Article Online

Articles Online (Volume 22, Issue 4)

Perspective

Machine Learning for AI Breeding in Plants

Qian Cheng, Xiangfeng Wang

no abstract
目前，作物育种已进入“5G”时代，而机器学习方法在5G育种中有巨大应用前景。在这篇综述中，研究人员结合众多代表性工作，从数据降维、特征工程、数据驱动的设计育种等近十个不同方面或应用场景，阐述了机器学习技术对于植物智能育种的促进作用。最后，提出了一个以机器学习技术为核心驱动里的植物智能育种的生态系统，为未来植物育种的数字化、智能化提供参考和指导。

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Perspective

Laws of Genome Nucleotide Composition

Zhang Zhang

no abstract

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Review

The Role of N6-methyladenosine Modification in Gametogenesis and Embryogenesis: Impact on Fertility

Yujie Wang, Chen Yang, Hanxiao Sun, Hui Jiang, Pin Zhang, Yue Huang, Zhenran Liu, Yaru Yu, Zuying Xu, Huifen Xiang, Chengqi Yi

The most common epigenetic modification of messenger RNAs (mRNAs) is N6-methyladenosine (m6A), which is mainly located near the 3′ untranslated region of mRNAs, near the stop codons, and within internal exons. The biological effect of m6A is dynamically modulated by methyltransferases (writers), demethylases (erasers), and m6A-binding proteins (readers). By controlling post-transcriptional gene expression, m6A has a significant impact on numerous biological functions, including RNA transcription, translation, splicing, transport, and degradation. Hence, m6A influences various physiological and pathological processes, such as spermatogenesis, oogenesis, embryogenesis, placental function, and human reproductive system diseases. During gametogenesis and embryogenesis, genetic material undergoes significant changes, including epigenomic modifications such as m6A. From spermatogenesis and oogenesis to the formation of an oosperm and early embryogenesis, m6A changes occur at every step. m6A abnormalities can lead to gamete abnormalities, developmental delays, impaired fertilization, and maternal-to-zygotic transition blockage. Both mice and humans with abnormal m6A modifications exhibit impaired fertility. In this review, we discuss the dynamic biological effects of m6A and its regulators on gamete and embryonic development and review the possible mechanisms of infertility caused by m6A changes. We also discuss the drugs currently used to manipulate m6A and provide prospects for the prevention and treatment of infertility at the epigenetic level.
表观遗传学是研究影响基因表达的可遗传变化，但不是由脱氧核糖核酸(DNA)或其他核苷酸序列改变引起的。信使核糖核酸（messenger ribonucleic acids，mRNA）最常见的表观遗传修饰是N6-甲基腺苷（N6-methyladenosine，m6A），它主要位于mRNA的3'非翻译区、终止密码子附近和内部外显子内。m6A的生物效应是由甲基转移酶（写入者）、去甲基化酶（擦除者）和m6A结合蛋白（读取者）动态改变的。通过控制转录后基因的表达，m6A对许多生物功能（包括RNA转录、翻译、剪接、转运和降解）都有重大影响。m6A对精子发生、卵子发育、胚胎发育、胎盘功能和人类生殖系统疾病等各种生理和病理过程都有影响。在配子发生和胚胎发育过程中，包括表观基因组修饰m6A在内的遗传物质会发生重大变化。m6A异常可导致配子异常、发育迟缓、受精能力受损以及母-合转换受阻。有性生殖是真核生物生命周期中控制最严格的生物过程之一，生殖细胞是一种可以进行减数分裂的特殊类型的细胞，亲本配子形成受损或后代胚胎发育异常将导致不孕不育。 本文总结了m6A及其调节因子对配子和胚胎发育的动态生物学效应，并综述了m6A变化导致不孕的可能机制，同时讨论了目前用于操纵m6A的药物，并为在表观遗传学水平上预防和治疗不孕提供了前景。

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Review

The Bioinformatic Applications of Hi-C and Linked Reads

Libo Jiang, Michael A Quail, Jack Fraser-Govil, Haipeng Wang, Xuequn Shi, Karen Oliver, Esther Mellado Gomez, Fengtang Yang, Zemin Ning

Long-range sequencing grants insight into additional genetic information beyond what can be accessed by both short reads and modern long-read technology. Several new sequencing technologies, such as “Hi-C” and “Linked Reads”, produce long-range datasets for high-throughput and high-resolution genome analyses, which are rapidly advancing the field of genome assembly, genome scaffolding, and more comprehensive variant identification. In this review, we focused on five major long-range sequencing technologies: high-throughput chromosome conformation capture (Hi-C), 10X Genomics Linked Reads, haplotagging, transposase enzyme linked long-read sequencing (TELL-seq), and single- tube long fragment read (stLFR). We detailed the mechanisms and data products of the five platforms and their important applications, evaluated the quality of sequencing data from different platforms, and discussed the currently available bioinformatics tools. This work will benefit the selection of appropriate long-range technology for specific biological studies.
研究团队重点探讨了短读长和长读长的long-range测序技术，这些技术能够提供更为丰富和全面的基因组信息，极大地促进了复杂基因组的组装和结构变异的挖掘。目前，有多种新兴测序技术能够生成高通量的long-range数据集，其中最具代表性的是Hi-C和Linked Reads技术。文章详细介绍了五种主要的long-range测序技术，包括Hi-C、10x Genomics Linked Reads、haplotagging、TELL-seq和stLFR的原理（图1），并探讨了它们的应用场景。研究团队还评估了不同技术所产生的测序数据质量，且总结了适用于long-range数据分析的生物信息学工具，为相关技术的使用提供了有价值的指导和借鉴。

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Original Research

Hidden Links Between Skin Microbiome and Skin Imaging Phenome

Mingyue Cheng, Hong Zhou, Haobo Zhang, Xinchao Zhang, Shuting Zhang, Hong Bai, Yugo Zha, Dan Luo, Dan Chen, Siyuan Chen, Kang Ning, Wei Liu

Despite the skin microbiome has been linked to skin health and diseases, its role in modulating human skin appearance remains understudied. Using a total of 1244 face imaging phenomes and 246 cheek metagenomes, we first established three skin age indices by machine learning, including skin phenotype age (SPA), skin microbiota age (SMA), and skin integration age (SIA) as surrogates of phenotypic aging, microbial aging, and their combination, respectively. Moreover, we found that besides aging and gender as intrinsic factors, skin microbiome might also play a role in shaping skin imaging phenotypes (SIPs). Skin taxonomic and functional α diversity was positively linked to melanin, pore, pigment, and ultraviolet spot levels, but negatively linked to sebum, lightening, and porphyrin levels. Furthermore, certain species were correlated with specific SIPs, such as sebum and lightening levels negatively correlated with Corynebacterium matruchotii, Staphylococcus capitis, and Streptococcus sanguinis. Notably, we demonstrated skin microbial potential in predicting SIPs, among which the lightening level presented the least error of 1.8%. Lastly, we provided a reservoir of potential mechanisms through which skin microbiome adjusted the SIPs, including the modulation of pore, wrinkle, and sebum levels by cobalamin and heme synthesis pathways, predominantly driven by Cutibacterium acnes. This pioneering study unveils the paradigm for the hidden links between skin microbiome and skin imaging phenome, providing novel insights into how skin microbiome shapes skin appearance and its healthy aging.
研究问题 尽管皮肤微生物群与皮肤健康和疾病有关，但其在调节人类皮肤外观方面的作用仍未得到充分研究。 研究方法 测试了1,244位健康个体的10个面颊皮肤影像表型特征（Skin imaging phenotypes, SIPs），包括亮度、皮脂、卟啉、纹理、黑色素、毛孔、色素、皱纹、血红蛋白和紫外斑；以及检测了其中246位个体的皮肤（脸颊）宏基因组，利用机器学习技术与多组学研究框架以探究皮肤微生物群与皮肤影像表型之间复杂的相互作用。 主要成果 1. 建立了皮肤年龄指数模型，用以代表个体皮肤的表型和微生物状态。 2. 皮肤微生物群落物种、功能多样性与黑色素、毛孔、色素和紫外斑水平呈正相关，而与皮脂、亮度和卟啉水平负相关。 3. 挖掘了皮肤微生物组调节SIPs的多种潜在机制。 4. 数据链接：https://ngdc.cncb.ac.cn/gsa/browse/CRA008646

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Original Research

Single-cell RNA-seq Reveals the Inhibitory Effect of Methamphetamine on Liver Immunity with the Involvement of Dopamine Receptor D1

Jin-Ting Zhou, Yungang Xu, Xiao-Huan Liu, Cheng Cheng, Jing-Na Fan, Xiaoming Li, Jun Yu, Shengbin Li

Methamphetamine (METH) is a highly addictive psychostimulant that causes physical and psychological damage and immune system disorder, especially in the liver which contains a significant number of immune cells. Dopamine, a key neurotransmitter in METH addiction and immune regulation, plays a crucial role in this process. Here, we developed a chronic METH administration model and conducted single-cell RNA sequencing (scRNA-seq) to investigate the effect of METH on liver immune cells and the involvement of dopamine receptor D1 (DRD1). Our findings reveal that chronic exposure to METH induces immune cell identity shifts from IFITM3+ macrophage (Mac) and CCL5+ Mac to CD14+ Mac, as well as from FYN+CD4+ T effector (Teff), CD8+ T, and natural killer T (NKT) to FOS+CD4+ T and RORα+ group 2 innate lymphoid cell (ILC2), along with the suppression of multiple functional immune pathways. DRD1 is implicated in regulating certain pathways and identity shifts among the hepatic immune cells. Our results provide valuable insights into the development of targeted therapies to mitigate METH-induced immune impairment.

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Original Research

Comprehensive Characterization of the Integrin Family Across 32 Cancer Types

Cheng Zou, Jinwei Zhu, Jiangling Xiong, Yu Tian, Yousong Peng, Edwin Cheung, Dingxiao Zhang

Integrin genes are widely involved in tumorigenesis. Yet, a comprehensive characterization of integrin family members and their interactome at the pan-cancer level is lacking. Here, we systematically analyzed integrin family in approximately 10,000 tumors across 32 cancer types. Globally, integrins represent a frequently altered and misexpressed pathway, with alteration and dysregulation overall being protumorigenic. Expression dysregulation, better than mutational landscape, of integrin family successfully identifies a subgroup of aggressive tumors with a high level of proliferation and stemness. The results reveal that several molecular mechanisms collectively regulate integrin expression in a context-dependent manner. For potential clinical usage, we constructed a weighted scoring system, integrinScore, to measure integrin signaling patterns in individual tumors. Remarkably, integrinScore was consistently correlated with predefined molecular subtypes in multiple cancers, with integrinScore-high tumors being more aggressive. Importantly, integrinScore was cancer-dependent and closely associated with proliferation, stemness, tumor microenvironment, metastasis, and immune signatures. IntegrinScore also predicted patients’ response to immunotherapy. By mining drug databases, we unraveled an array of compounds that may modulate integrin signaling. Finally, we built a user-friendly database, Pan-cancer Integrin Explorer (PIExplorer; http://computationalbiology.cn/PIExplorer), to facilitate researchers to explore integrin-related knowledge. Collectively, we provide a comprehensive characterization of integrins across cancers and offer gene-specific and cancer-specific rationales for developing integrin-targeted therapy.
整合素基因家族广泛参与肿瘤的发生和发展过程。然而在泛癌水平，不同整合素基因的整体分子变异特征和互作网络尚无报道。在本研究中，我们系统地比较和分析了整合素家族在32种肿瘤近10000个样本中的变异情况。总体而言，整合素家族在基因组和转录水平上变异水平高，且这些变异整体上促癌；其中，相较于基因突变，表达异常可以更好地鉴定出一类具有高增殖能力和干性的恶性肿瘤亚群。在机制方面，我们揭示了多种遗传和表观遗传因素共同调控整合素家族的异常表达，且这些调控具有明显的癌种特异性。进一步，我们通过构建integrinScore模型来表征具体单个样本中的integrin通路活性。分析发现integrinScore与多种肿瘤中已发表的分子亚型分类相互印证，表现为integrinScore-high的肿瘤恶性程度更高。多通路整合分析发现integrinScore与增殖、干性、肿瘤微环境、转移和多种免疫特征密切相关，且整体亦呈现癌种特异性。此外基于integrinScore，我们还发现该模型可以有效预测病人对免疫治疗的应答情况，以及鉴定出诸多潜在靶向整合素通路的小分子药物。最后，我们建立了免费的在线网站PIExplorer（http://computationalbiology.cn/PIExplorer），以分享该研究中的所有相关数据。总之，我们全面解析了整合素家族在不同肿瘤中的变异特征，揭示了其基因特异性和癌种特异性的调控通路和互作网络，为后续开发精准靶向整合素治癌的策略提供了理论依据。

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Original Research

Integrative Omics Uncovers Low Tumorous Magnesium Content as A Driver Factor of Colorectal Cancer

Rou Zhang, Meng Hu, Yu Liu, Wanmeng Li, Zhiqiang Xu, Siyu He, Ying Lu, Yanqiu Gong, Xiuxuan Wang, Shan Hai, Shuangqing Li, Shiqian Qi, Yuan Li, Yang Shu, Dan Du, Huiyuan Zhang, Heng Xu, Zongguang Zhou, Peng Lei, Hai-Ning Chen, Lunzhi Dai

Magnesium (Mg) deficiency is associated with increased risk and malignancy in colorectal cancer (CRC), yet the underlying mechanisms remain elusive. Here, we used genomic, proteomic, and phosphoproteomic data to elucidate the impact of Mg deficiency on CRC. Genomic analysis identified 160 genes with higher mutation frequencies in Low-Mg tumors, including key driver genes such as KMT2C and ERBB3. Unexpectedly, initiation driver genes of CRC, such as TP53 and APC, displayed higher mutation frequencies in High-Mg tumors. Additionally, proteomic and phosphoproteomic data indicated that low Mg content in tumors may activate epithelial–mesenchymal transition (EMT) by modulating inflammation or remodeling the phosphoproteome of cancer cells. Notably, we observed a negative correlation between the phosphorylation of DBN1 at S142 (DBN1S142p) and Mg content. A mutation in S142 to D (DBN1S142D) mimicking DBN1S142p up-regulated MMP2 and enhanced cell migration, while treatment with MgCl2 reduced DBN1S142p, thereby reversing this phenotype. Mechanistically, Mg2+ attenuated the DBN1–ACTN4 interaction by decreasing DBN1S142p, which in turn enhanced the binding of ACTN4 to F-actin and promoted F-actin polymerization, ultimately reducing MMP2 expression. These findings shed new light on the crucial role of Mg deficiency in CRC progression and suggest that Mg supplementation may be a promising preventive and therapeutic strategy for CRC.
研究问题： 镁（Mg）缺乏与结直肠癌的患病风险和恶性程度增加相关，但其潜在机制尚不清楚。 研究方法： 本研究基于结直肠癌患者的基因组、蛋白质组和磷酸化组数据整合分析揭示了肿瘤中低Mg与结直肠癌发生发展的关系。 主要结果1： 肿瘤组织中低Mg与CRC患者不良预后相关。 主要结果2： 低Mg增加了结直肠癌基因组的不稳定性。 主要结果3： 肿瘤中低Mg可能通过调节炎症和重塑蛋白磷酸化信号通路激活上皮间质转化。 数据链接： https://www.iprox.cn//page/project.html?id=IPX0005732000 https://www.iprox.cn//page/project.html?id=IPX0005705000 https://ngdc.cncb.ac.cn/gsa-human/browse/HRA003386

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Original Research

Characterization of Cancer Stem Cells in Laryngeal Squamous Cell Carcinoma by Single-cell RNA Sequencing

Yanguo Li, Chen Lin, Yidian Chu, Zhengyu Wei, Qi Ding, Shanshan Gu, Hongxia Deng, Qi Liao, Zhisen Shen

Cancer stem cells (CSCs) constitute a pivotal element within the tumor microenvironment (TME), driving the initiation and progression of cancer. However, the identification of CSCs and their underlying molecular mechanisms in laryngeal squamous cell carcinoma (LSCC) remains a formidable challenge. Here, we employed single-cell RNA sequencing of matched primary tumor tissues, paracancerous tissues, and local lymph nodes from three LSCC patients to comprehensively characterize the CSCs in LSCC. Two distinct clusters of stem cells originating from epithelial populations were delineated and verified as CSCs and normal stem cells (NSCs), respectively. CSCs were abundant in the paracancerous tissues compared to those in the tumor tissues. CSCs showed high expression of stem cell marker genes such as PROM1, ALDH1A1, and SOX4, and increased the activity of tumor-related hypoxia, Wnt/β-catenin, and Notch signaling pathways. We then explored the intricate crosstalk between CSCs and the TME cells and identified targets within the TME that related with CSCs. We also found eight marker genes of CSCs that were correlated significantly with the prognosis of LSCC patients. Furthermore, bioinformatics analyses showed that drugs such as erlotinib, OSI-027, and ibrutinib selectively targeted the CSC-specifically expressed genes. In conclusion, our results represent the first comprehensive characterization of CSC properties in LSCC at the single-cell level.
研究问题：肿瘤干细胞（CSC）是肿瘤中一群具有自我更新能力、高分化潜能、强致瘤性和显著耐药性的独特细胞亚群。它们隐藏在肿瘤微环境中，并与肿瘤的起始、发展、转移及复发密切相关。然而，肿瘤干细胞在单细胞水平的分子特征及其在肿瘤微环境中的生态位仍然知之甚少。 研究方法：研究对喉鳞状细胞癌（LSCC）患者的原发肿瘤组织、匹配的癌旁组织和局部淋巴结进行了单细胞转录组测序分析。通过对基因表达、功能富集、转录因子活性等方面的系统性研究，详细阐明了CSC的分子特征。结果通过免疫组化和公共数据集进行了验证。 主要结果： 1、利用单细胞转录组测序，在上皮细胞群体中，鉴定出一类在细胞发育起始阶段的干细胞群体。这一群体可进一步细分为肿瘤干细胞和正常干细胞，肿瘤干细胞高表达PROM1、ALDH1A1和SOX4等标志基因。肿瘤干细胞显示出低氧诱导通路、Wnt/β-catenin信号通路及Notch信号通路的高活性，转录因子RUNX1和SOX4也发生明显激活。 2、公开数据集进一步支持了LSCC患者中存在独特的肿瘤干细胞群体。利用TCGA数据集和肿瘤干细胞标志基因构建了一个可靠的LSCC预后预测模型。此外，通过肿瘤干细胞特异性表达基因和iLINCS数据库预测了若干潜在的CSCs靶向药物。 3、系统性分析了肿瘤干细胞的生态位及其细胞通讯网络，揭示了多种与肿瘤干细胞发展和免疫逃逸的潜在特征与靶点。

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Original Research

Pan-cancer Analysis Reveals m6A Variation and Cell-specific Regulatory Network in Different Cancer Types

Yao Lin, Jingyi Li, Shuaiyi Liang, Yaxin Chen, Yueqi Li, Yixian Cun, Lei Tian, Yuanli Zhou, Yitong Chen, Jiemei Chu, Hubin Chen, Qiang Luo, Ruili Zheng, Gang Wang, Hao Liang, Ping Cui, Sanqi An

As the most abundant messenger RNA (mRNA) modification, N6-methyladenosine (m6A) plays a crucial role in RNA fate, impacting cellular and physiological processes in various tumor types. However, our understanding of the role of the m6A methylome in tumor heterogeneity remains limited. Herein, we collected and analyzed m6A methylomes across nine human tissues from 97 m6A sequencing (m6A-seq) and RNA sequencing (RNA-seq) samples. Our findings demonstrate that m6A exhibits different heterogeneity in most tumor tissues compared to normal tissues, which contributes to the diverse clinical outcomes in different cancer types. We also found that the cancer type-specific m6A level regulated the expression of different cancer-related genes in distinct cancer types. Utilizing a novel and reliable method called “m6A-express”, we predicted m6A-regulated genes and revealed that cancer type-specific m6A-regulated genes contributed to the prognosis, tumor origin, and infiltration level of immune cells in diverse patient populations. Furthermore, we identified cell-specific m6A regulators that regulate cancer-specific m6A and constructed a regulatory network. Experimental validation was performed, confirming that the cell-specific m6A regulator CAPRIN1 controls the m6A level of TP53. Overall, our work reveals the clinical relevance of m6A in various tumor tissues and explains how such heterogeneity is established. These results further suggest the potential of m6A in cancer precision medicine for patients with different cancer types.
研究问题： 现在大多数的研究通过m6A的调节因子预测m6A修饰水平，进而探索肿瘤的致病机制与临床预后，其忽视了肿瘤间的异质性和同质性。目前对m6A甲基化修饰在多种癌症中的调节作用知之甚少，并且癌症的异质性是导致恶性肿瘤治疗效果不佳的重要因素。 研究方法： 本研究收集了人类多种组织的m6A测序数据，通过改良winscore方法，实现对m6A水平的精确定量，并利用“m6A-express”方法预测了m6A的下游靶基因。结合TCGA中31种肿瘤类型的相关数据，联系经典的m6A调控因子以及安三奇等人在先前研究中发现的细胞特异性m6A调控因子（10.1093/nar/gkz1206），分析m6A甲基化修饰在泛癌症中的修饰特点与上下游调控作用，以探索m6A在不同肿瘤组织间的调控网络及异质性。 主要结果1： 与正常人体组织相比，m6A在大多数肿瘤组织中表现出更高的异质性，m6A是肿瘤异质性的遗传学原因之一。 主要结果2： 肿瘤类型特异性m6A影响不同的癌症相关基因和免疫相关基因的表达。 主要结果3： 依据m6A调控的靶基因对不同类型肿瘤患者的分类与肿瘤微环境及其组织来源相关。 主要结果4： 细胞特异性m6A调节因子对癌症特异性m6A的丰度有重要影响。 新发数据链接： https://ngdc.cncb.ac.cn/gsa-human/browse/HRA006237

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Original Research

Scm6A: A Fast and Low-cost Method for Quantifying m6A Modifications at the Single-cell Level

Yueqi Li, Jingyi Li, Wenxing Li, Shuaiyi Liang, Wudi Wei, Jiemei Chu, Jingzhen Lai, Yao Lin, Hubin Chen, Jinming Su, Xiaopeng Hu, Gang Wang, Jun Meng, Junjun Jiang, Li Ye, Sanqi An

It is widely accepted that N6-methyladenosine (m6A) exhibits significant intercellular specificity, which poses challenges for its detection using existing m6A quantitative methods. In this study, we introduced Single-cell m6A Analysis (Scm6A), a machine learning-based approach for single-cell m6A quantification. Scm6A leverages input features derived from the expression levels of m6A trans regulators and cis sequence features, and offers remarkable prediction efficiency and reliability. To further validate the robustness and precision of Scm6A, we first applied Scm6A to single-cell RNA sequencing (scRNA-seq) data from peripheral blood mononuclear cells (PBMCs) and calculated the m6A levels in CD4+ and CD8+ T cells. We also applied a winscore-based m6A calculation method to conduct N6-methyladenosine sequencing (m6A-seq) analysis on CD4+ and CD8+ T cells isolated through magnetic-activated cell sorting (MACS) from the same samples. Notably, the m6A levels calculated by Scm6A exhibited a significant positive correlation with those quantified through m6A-seq in different cells isolated by MACS, providing compelling evidence for Scm6A’s reliability. Additionally, we performed single-cell-level m6A analysis on lung cancer tissues as well as blood samples from patients with coronavirus disease 2019 (COVID-19), and demonstrated the landscape and regulatory mechanisms of m6A in different T cell subtypes from these diseases. In summary, Scm6A is a novel, dependable, and accurate method for single-cell m6A detection and has broad applications in the realm of m6A-related research.
研究问题： 目前研究普遍认为N6-甲基腺苷(m6A)具有显著的细胞间特异性，但现有的m6A检测方法并不能从纯计算的角度实现单细胞水平m6A的定量分析。 研究方法： 我们利用机器学习算法构建Scm6A定量分析模型，应用与于scRNA-seq进行预测，与经过MACS分选然后m6A-seq的获得的数据进行比较分析，并反复验证Scm6A模型快速、稳健、准确的性能。 主要结果1： 使用随机森林构建的Scm6A的模型表现出了最佳的性能，精确度达到了0.91。 主要结果2： 通过与经过磁珠分选的PBMCs m6A-seq结果进行对比，验证了Scm6A模型的准确性和可靠性。 主要结果3： 分别通过m6A-seq和Scm6A鉴定m6A在CD4+和CD8+ T细胞中的表达，并对差异m6A进行功能富集分析，二者结果具有一致性，进一步强调了Scm6A作为单细胞水平m6A分析方法的可靠性。 主要结果4： 将Scm6A应用于不同类型肺癌中，揭示了m6A在耗竭型CD8+ T细胞的潜在作用和调节因子。 算法链接： Scm6A, https://github.com/Ansanqi/Scm6A

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Web Server

Cancer Stemness Online: A Resource for Investigating Cancer Stemness and Associations with Immune Response

Weiwei Zhou, Minghai Su, Tiantongfei Jiang, Yunjin Xie, Jingyi Shi, Yingying Ma, Kang Xu, Gang Xu, Yongsheng Li, Juan Xu

Cancer progression involves the gradual loss of a differentiated phenotype and the acquisition of progenitor and stem cell-like features, which are potential culprits of immunotherapy resistance. Although the state-of-the-art predictive computational methods have facilitated the prediction of cancer stemness, there remains a lack of efficient resources to accommodate various usage requirements. Here, we present the Cancer Stemness Online, an integrated resource for efficiently scoring cancer stemness potential at both bulk and single-cell levels. This resource integrates eight robust predictive algorithms as well as 27 signature gene sets associated with cancer stemness for predicting stemness scores. Downstream analyses were performed from five distinct aspects: identifying the signature genes of cancer stemness; exploring the associations with cancer hallmarks and cellular states; exploring the associations with immune response and the communications with immune cells; investigating the contributions to patient survival; and performing a robustness analysis of cancer stemness among different methods. Moreover, the pre-calculated cancer stemness atlas for more than 40 cancer types can be accessed by users. Both the tables and diverse visualizations of the analytical results are available for download. Together, Cancer Stemness Online is a powerful resource for scoring cancer stemness and expanding downstream functional interpretation, including immune response and cancer hallmarks. Cancer Stemness Online is freely accessible at http://bio-bigdata.hrbmu.edu.cn/CancerStemnessOnline.

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Web Server

eRNA-IDO: A One-stop Platform for Identification, Interactome Discovery, and Functional Annotation of Enhancer RNAs

Yuwei Zhang, Lihai Gong, Ruofan Ding, Wenyan Chen, Hao Rong, Yanguo Li, Fawziya Shameem, Korakkandan Arshad Ali, Lei Li, Qi Liao

Growing evidence supports the transcription of enhancer RNAs (eRNAs) and their important roles in gene regulation. However, their interactions with other biomolecules and their corresponding functionality remain poorly understood. In an attempt to facilitate mechanistic research, this study presents eRNA-IDO, the first integrative computational platform for the identification, interactome discovery, and functional annotation of human eRNAs. eRNA-IDO comprises two modules: eRNA-ID and eRNA-Anno. Functionally, eRNA-ID can identify eRNAs from de novo assembled transcriptomes. eRNA-ID includes eight kinds of enhancer makers, enabling users to customize enhancer regions flexibly and conveniently. In addition, eRNA-Anno provides cell-/tissue-specific functional annotation for both new and known eRNAs by analyzing the eRNA interactome from prebuilt or user-defined networks between eRNAs and protein-coding genes. The prebuilt networks include the Genotype-Tissue Expression (GTEx)-based co-expression networks in normal tissues, The Cancer Genome Atlas (TCGA)-based co-expression networks in cancer tissues, and omics-based eRNA-centric regulatory networks. eRNA-IDO can facilitate research on the biogenesis and functions of eRNAs. The eRNA-IDO server is freely available at http://bioinfo.szbl.ac.cn/eRNA_IDO/.

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Web Server

TCRosetta: An Integrated Analysis and Annotation Platform for T-cell Receptor Sequences

Tao Yue, Si-Yi Chen, Wen-Kang Shen, Zhan-Ye Zhang, Liming Cheng, An-Yuan Guo

T cells and T-cell receptors (TCRs) are essential components of the adaptive immune system. Characterization of the TCR repertoire offers a promising and highly informative source for understanding the functions of T cells in the immune response and immunotherapy. Although TCR repertoire studies have attracted much attention, there are few online servers available for TCR repertoire analysis, especially for TCR sequence annotation or advanced analyses. Therefore, we developed TCRosetta, a comprehensive online server that integrates analytical methods for TCR repertoire analysis and visualization. TCRosetta combines general feature analysis, large-scale sequence clustering, network construction, peptide–TCR binding prediction, generation probability calculation, and k-mer motif analysis for TCR sequences, making TCR data analysis as simple as possible. The TCRosetta server accepts multiple input data formats and can analyze ∼ 20,000 TCR sequences in less than 3 min. TCRosetta is the most comprehensive web server available for TCR repertoire analysis and is freely available at https://guolab.wchscu.cn/TCRosetta/.

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Research Highlight

Aberrant Somatic Hypermutation at Super-enhancer Drives B Cell Lymphoma Transformation

Xueshuai Han, Zhaoqi Liu

no abstract

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