1. Why Did Treg and Immune Tolerance Win Nobel Prize This Year?
Song Guo Zheng
View abstract
中文摘要
从1995年Shimon Sakaguchi首次鉴定出CD4⁺CD25⁺调节性T细胞（Treg），到2025年斯德哥尔摩钟声敲响，这群“少数细胞群体”终于登上了免疫耐受研究的中心舞台。本文以第一人称视角回顾Treg研究历程中的关键里程碑。每一个实验都在追问同一个问题：为什么免疫系统不会攻击自身？诺贝尔委员会同时授予天然Treg细胞的发现者（Shimon Sakaguchi）及其调控因子Foxp3基因点突变的发现者（Mary E. Brunkow和Fred Ramsdell）这一殊荣，不仅是在庆祝一段科学传奇，更是在宣告掌握Treg细胞，就等于拥有了治疗自身免疫病、移植排斥反应甚至肿瘤免疫逃逸的“万能遥控器”。
Page qzaf124
2. Computational Analyses and Challenges of Single-cell ATAC-seq
Chenfei Wang, Jiaojiao Zhou, Hong Zhang, Zihan Zhuang, Gali Bai, Ming Tang, Song Liu, Tao Liu
View abstract
中文摘要
Single-cell Assay for Transposase-Accessible Chromatin using sequencing (scATAC-seq) has emerged as a powerful technique to study cell-specific epigenetic landscapes and to provide a multidimensional portrait of gene regulation. However, low genomic coverage per cell results in intrinsic data sparsity and missing-data issues, presenting unique methodological challenges. Consequently, numerous computational methods and techniques have been developed to address these challenges. This review provides a concise overview of published workflows for scATAC-seq analysis, covering preprocessing through downstream analysis including quality control, alignment, peak calling, dimensionality reduction, clustering, gene regulation score calculation, cell type annotation, and multiomics integration. Additionally, we survey key scATAC-seq databases that offer curated, accessible resources; discuss emerging deep-learning methods and Artificial Intelligence (AI) foundation models tailored to scATAC-seq data; and highlight recent advances in spatial ATAC-seq technologies and associated computational approaches. Our objective is to equip readers with a clear understanding of current scATAC-seq methodologies so they can select appropriate tools and construct customized workflows for exploring gene regulation and cellular diversity.
单细胞染色质可及性测序（Single-cell Assay for Transposase-Accessible Chromatin using sequencing, scATAC-seq）是一种革命性技术，能够在表观遗传层面揭示细胞特异性的基因调控景观。这项技术通过分析单个细胞中染色质的开放区域，帮助科学家理解基因表达调控如何决定细胞身份和功能。尽管scATAC-seq技术取得了巨大进展，但由于每个细胞获得的测序片段数量较少，导致数据存在内在的稀疏性和缺失值问题，这为数据分析带来了独特的方法学挑战。因此，亟需通过计算手段来优化分析流程，以实现从原始数据到生物学洞察的完整解析。
Page qzaf115
3. Macrophages in Hematopoiesis and Related Blood Diseases
Hong Huang, Mengya Gao, Francesca Vinchi, Xiuli An, Wei Li, Yaomei Wang
View abstract
中文摘要
Emerging evidence indicates that macrophages play important roles in hematopoiesis in addition to their immune functions. The well-known immune-unrelated functions of macrophages include their roles in hematopoiesis, especially the quality control of hematopoietic stem cells (HSCs) and hematopoietic stem and progenitor cells (HSPCs), the support of erythropoiesis, and the regulation of megakaryopoiesis. Several studies, most using mouse models, have explored the roles of macrophages in hematopoiesis in different organs such as the yolk sac (YS), fetal liver (FL), bone marrow (BM), and spleen (SP). We have recently documented the potential roles and underlying mechanisms of macrophages in myeloproliferative neoplasm (MPN), aplastic anemia (AA), and idiopathic thrombocytopenic purpura (ITP). In this article, we review the origin of macrophages, introduce their roles in regulating HSCs/HSPCs, erythropoiesis, and megakaryopoiesis within four hematopoietic organs, and summarize the recent advances of macrophages in MPN, AA, and ITP. Finally, we outline the unresolved questions that future studies should address to explore in greater depth the role of macrophages in both normal and disordered hematopoiesis.
要点介绍：
1. 巨噬细胞不仅是免疫细胞，更是造血调控的重要组成部分；
2. 不同来源巨噬细胞具有显著异质性，共同参与造血器官稳态维持；
3. 巨噬细胞是红系造血岛核心细胞，促进红细胞生成和成熟；
4. 巨噬细胞参与巨核细胞发育及血小板稳态调控；
5. 骨髓增殖性肿瘤 (MPN)、再生障碍性贫血 (AA)和特发性血小板减少性紫癜 (ITP)等血液疾病中均存在巨噬细胞异常，具有重要治疗潜力。
Page qzaf112
4. High-quality Population-specific Haplotype-resolved Reference Panel in the Genomic and Pangenomic Eras
Qingxin Yang, Yuntao Sun, Shuhan Duan, Shengjie Nie, Chao Liu, Hong Deng, Mengge Wang, Guanglin He
View abstract
中文摘要
Large-scale international and regional human genomic and pangenomic resources derived from population-scale biobanks and ancient DNA sequences have provided significant insights into human evolution and the genetic determinants of complex diseases and traits. Despite these advances, challenges persist in optimizing the integration of phasing tools, merging haplotype reference panels (HRPs), developing imputation algorithms, and fully exploiting the diverse applications of post-imputation data. This review comprehensively summarizes the advancements, applications, limitations, and future directions of HRPs in human genomics research. Recent progress in the reconstruction of HRPs, based on over 830,000 human whole-genome sequences, has been synthesized, highlighting the broad spectrum of human genetic diversity captured. Additionally, we recapitulate advancements in 56 HRPs for global and regional populations. The evaluation of imputation accuracy indicated that Beagle and Glimpse are the most effective tools for phasing and imputing data from genotyping arrays and low-coverage sequencing, respectively. A critical strategy for selecting an appropriate HRP involves matching the population background of target groups with HRP reference populations and considering multi-ancestry or homogeneous genetic structures. The necessity of a single, integrative, high-quality HRP that captures haplotype structures and genetic diversity across various genetic variation types from globally representative populations is emphasized to support both modern and ancient genomic research and advance human precision medicine.
在基因组学和泛基因组学迅速发展的背景下，大规模国际性和区域性的人类基因组及泛基因组资源的涌现，为解析人类演化历史及复杂性状和疾病的遗传基础提供了重要见解，并衍生出大量单倍型参考面板（Haplotype Reference Panels, HRP）的构建与应用。尽管近年来HRP相关研究取得了显著进展，但在定相（Phasing）工具的优化、不同HRP的整合、填补（Imputation）方法的开发，以及数据的多维应用与共享方面，仍面临诸多挑战。本综述系统总结了全球及特定群体中已构建的56个HRP，深入探讨了HRP在当代人类基因组学研究中的研究进展、应用局限性和未来发展方向，同时提供定相、填补软件及HRP选择的策略建议。我们强调，高质量HRP的构建对于全面捕获全球代表性人群中的各种遗传变异类型与遗传多样性至关重要，不仅有助于现代和古代基因组学研究，也进一步促进人类精准医学的发展。
Page qzaf022
5. YanHuang Paternal Genomic Resource Suggests A Weakly-differentiated Multi-source Admixture in the Formation of Han Founding Ancestral Lineages
Zhiyong Wang, Kaijun Liu, Haibing Yuan, Shuhan Duan, Yunhui Liu, Lintao Luo, Xiucheng Jiang, Shijia Chen, Lanhai Wei , Renkuan Tang, Liping Hu, Jing Chen, Xiangping Li, Qingxin Yang, Yuntao Sun, Qiuxia Sun, Yuguo Huang, Haoran Su, Jie Zhong, Hongbing Yao, Libing Yun, Jianbo Li, Junbao Yang, Yan Cai, Hong Deng, Jiangwei Yan, Bofeng Zhu, 10K_CPGDP Consortium, Kun Zhou, Shengjie Nie, Chao Liu, Mengge Wang, Guanglin He
View abstract
中文摘要
The revolution in large-scale human genomics and advancements in statistical methods have profoundly refined our understanding of genetic diversity and structure within human populations. Y-chromosome variations, with their distinct evolutionary characteristics, play crucial roles in reconstructing the origins and interactions of ancient East Asian paternal lineages. We launched the YanHuang cohort employing a high-resolution capture sequencing panel to explore the evolutionary trajectory of Han Chinese, one of the world’s largest ethnic groups. We generated paternal genomic data for 5020 Han Chinese individuals across 29 Chinese administrative regions. We observed that multiple founding paternal lineages originating from ancient western Eurasia, Siberia, and East Asia contributed significantly to the Han Chinese gene pool. We identified fine-scale paternal genetic structures shaped by interactions among ancient populations and geographic barriers like the Qinling-Huaihe line and the Nanling Mountains. These structures reflect both isolation-enhanced and admixture-driven genetic differentiation, underscoring the complexity of Han Chinese genomic diversity. We observed a strong correlation between the frequency of multiple founding lineages and subsistence-related ancestral sources, including western pastoralists, Holocene Mongolian Plateau populations, and ancient East Asians. This relationship highlights the impact of ancient migrations and admixture on Chinese paternal genomic diversity. We introduced the Weakly-Differentiated Multi-Source Admixture model to clarify the intricate interactions among multiple ancestral sources influencing the Han Chinese paternal landscape. This study provides a comprehensive uniparental genomic resource from the YanHuang cohort, proposes a novel admixture model, and delineates the complex genomic landscape shaped by ancient herders, hunter-gatherers, and farmers integral to Han Chinese ancestry.
研究问题：
人类Y染色体具有单倍型遗传与非重组的特性，这些特性使其成为解析人类演化历史、助力法医学父系生物地理溯源和复杂家系排查的独特分子遗传标记。受限于东亚古基因组数据的时空覆盖度不足，人类精细演化历史的重建仍面临挑战，而高质量Y染色体数据可有效弥补这一缺陷。然而，现有的高质量Y染色体基因组资源在全球人群中分布不均，这一现象在东亚人群中尤为突出。汉族作为全球人口数量最多的单一民族，拥有复杂多源融合的演化历史及独特的民族、文化特征，但针对该民族大规模系统性Y染色体研究仍显不足，对其父系精细遗传背景、演化驱动力解析及演化模型构建尤为欠缺。
研究方法：
本研究旨在通过构建汉族高覆盖度Y染色体靶向捕获测序基因组数据库（炎黄基因组资源），完善中国人群父系演化框架。基于自主研发的高分辨率SNP分型体系（YHseqY3000），对来自中国29个省份的5,020例汉族男性个体进行了Y染色体靶向捕获测序。随后，整合主成分分析、系统发育树和群体遗传结构建模等多维度群体遗传学分析方法，系统评估了汉族群体的遗传多样性分布模式、空间遗传结构特征及历史演化动态。同时，精细化解析了古今东亚人群的Y染色体支系频率，并结合遗传多样性和分化指数等量化指标，揭示了汉族人群的父系遗传多样性模式及其形成的演化机制。
主要结果：
本研究基于炎黄基因组资源，构建了包含1,899种单倍型和1,766个末端单倍群的精细化谱系数据库。从基因组角度系统地证实了汉族存在北方、南方与岭南三大父系遗传亚群，其地理分界与秦岭-淮河线、南岭山脉等自然屏障呈现显著的空间对应关系。Fisher精确检验和Mantel相关性检验显示，单倍群O1a、O1b、C2a以及C2b的频率梯度变异是亚群分化的关键遗传基础。通过整合常染色体基因组多样性、东亚人群精细遗传背景与古DNA父系特征，并在常染色体和Y染色体层面联合建模，本研究提出了汉族人群父系遗传结构形成的“弱分化-多祖源混合”模型：新石器时代晚期，多个遗传分化较弱但具有地域特异性的祖先群体在不同地区发生了差异性的混合，进而塑造了各地汉族人群之间不同的遗传多样性模式。该研究阐明了不同地区汉族与周边人群的遗传互动，揭示了汉族群体历史演化动态，为东亚人群遗传多样性研究提供了关键数据和演化模型，也为人类迁徙与混合历史提供新的见解。
Page qzaf049
6. A Telomere-to-telomere Diploid Reference Genome and Centromere Structure of the Chinese Quartet
Bo Wang, Peng Jia, Stephen J Bush, Xia Wang, Yi Yang, Yu Zhang, Shijie Wan, Xiaofei Yang, Pengyu Zhang, Yuanting Zheng, Leming Shi, Lianhua Dong, Kai Ye
View abstract
中文摘要
Recent advances in sequencing technologies have enabled the complete assembly of human genomes from telomere to telomere (T2T), resolving previously inaccessible regions such as centromeres and segmental duplications. Here, we present an updated, higher-quality, haplotype-phased T2T assembly of the Chinese Quartet (T2T-CQ), a family cohort comprising monozygotic twins and their parents, generated using high-coverage Oxford Nanopore Technologies (ONT) ultralong and PacBio high-fidelity (HiFi) sequencing. The T2T-CQ assembly serves as a crucial reference genome for integrating publicly available multi-omics data and advances the utility of the Quartet reference materials. The T2T-CQ assembly scores highly on multiple metrics of continuity and completeness, with Genome Continuity Inspector (GCI) scores of 77.76 (maternal) and 76.41 (paternal), 21-mer quality values (QVs) > 66, and Clipping Reveals Assembly Quality (CRAQ) scores > 99.6 for both haplotypes, enabling complete annotation of centromeric regions. Within these regions, we identified novel 13-mer higher-order repeat patterns on chromosome 17 which exhibited a monophyletic origin and emerged approximately 230 thousand years ago. Overall, this work establishes an essential genomic resource for the Han Chinese population and advances the development of a T2T pan-Chinese reference genome, which will significantly enable future investigations both into population-specific structural variants and the evolutionary dynamics of centromeres.
研究问题：
人类基因组端粒到端粒（T2T）完整组装，是破解复杂重复区域结构和功能的关键，但现有T2T参考基因组仍存在人群代表性不足的问题，中国人群高精度二倍体T2T参考基因组构建、着丝粒结构解析及演化规律仍有待阐明。本研究依托中华家系1号（Chinese Quartet）独特材料，构建高质量T2T二倍体参考基因组，并系统解析着丝粒区域结构特征与演化动态。
研究方法：
本研究整合超高深度Oxford Nanopore Technologies（ONT）超长读长测序（> 100kb）与PacBio HiFi测序数据，采用Verkko、hifiasm工具在trio binning模式下完成初始组装，经基因组补洞、结构变异校正与人工核验获得最终T2T组装版本（T2T-CQ）；通过对着丝粒α-卫星区域精细注释、跨人群基因组比对、系统发育分析与分子钟估算，解析新型高阶重复序列（HOR）的分布特征与起源演化；同时利用家系内同卵双胞胎数据评估不同组装工具在着丝粒区域的稳健性。
主要结果：
1. 获得连续性与完整性优异的二倍体T2T组装，母本单倍型和父本单倍型的GCI分别达到77.76和76.41，21-mer QV均大于66，contig N50均超过155Mb，填补了此前中华家系基因组的剩余缺口。
2. 完成着丝粒区域完整注释，在17号染色体鉴定出欧洲人群T2T-CHM13参考基因组中缺失的新型13-mer HOR模式。
3. 跨人群分析显示该新型HOR模式在全球广泛分布，并非汉族特有；系统发育分析证实其为单系起源，分子钟估算约于23万年前出现。
4. 组装工具评估显示，主流工具在着丝粒区域的组装误差最大不超过300 kb，远小于自然单倍型间的Mb级遗传差异，可支撑高质量遗传变异研究。
Page qzaf118
7. Genomic Insights into Hybridization and Speciation of Mitten Crabs in the Eriocheir Genus
Jun Wang, Xin Hou, Xiaowen Chen, Roland Nathan Mandal, Nusrat Hasan Kanika, Chunhong Yuan, Yongju Luo, Chenghui Wang
View abstract
中文摘要
Hybridization is a prominent and influential phenomenon with significant implications for adaptive evolution, species distribution, and biodiversity. However, the intricacies of how hybridization influences genomic structure and facilitates adaptive evolution remain poorly understood. By analyzing whole-genome data from seven populations within the Eriocheir genus across diverse geographic regions, we validated a complex hybridization history between Chinese and Japanese mitten crabs. This hybridization gave rise to two distinct ecological species: Hepu and Russian mitten crabs with unique genomic architectures and adaptations. Genes related to reproduction, development, and temperature adaptation exhibited divergent selection signals, potentially contributing to their phenotypic diversity and ecological niches. Meanwhile, genes associated with reproduction, namely Birc6, Bap31, and Poxn, displayed robust evidence of selective sweeps in Hepu mitten crab. Notably, the favored alleles for these genes originated from the parental lineages during the hybridization process. Furthermore, Hepu mitten crab is a homoploid hybrid species that originated from an ancient hybridization event, resolving its longstanding taxonomic controversy. Our study sheds light on the evolutionary history of mitten crabs and highlights the crucial role of hybridization in driving adaptation, range expansion, and diversification within the Eriocheir genus.
研究问题：
杂交是生物学领域中一种具有深远影响的现象，对物种生态分布格局的塑造、适应性进化的推动以及生物多样性的形成均发挥关键作用。然而，杂交如何影响物种基因组结构并促进适应性进化的具体机制仍未被完全揭示。绒螯蟹属（Eriocheir）包含中华绒螯蟹（Eriocheir sinensis）、日本绒螯蟹（Eriocheir japonica）与合浦绒螯蟹（Eriocheir hepuensis）三个主要类群，然而由于三者在形态上相似且分子遗传学证据有限，导致学界难以明确界定它们的分类地位。其中，合浦绒螯蟹的分类争议尤为突出，关于其属于杂交种、独立物种还是日本绒螯蟹的亚种一直存在争论。中华、日本和合浦绒螯蟹自然分布在不同的地理区域，三者具有明显的表型和遗传差异。值得注意的是，分布于俄罗斯符拉迪沃斯托克（海参崴）水域的绒螯蟹，以及中国南方闽江流域等的绒螯蟹，前期研究推测是通过自然杂交形成的种群。同时，中华绒螯蟹是一种具有较高经济价值的水产甲壳动物，在中国广泛养殖，不同水系绒螯蟹具有较明显的生物学特性差异。鉴于绒螯蟹属存在的分类争议、复杂杂交现象及重要经济价值，深入探究其分类地位、杂交历史与适应性演化规律，具有重要的理论意义与应用价值。
研究方法：
本研究以绒螯蟹属7个地理种群的139个个体为对象，首先测定其核心表型与繁殖性状，量化不同水系种群在表型及繁殖特性上的差异；其次基于群体重测序数据，开展系统进化分析、群体遗传结构解析、有效群体大小评估及基因流检测，进而明确该属地理分布格局，揭示其复杂杂交与演化历史；同时完成日本绒螯蟹与合浦绒螯蟹参考基因组拼接，并结合中华绒螯蟹染色体水平参考基因组及其他代表性甲壳动物基因组，通过单拷贝直系同源基因估算三者的物种分化时间；最后通过群体基因组的遗传分化、遗传多样性分析及自然选择信号检测，鉴定出驱动绒螯蟹种群适应性进化的关键功能基因。
主要结果：
1. 绒螯蟹群体基因组分析表明中华绒螯蟹和日本绒螯蟹间存在复杂的杂交历史。
2. 中华绒螯蟹与日本绒螯蟹分别向南北方向扩散，在地理分布上形成两个独立杂交区，进而演化出俄罗斯绒螯蟹与合浦绒螯蟹两个生态杂交种，且这两个杂交种在表型特征与遗传组成上均表现出显著差异。
3. 与繁殖习性、脂类代谢、温度适应及肌肉发育等相关的基因在中华和日本绒螯蟹以及俄罗斯和合浦绒螯蟹之间均检测到强烈的自然选择信号，这些受选择基因可能是推动各类群适应特定生态环境的关键遗传因素。
4. 合浦绒螯蟹中，Birc6、Bap31、Poxn 等繁殖相关基因呈现强烈自然选择信号，且其基因序列特征与中华绒螯蟹、日本绒螯蟹亲本存在显著差异。
5. 合浦绒螯蟹为中华绒螯蟹与日本绒螯蟹杂交起源的同倍体杂交种，该结论不仅为物种杂交成种机制提供新例证，更解决了合浦绒螯蟹分类地位长期存疑的争议。
原始数据链接：https://ngdc.cncb.ac.cn/gsa/browse/CRA013348
原始数据链接：https://ngdc.cncb.ac.cn/gwh/Genome/231936/show
Page qzaf079
8. Crosstalk Between Lysine Lactylation and Acetylation Regulates Lactate Dehydrogenase in Streptococcus mutans
Qizhao Ma, Tao Hu, Yongwang Lin, Jing Li, Jun Huang, Qiong Zhang, Tao Gong, Xuedong Zhou, Lei Lei, Jing Zou, Yuqing Li
View abstract
中文摘要
Post-translational modifications (PTMs) provide essential fine-tuning of protein functions in response to environmental changes. Among the PTMs, lysine acetylation (Kac) and the recently identified lysine lactylation (Kla) play crucial roles in metabolic regulation, as lactate and acetyl-CoA (Ac-CoA) are generated from pyruvate at the end of glycolysis. However, their crosstalk and regulatory mechanisms remain largely unknown, particularly in prokaryotes. Here, we investigated the intricate interrelation between Kla and Kac in the cariogenic bacterium Streptococcus mutans, a prolific producer of lactate. We conducted a comprehensive profiling of Kla and Kac, revealing their widespread distribution in glycolytic enzymes. Lactate dehydrogenase (LDH), the terminal enzyme of glycolysis, exhibited dynamic Kla and Kac shifts in line with glycolytic intermediates, with the Kla/Kac ratio reflecting the metabolic influx. Furthermore, ActA was pinpointed as a dual-function acyltransferase that catalyzes the Kla and Kac of LDH, both of which negatively regulate its enzymatic activity. Importantly, the study identified lysine 307 (K307) on LDH as a critical site, with its acylation significantly altering LDH activity, thereby affecting lactate production and bacterial growth. Our insights into the metabolic regulation mediated by Kla and Kac contribute to understanding the metabolism-PTM-metabolism feedback loop, allowing bacteria to fine-tune their metabolism in response to the availability of metabolic intermediates.
要点介绍
研究问题：
蛋白质翻译后修饰（PTMs）如何与代谢状态相互作用？新近发现的赖氨酸乳酰化（lysine lactylation, Kla）是否与经典的赖氨酸乙酰化（lysine acetylation, Kac）在细菌中存在功能“串扰”？Kla和Kac是否共同调控核心代谢酶的活性与代谢流向？
研究方法：
1. 以致龋菌变异链球菌为模型，构建全蛋白Kla/Kac双修饰谱，结合GO/KEGG富集与蛋白互作网络分析，定位潜在的代谢关键节点。
2 模拟糖酵解过程，动态监测胞内/外乳酸、La-CoA与Ac-CoA水平、LDH活性及LDH的Kla/Kac变化。
3 构建体外酰化体系，鉴定ActA作为双功能酰基转移酶，催化LDH的Kla/Kac；
4. 体外构建LDH点突变重组蛋白，筛选鉴定Kla/Kac关键位点。
5. 通过CRISPR-Cas9在菌体内构建ldh K307Q/K307R位点突变菌株，解析关键位点对酶活/产酸/生长的影响。
主要结果：
1. Kla/Kac在变异链球菌内普遍存在且高度重叠，并在糖酵解通路中高度富集；越靠近通路末端的酶，越易出现多位点双修饰。
2. LDH同时受Kla/Kac调控，两种修饰随糖酵解进程与代谢物水平动态变化，均可降低LDH活性并限制乳酸过量生成。
3. ActA是催化LDH发生Kla/Kac的双功能酰基转移酶；其修饰程度受La-CoA/Ac-CoA供体浓度影响。
4. K307为LDH发生Kla/Kac“串扰”的关键位点；K307Q（模拟酰化）显著降低LDH活性与乳酸生成并减缓生长；K307R（模拟去酰化）接近或略优于野生型。
5. 提出“代谢-PTM-代谢”反馈调节模型：中间代谢产物→驱动Kla/Kac→调节代谢酶活性→反过来重塑代谢通量，实现对环境变化的快速响应。
Page qzaf073
9. Proteome and Phosphoproteome of Tomato Fruit Identify REDUCED CHLOROPLAST COVERAGE 1a as A Ripening
Jinjuan Tan, Zhongjing Zhou, Hanqian Feng, Jiateng Zhang, Ruikai Zhang, Zhongkai Chen, Yujie Niu, Fangyu Liu, Zhiping Deng
View abstract
中文摘要
Fruit ripening in tomato (Solanum lycopersicum) has been extensively studied at the transcriptomic level. However, comprehensive profiling of the tomato fruit proteome and phosphoproteome remains limited. In this study, we performed large-scale proteome and phosphoproteome profiling of tomato (Ailsa Craig) fruits across five ripening stages using tandem mass tags (TMT)-based quantitative proteomics. Our analysis quantified over 8800 proteins and 20,000 high-confidence phosphorylation sites. Ripening-associated phosphorylation and dephosphorylation events were identified in diverse ripening regulators, including transcription factors, ethylene biosynthesis and signaling proteins, and epigenetic modifiers. Weighted gene co-expression network analysis (WGCNA) revealed a tetratricopeptide repeat protein, REDUCED CHLOROPLAST COVERAGE 1a (REC1a), as a key regulator of fruit ripening. Parallel reaction monitoring (PRM)-based targeted proteomic analysis validated the expression profiles of REC1a and its three phosphorylation sites. Clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein 9 (Cas9)-mediated knockout of REC1a resulted in reduced lycopene accumulation and slower chlorophyll degradation, highlighting its role in the chloroplast-to-chromoplast transition, which is critical for fruit pigmentation during ripening. Quantitative proteomic analyses of rec1a mutants demonstrated reduced levels of Clp proteases and chaperones, proteins known to regulate plastid transitions. Additionally, co-immunoprecipitation and split-luciferase complementation assays revealed that REC1a interacts with the eukaryotic translation initiation factor subunits eIF2α and eIF2Bβ, suggesting its role in regulating protein synthesis during ripening. This study provides the most comprehensive quantitative proteome and phosphoproteome atlas of tomato fruits to date and identifies REC1a as a regulator of fruit ripening, offering new insights into the underlying molecular mechanisms.
Page qzaf050
10. Deep Transfer Learning Links Benign Glands to Prostate Cancer Progression via Transcriptomics
Justin L Couetil, Ziyu Liu, Chao Chen, Ahmed K Alomari, Kun Huang, Jie Zhang, Travis S Johnson
View abstract
中文摘要
The field effect describes the phenomena where environmental exposures, infection, and genetic predisposition result in molecular changes in cells that predispose them to developing cancer. Though this is a well-established concept in pathology, it remains underexplored in the context of high-resolution omics. We utilized the Diagnostic Evidence Gauge of Single Cells (DEGAS) deep transfer learning framework to analyze prostate cancer spatial transcriptomics to identify cells and tissues that are highly associated with cancer progression. DEGAS highlighted morphologically benign glands with reduced expression of microseminoprotein-beta (MSMB), a differentiation marker downregulated in aggressive tumors. These glands have upregulated genes associated with antigen presentation and aggressive neoplasms. Integration of single-cell transcriptomics and deep learning image analysis separately revealed altered immune-cell infiltration, suggesting a complex interplay in the tumor environment, facilitating aggressiveness. We used immunohistochemistry to quantify the MSMB protein (PSP-94) expression in morphologically normal and tumor tissues from patients with and without 5-year distant metastasis. Samples from patients who developed metastasis consistently showed lower fractions of positively stained cells, indicating a subtle yet significant “field effect” in seemingly benign regions. These proteomic results validate the transcriptomic findings and further underscore that inflammatory or immune-related changes in ostensibly normal tissue may contribute to aggressive disease progression.
Page qzaf119
11. A Co-essentiality Network of Cancer Driver Genes Better Prioritizes Anticancer Drugs
Kwanghwan Lee, Donghyo Kim, Inhae Kim, Juhee Lee, Doyeon Ha, Seongsu Lim, Eunjee Kim, Sin-Hyeog Im, Kunyoo Shin, Sanguk Kim
View abstract
中文摘要
Diverse molecular networks have been extensively studied to discover therapeutic targets and repurpose approved drugs. However, it is necessary to select a suitable network since the performance of network medicine relies heavily on the completeness and characteristics of the selected network. Although a network using gene essentiality in cancer cells could be an effective platform for identifying anticancer targets, efforts to apply these networks to therapeutic applications have been limited. We constructed a phenotype-level network using co-essentiality relationships among genes from CRISPR screens across 769 cancer cell lines to discover therapeutic targets for diverse cancer types. By leveraging cancer driver genes and network propagation, we found that the co-essentiality network better prioritized anticancer targets and biomarkers and predicted more precise drug responses in cancer cells than other molecular networks. The co-essentiality network outperformed conventional molecular networks in drug repurposing and was validated in silico by clinical trial records. Notably, the co-essentiality network identified 30 repurposed drugs that the other networks have not yet covered, and we showcased three approved drugs repurposed for lung adenocarcinoma (atovaquone, eflornithine, and teriflunomide). Our study provides a novel network for precision oncology to improve the identification of therapeutic targets in specific cancers.
人们已广泛研究多种分子网络，以发现治疗靶点和进行已批准药物的再利用。然而，由于网络医学的性能在很大程度上依赖于所选网络的完整性和特性，因此选择一个合适的网络至关重要。尽管利用癌细胞基因必需性构建的网络可能是一个识别抗癌靶点的有效平台，但将这类网络应用于治疗的尝试仍然有限。
我们利用来自769种癌细胞系的CRISPR筛选数据，通过基因间的“共必需性”关系，构建了一个表型层面的网络，旨在为多种癌症类型发现治疗靶点。通过在该网络上利用癌症驱动基因和网络传播算法，我们发现，与其它分子网络相比，共必需性网络能够更好地优先筛选出抗癌靶点和生物标志物，并更精确地预测癌细胞的药物反应。
在药物再利用方面，共必需性网络也优于传统的分子网络，这一点通过临床试验记录进行了计算机模拟验证。值得注意的是，共必需性网络找到了30种其他网络未能覆盖的可再利用药物，我们重点展示了其中三种被重新用于治疗肺腺癌的已批准药物：阿托伐醌（atovaquone）、依氟鸟氨酸（eflornithine）和特立氟胺（teriflunomide）。
我们的研究为精准肿瘤学提供了一种新颖的网络工具，以改进特定癌症中治疗靶点的识别。
Page qzaf070
View More
Download 1
