fusion to regulate inner membrane quality control and maintain mtDNA levels
MTFP1通过控制线粒体融合来调节内膜质量控制并维持mtDNA水平
Summary
Mitochondrial dynamics play a critical role in cell fate decisions and in controlling mtDNA levels and distribution. However, the molecular mechanisms linking mitochondrial membrane remodeling and quality control to mtDNA copy number (CN) regulation remain elusive. Here, we demonstrate that the inner mitochondrial membrane (IMM) protein mitochondrial fission process 1 (MTFP1) negatively regulates IMM fusion. Moreover, manipulation of mitochondrial fusion through the regulation of MTFP1 levels results in mtDNA CN modulation. Mechanistically, we found that MTFP1 inhibits mitochondrial fusion to isolate and exclude damaged IMM subdomains from the rest of the network. Subsequently, peripheral fission ensures their segregation into small MTFP1-enriched mitochondria (SMEM) that are targeted for degradation in an autophagic-dependent manner. Remarkably, MTFP1-dependent IMM quality control is essential for basal nucleoid recycling and therefore to maintain adequate mtDNA levels within the cell.
摘要：
线粒体动态在细胞命运决策和控制线粒体DNA水平及分布中起着关键作用。然而，线粒体膜重塑和质量控制与线粒体DNA拷贝数调控的分子机制仍不明确。该研究展示了线粒体内膜蛋白线粒体分裂过程1（MTFP1）负调控线粒体内膜融合的作用。此外，通过调控MTFP1水平来操纵线粒体融合会导致线粒体DNA拷贝数的变化。在机制上，该研究发现MTFP1通过抑制线粒体融合，将损伤的线粒体内膜亚域从网格中隔离出来并排除在外。随后，外围分裂确保这些受损的亚区被分离成富含MTFP1的小型线粒体（SMEM），这些小型线粒体会通过自噬依赖的方式被定向降解。值得注意的是，MTFP1依赖的线粒体内膜质量控制对于基础核小体的再循环至关重要，因此也是维持细胞内足够的线粒体DNA水平的关键。
7. POT1 recruits and regulates CST-Polα/primase at human telomeres
POT1 在人类端粒处招募并调节 CST-Polα/引物酶
Summary
Telomere maintenance requires the extension of the G-rich telomeric repeat strand by telomerase and the fill-in synthesis of the C-rich strand by Polα/primase. At telomeres, Polα/primase is bound to Ctc1/Stn1/Ten1 (CST), a single-stranded DNA-binding complex. Like mutations in telomerase, mutations affecting CST-Polα/primase result in pathological telomere shortening and cause a telomere biology disorder, Coats plus (CP). We determined cryogenic electron microscopy structures of human CST bound to the shelterin heterodimer POT1/TPP1 that reveal how CST is recruited to telomeres by POT1. Our findings suggest that POT1 hinge phosphorylation is required for CST recruitment, and the complex is formed through conserved interactions involving several residues mutated in CP. Our structural and biochemical data suggest that phosphorylated POT1 holds CST-Polα/primase in an inactive, autoinhibited state until telomerase has extended the telomere ends. We propose that dephosphorylation of POT1 releases CST-Polα/primase into an active state that completes telomere replication through fill-in synthesis.
摘要：
端粒的维护需要通过端粒酶延长富含鸟嘌呤（G）的端粒重复序列链，以及通过Polα/引物酶填补合成富含胞嘧啶（C）的链。在端粒处，Polα/引物酶与Ctc1/Stn1/Ten1（CST）复合体结合，CST是一个单链DNA结合复合物。与端粒酶中的突变类似，影响CST-Polα/引物酶的突变会导致病理性端粒缩短，并引起一种端粒生物学疾病，如柯茨加综合征（CP）。该研究确定了人类CST与shelterin异二聚体POT1/TPP1结合的冷冻电子显微镜结构，揭示了CST如何通过POT1被招募到端粒。该研究的发现表明，CST的招募需要POT1的铰链磷酸化，并且该复合物的形成依赖于包括CP中发生突变的多个残基在内的保守相互作用。该研究的结构和生化数据表明，磷酸化的POT1使CST-Polα/引物酶处于非活跃的自抑制状态，直到端粒酶延长端粒末端。该研究提出，POT1的去磷酸化使CST-Polα/引物酶释放进入活跃状态，从而通过填充合成完成端粒复制过程。
8. The ribotoxic stress response drives UV-mediated cell death
核糖体毒性应激反应驱动紫外线介导的细胞死亡
Summary
While ultraviolet (UV) radiation damages DNA, eliciting the DNA damage response (DDR), it also damages RNA, triggering transcriptome-wide ribosomal collisions and eliciting a ribotoxic stress response (RSR). However, the relative contributions, timing, and regulation of these pathways in determining cell fate is unclear. Here we use time-resolved phosphoproteomic, chemical-genetic, single-cell imaging, and biochemical approaches to create a chronological atlas of signaling events activated in cells responding to UV damage. We discover that UV-induced apoptosis is mediated by the RSR kinase ZAK and not through the DDR. We identify two negative-feedback modules that regulate ZAK-mediated apoptosis: (1) GCN2 activation limits ribosomal collisions and attenuates ZAK-mediated RSR and (2) ZAK activity leads to phosphodegron autophosphorylation and its subsequent degradation. These events tune ZAK's activity to collision levels to establish regimes of homeostasis, tolerance, and death, revealing its key role as the cellular sentinel for nucleic acid damage.
摘要：
紫外线（UV）辐射会损伤DNA，引发DNA损伤应答（DDR），同时也损伤RNA，触发全转录组范围的核糖体碰撞，引发核糖体毒性应激反应（RSR）。然而，这些途径在决定细胞命运中的相对贡献、时间顺序和调节机制尚不清楚。该研究利用时间分辨的磷酸蛋白组学、化学遗传学、单细胞成像和生化方法，创建了UV损伤应答细胞中信号事件激活的时间序列图谱。该研究发现，UV诱导的凋亡是通过RSR激酶ZAK介导的，而不是通过DDR。该研究识别了两个负反馈模块来调控ZAK介导的凋亡：（1）GCN2的激活限制核糖体碰撞，并减弱ZAK介导的RSR；（2）ZAK活性导致其磷酸化降解位点自磷酸化，并随后阿生降解。这些事件调节ZAK的活性以适应碰撞水平，从而建立稳态、耐受和死亡的不同状态，揭示了ZAK作为细胞核酸损伤的哨兵的关键作用。
9. TNF-NF-κB-p53 axis restricts in vivo survival of hPSC-derived dopamine neurons
TNF-NF-κB-p53轴限制人源多能干细胞（hPSC）来源的多巴胺神经元的体内存活
Summary
Ongoing, early-stage clinical trials illustrate the translational potential of human pluripotent stem cell (hPSC)-based cell therapies in Parkinson’s disease (PD). However, an unresolved challenge is the extensive cell death following transplantation. Here, we performed a pooled CRISPR-Cas9 screen to enhance postmitotic dopamine neuron survival in vivo. We identified p53-mediated apoptotic cell death as a major contributor to dopamine neuron loss and uncovered a causal link of tumor necrosis factor alpha (TNF-α)-nuclear factor κB (NF-κB) signaling in limiting cell survival. As a translationally relevant strategy to purify postmitotic dopamine neurons, we identified cell surface markers that enable purification without the need for genetic reporters. Combining cell sorting and treatment with adalimumab, a clinically approved TNF-α inhibitor, enabled efficient engraftment of postmitotic dopamine neurons with extensive reinnervation and functional recovery in a preclinical PD mouse model. Thus, transient TNF-α inhibition presents a clinically relevant strategy to enhance survival and enable engraftment of postmitotic hPSC-derived dopamine neurons in PD.
摘要：
正在进行的早期临床试验展示了基于人类多能干细胞（hPSC）的细胞疗法在帕金森病（PD）中的转化潜力。然而，一个尚未解决的挑战是移植后细胞的大量死亡。该研究进行了一项CRISPR-Cas9集合筛选，以提高有丝分裂后多巴胺神经元的体内存活率。该研究发现p53介导的凋亡细胞死亡是多巴胺神经元丢失的主要原因，并揭示了肿瘤坏死因子α（TNF-α）-核因子κB（NF-κB）信号在限制细胞存活中的因果关系。作为一个与转化相关的策略，该研究确定了细胞表面标记物，使得无需基因报告物即可纯化有丝分裂后的多巴胺神经元。结合细胞分选和临床批准的TNF-α抑制剂修美乐（adalimumab）治疗，使有丝分裂后的多巴胺神经元能够在临床前PD小鼠模型中有效移植，并实现了广泛的再神经化和功能恢复。因此，短期抑制TNF-α为增强存活率并使有丝分裂后hPSC来源的多巴胺神经元在PD中成功移植提供了一种具有临床意义的策略。
10. Clonal hematopoiesis driven by mutated DNMT3A promotes inflammatory bone loss
DNMT3A突变驱动的克隆造血促进炎性骨质流失
Summary
Clonal hematopoiesis of indeterminate potential (CHIP) arises from aging-associated acquired mutations in hematopoietic progenitors, which display clonal expansion and produce phenotypically altered leukocytes. We associated CHIP-DNMT3A mutations with a higher prevalence of periodontitis and gingival inflammation among 4,946 community-dwelling adults. To model DNMT3A-driven CHIP, we used mice with the heterozygous loss-of-function mutation R878H, equivalent to the human hotspot mutation R882H. Partial transplantation with Dnmt3aR878H/+ bone marrow (BM) cells resulted in clonal expansion of mutant cells into both myeloid and lymphoid lineages and an elevated abundance of osteoclast precursors in the BM and osteoclastogenic macrophages in the periphery. DNMT3A-driven clonal hematopoiesis in recipient mice promoted naturally occurring periodontitis and aggravated experimentally induced periodontitis and arthritis, associated with enhanced osteoclastogenesis, IL-17-dependent inflammation and neutrophil responses, and impaired regulatory T cell immunosuppressive activity. DNMT3A-driven clonal hematopoiesis and, subsequently, periodontitis were suppressed by rapamycin treatment. DNMT3A-driven CHIP represents a treatable state of maladaptive hematopoiesis promoting inflammatory bone loss.
摘要：
克隆性造血功能异常（CHIP）源于造血祖细胞中与衰老相关的获得性突变，这些突变表现为克隆性扩增并产生表型改变的白细胞。该研究在4946名社区居住的成年人中，发现携带CHIP-DNMT3A突变的人群中牙周炎和牙龈炎症的发病率更高。为了模拟DNMT3A驱动的CHIP，该研究使用了携带杂合性失功能突变R878H的小鼠，该突变相当于人类热点突变R882H。部分移植携带Dnmt3aR878H/+突变的骨髓（BM）细胞后，突变细胞在髓系和淋巴系中均发生克隆性扩增，骨髓中破骨细胞前体的数量增加，外周血中单核巨噬细胞向破骨细胞的分化能力增强。在受体小鼠中，DNMT3A驱动的克隆性造血促进了自然发生的牙周炎，并加重了实验诱导的牙周炎和关节炎，这与破骨细胞生成增加、IL-17依赖的炎症反应和中性粒细胞反应增强以及调节性T细胞免疫抑制活性受损有关。雷帕霉素治疗可抑制DNMT3A驱动的克隆性造血和随后的牙周炎。因此，DNMT3A驱动的CHIP代表了一种可治疗的骨髓造血功能不良状态，这种状态会促进炎症性骨丢失。
11. Structure-based discovery of CFTR potentiators and inhibitors
基于结构的 CFTR 增强剂和抑制剂的发现
Summary
The cystic fibrosis transmembrane conductance regulator (CFTR) is a crucial ion channel whose loss of function leads to cystic fibrosis, whereas its hyperactivation leads to secretory diarrhea. Small molecules that improve CFTR folding (correctors) or function (potentiators) are clinically available. However, the only potentiator, ivacaftor, has suboptimal pharmacokinetics and inhibitors have yet to be clinically developed. Here, we combine molecular docking, electrophysiology, cryo-EM, and medicinal chemistry to identify CFTR modulators. We docked ∼155 million molecules into the potentiator site on CFTR, synthesized 53 test ligands, and used structure-based optimization to identify candidate modulators. This approach uncovered mid-nanomolar potentiators, as well as inhibitors, that bind to the same allosteric site. These molecules represent potential leads for the development of more effective drugs for cystic fibrosis and secretory diarrhea, demonstrating the feasibility of large-scale docking for ion channel drug discovery.
摘要：
囊性纤维化跨膜传导调节因子（CFTR）是一个关键的离子通道，其功能丧失会导致囊性纤维化，而其过度活化则会引起分泌性腹泻。目前临床上已有改善CFTR折叠（修正剂）或功能（增效剂）的小分子药物。然而，目前唯一的增效剂伊瓦卡夫托（ivacaftor）的药代动力学表现不佳，抑制剂又尚未进入临床开发阶段。该研究结合分子对接、电生理学、冷冻电子显微镜和药物化学技术，以识别CFTR调节剂。该研究将约1.55亿种分子对接到CFTR上的增效剂位点，合成了53个测试配体，并利用基于结构的优化方法鉴定候选调节剂。这种方法发现了中等纳摩尔级别的增效剂，以及结合同一变构位点的抑制剂。这些分子为开发囊性纤维化和分泌性腹泻更有效药物提供了潜在的先导化合物，展示了大规模分子对接在离子通道药物发现中的可行性。
12. Modulation of FGF pathway signaling and vascular differentiation using designed oligomeric assemblies
利用设计的寡聚组件调节FGF信号通路和血管分化
Summary
Many growth factors and cytokines signal by binding to the extracellular domains of their receptors and driving association and transphosphorylation of the receptor intracellular tyrosine kinase domains, initiating downstream signaling cascades. To enable systematic exploration of how receptor valency and geometry affect signaling outcomes, we designed cyclic homo-oligomers with up to 8 subunits using repeat protein building blocks that can be modularly extended. By incorporating a de novo-designed fibroblast growth factor receptor (FGFR)-binding module into these scaffolds, we generated a series of synthetic signaling ligands that exhibit potent valency- and geometry-dependent Ca2+ release and mitogen-activated protein kinase (MAPK) pathway activation. The high specificity of the designed agonists reveals distinct roles for two FGFR splice variants in driving arterial endothelium and perivascular cell fates during early vascular development. Our designed modular assemblies should be broadly useful for unraveling the complexities of signaling in key developmental transitions and for developing future therapeutic applications.
摘要：
许多生长因子和细胞因子通过与受体的细胞外结构域结合，驱动受体细胞内酪氨酸激酶结构域的结合和跨磷酸化，从而启动下游信号级联反应。为了系统地探索受体价态和几何形状如何影响信号传导结果，该研究利用可模块化扩展的重复蛋白构建块设计了最多包含8个亚基的环状同型寡聚体。通过将新设计的成纤维细胞生长因子受体（FGFR）结合模块整合到这些支架中，该研究生成了一系列合成信号配体，这些配体展示出强大的价态和几何形状依赖性的钙离子（Ca²⁺）释放以及丝裂原活化蛋白激酶（MAPK）通路激活能力。所设计的激动剂的高特异性揭示了两种FGFR剪接变体在早期血管发育过程中驱动动脉内皮细胞和血管周细胞命运的不同作用。该研究设计的模块化组装物应该广泛适用于揭示关键发育转变中信号传导的复杂性，并为未来的治疗应用开发提供助力。
13. Heterologous survey of 130 DNA transposons in human cells highlights their functional divergence and expands the genome engineering toolbox
在人类细胞中进行的130种DNA转座子的异源调查突显了它们的功能差异并扩展了基因组工程工具箱
Summary
Experimental studies on DNA transposable elements (TEs) have been limited in scale, leading to a lack of understanding of the factors influencing transposition activity, evolutionary dynamics, and application potential as genome engineering tools. We predicted 130 active DNA TEs from 102 metazoan genomes and evaluated their activity in human cells. We identified 40 active (integration-competent) TEs, surpassing the cumulative number (20) of TEs found previously. With this unified comparative data, we found that the Tc1/mariner superfamily exhibits elevated activity, potentially explaining their pervasive horizontal transfers. Further functional characterization of TEs revealed additional divergence in features such as insertion bias. Remarkably, in CAR-T therapy for hematological and solid tumors, Mariner2_AG (MAG), the most active DNA TE identified, largely outperformed two widely used vectors, the lentiviral vector and the TE-based vector SB100X. Overall, this study highlights the varied transposition features and evolutionary dynamics of DNA TEs and increases the TE toolbox diversity.
摘要：
关于DNA可转座元件（TEs）的实验研究规模有限，导致对影响转座活性、进化动态以及作为基因组工程工具应用潜力的因素理解不足。该研究从102个后生动物基因组中预测了130个活跃DNA TEs，并在人类细胞中评估了它们的活性。该研究确定了40个具有活性（具有整合能力）的TEs，超过了之前发现的TEs总数（20个）。基于这些统一的比较数据，该研究发现Tc1/mariner超家族显示出较高的活性，这可能解释了它们普遍的水平转移现象。进一步对TEs的功能特征进行表征揭示了它们在插入偏好等特征上的额外差异。值得注意的是，在治疗血液和实体肿瘤的CAR-T疗法中，已鉴定的最活跃DNA TE——Mariner2_AG（MAG），大大优于两种广泛使用的载体，即慢病毒载体和基于TE的载体SB100X。总体而言，该研究强调了DNA TEs的多样化转座特征和进化动态，并增加了TE工具箱的多样性。
汇报人：王肖宇
导师：赵宇教授
审核：毛敏姿、任建君
