Pub Date : 2024-10-04DOI: 10.1007/s10142-024-01453-5
Justin L. Blaize, Jada Lauren N. Garzon, Niall G. Howlett
Fanconi anemia (FA) is a rare genetic disease characterized by congenital abnormalities and increased risk for bone marrow failure and cancer. Central nervous system defects, including acute and irreversible loss of neurological function and white matter lesions with calcifications, have become increasingly recognized among FA patients, and are collectively referred to as Fanconi Anemia Neurological Syndrome or FANS. The molecular etiology of FANS is poorly understood. In this study, we have used a functional integrative genomics approach to further define the function of the FANCD2 protein and FA pathway. Combined analysis of new and existing FANCD2 ChIP-seq datasets demonstrates that FANCD2 binds nonrandomly throughout the genome with binding enriched at transcription start sites and in broad regions spanning protein-coding gene bodies. FANCD2 demonstrates a strong preference for large neural genes involved in neuronal differentiation, synapse function, and cell adhesion, with many of these genes implicated in neurodevelopmental and neuropsychiatric disorders. Furthermore, FANCD2 binds to regions of the genome that replicate late, undergo mitotic DNA synthesis (MiDAS) under conditions of replication stress, and are hotspots for copy number variation. Our analysis describes an important targeted role for FANCD2 and the FA pathway in the maintenance of large neural gene stability.
范可尼贫血(Fanconi anemia,FA)是一种罕见的遗传性疾病,其特点是先天畸形、骨髓衰竭和癌症风险增加。中枢神经系统缺陷,包括急性和不可逆的神经功能丧失以及伴有钙化的白质病变,在范可尼贫血患者中已被越来越多地发现,并统称为范可尼贫血神经综合征或FANS。人们对 FANS 的分子病因知之甚少。在本研究中,我们采用功能整合基因组学方法进一步明确了 FANCD2 蛋白和 FA 通路的功能。对新的和现有的 FANCD2 ChIP-seq 数据集的综合分析表明,FANCD2 在整个基因组中的结合是非随机的,其结合富集在转录起始位点和跨越蛋白编码基因体的广泛区域。FANCD2 对涉及神经元分化、突触功能和细胞粘附的大型神经基因表现出强烈的偏好,其中许多基因与神经发育和神经精神疾病有关。此外,FANCD2 与复制较晚的基因组区域结合,在复制压力条件下进行有丝分裂 DNA 合成(MiDAS),并且是拷贝数变异的热点。我们的分析描述了 FANCD2 和 FA 通路在维持大神经基因稳定性方面的重要靶向作用。
{"title":"FANCD2 genome binding is nonrandom and is enriched at large transcriptionally active neural genes prone to copy number variation","authors":"Justin L. Blaize, Jada Lauren N. Garzon, Niall G. Howlett","doi":"10.1007/s10142-024-01453-5","DOIUrl":"10.1007/s10142-024-01453-5","url":null,"abstract":"<div><p>Fanconi anemia (FA) is a rare genetic disease characterized by congenital abnormalities and increased risk for bone marrow failure and cancer. Central nervous system defects, including acute and irreversible loss of neurological function and white matter lesions with calcifications, have become increasingly recognized among FA patients, and are collectively referred to as Fanconi Anemia Neurological Syndrome or FANS. The molecular etiology of FANS is poorly understood. In this study, we have used a functional integrative genomics approach to further define the function of the FANCD2 protein and FA pathway. Combined analysis of new and existing FANCD2 ChIP-seq datasets demonstrates that FANCD2 binds nonrandomly throughout the genome with binding enriched at transcription start sites and in broad regions spanning protein-coding gene bodies. FANCD2 demonstrates a strong preference for large neural genes involved in neuronal differentiation, synapse function, and cell adhesion, with many of these genes implicated in neurodevelopmental and neuropsychiatric disorders. Furthermore, FANCD2 binds to regions of the genome that replicate late, undergo mitotic DNA synthesis (MiDAS) under conditions of replication stress, and are hotspots for copy number variation. Our analysis describes an important targeted role for FANCD2 and the FA pathway in the maintenance of large neural gene stability.</p></div>","PeriodicalId":574,"journal":{"name":"Functional & Integrative Genomics","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11452531/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142370673","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-04DOI: 10.1007/s10142-024-01464-2
Suhas K. Kadam, Jin-Suk Youn, Asif S. Tamboli, JiYoung Yang, Jae Hong Pak, Yeon-Sik Choo
The Asteraceae family, particularly the Artemisia genus, presents taxonomic challenges due to limited morphological characteristics and frequent natural hybridization. Molecular tools, such as chloroplast genome analysis, offer solutions for accurate species identification. In this study, we sequenced and annotated the chloroplast genome of Artemisia littoricola sourced from Dokdo Island, employing comparative analyses across six diverse Artemisia species. Our findings reveal conserved genome structures with variations in repeat sequences and junction boundaries. Notably, the chloroplast genome of A. littoricola spans 150,985 bp, consistent with other Artemisia species, and comprises 131 genes, including 86 protein-coding, 37 tRNA, and 8 rRNA genes. Among these genes, 16 possess a single intron, while clpP and ycf3 exhibit two introns each. Furthermore, 18 genes display duplicated copies within the IR regions. Moreover, the genome possesses 42 Simple Sequence Repeats (SSRs), predominantly abundant in A/T content and located within intergenic spacer regions. The analysis of codon usage revealed that the codons for leucine were the most frequent, with a preference for ending with A/U. While the chloroplast genome exhibited conservation overall, non-coding regions showed lower conservation compared to coding regions, with the Inverted Repeat (IR) region displaying higher conservation than single-copy regions. Phylogenetic analyses position A. littoricola within subgenus Dracunculus, indicating a close relationship with A. scoparia and A. desertorum. Additionally, biogeographic reconstructions suggest ancestral origins in East Asia, emphasizing Mongolia, China (North East and North Central and South Central China), and Korea. This study underscores the importance of chloroplast genomics in understanding Artemisia diversity and evolution, offering valuable insights into taxonomy, evolutionary patterns, and biogeographic history. These findings not only enhance our understanding of Artemisia’s intricate biology but also contribute to conservation efforts and facilitate the development of molecular markers for further research and applications in medicine and agriculture.
菊科植物,尤其是蒿属植物,由于形态特征有限和频繁的自然杂交,给分类学带来了挑战。叶绿体基因组分析等分子工具为准确的物种鉴定提供了解决方案。在这项研究中,我们对来自独岛的蒿属植物(Artemisia littoricola)的叶绿体基因组进行了测序和注释,并对六个不同的蒿属植物物种进行了比较分析。我们的研究结果表明,基因组结构是一致的,但重复序列和连接边界存在差异。值得注意的是,A. littoricola的叶绿体基因组跨度为150,985 bp,与其他蒿属植物一致,由131个基因组成,包括86个编码蛋白质的基因、37个tRNA基因和8个rRNA基因。在这些基因中,16 个基因有一个内含子,而 clpP 和 ycf3 则各有两个内含子。此外,18 个基因在内含子区域内有重复拷贝。此外,基因组中还有 42 个简单序列重复序列(SSR),主要以 A/T 含量为主,位于基因间间隔区。对密码子使用情况的分析表明,亮氨酸的密码子使用频率最高,且偏好以 A/U 结尾。虽然叶绿体基因组总体上表现出保护性,但与编码区相比,非编码区的保护性较低,其中反向重复区(IR)的保护性高于单拷贝区。系统发育分析将 A. littoricola 定位于龙舌兰亚属,表明它与 A. scoparia 和 A. desertorum 关系密切。此外,生物地理重建表明其祖先起源于东亚,重点是蒙古、中国(东北、华北中南)和韩国。这项研究强调了叶绿体基因组学在了解青蒿多样性和进化方面的重要性,为分类学、进化模式和生物地理历史提供了宝贵的见解。这些发现不仅加深了我们对青蒿错综复杂的生物学特性的了解,而且有助于保护工作,并促进了分子标记的开发,为进一步的研究以及在医药和农业领域的应用提供了便利。
{"title":"Complete chloroplast genome sequence of Artemisia littoricola (Asteraceae) from Dokdo Island Korea: genome structure, phylogenetic analysis, and biogeography study","authors":"Suhas K. Kadam, Jin-Suk Youn, Asif S. Tamboli, JiYoung Yang, Jae Hong Pak, Yeon-Sik Choo","doi":"10.1007/s10142-024-01464-2","DOIUrl":"10.1007/s10142-024-01464-2","url":null,"abstract":"<div><p>The Asteraceae family, particularly the <i>Artemisia</i> genus, presents taxonomic challenges due to limited morphological characteristics and frequent natural hybridization. Molecular tools, such as chloroplast genome analysis, offer solutions for accurate species identification. In this study, we sequenced and annotated the chloroplast genome of <i>Artemisia littoricola</i> sourced from Dokdo Island, employing comparative analyses across six diverse <i>Artemisia</i> species. Our findings reveal conserved genome structures with variations in repeat sequences and junction boundaries. Notably, the chloroplast genome of <i>A. littoricola</i> spans 150,985 bp, consistent with other <i>Artemisia</i> species, and comprises 131 genes, including 86 protein-coding, 37 tRNA, and 8 rRNA genes. Among these genes, 16 possess a single intron, while <i>clp</i>P and <i>ycf</i>3 exhibit two introns each. Furthermore, 18 genes display duplicated copies within the IR regions. Moreover, the genome possesses 42 Simple Sequence Repeats (SSRs), predominantly abundant in A/T content and located within intergenic spacer regions. The analysis of codon usage revealed that the codons for leucine were the most frequent, with a preference for ending with A/U. While the chloroplast genome exhibited conservation overall, non-coding regions showed lower conservation compared to coding regions, with the Inverted Repeat (IR) region displaying higher conservation than single-copy regions. Phylogenetic analyses position <i>A. littoricola</i> within subgenus <i>Dracunculus</i>, indicating a close relationship with <i>A. scoparia</i> and <i>A. desertorum</i>. Additionally, biogeographic reconstructions suggest ancestral origins in East Asia, emphasizing Mongolia, China (North East and North Central and South Central China), and Korea. This study underscores the importance of chloroplast genomics in understanding <i>Artemisia</i> diversity and evolution, offering valuable insights into taxonomy, evolutionary patterns, and biogeographic history. These findings not only enhance our understanding of <i>Artemisia’s</i> intricate biology but also contribute to conservation efforts and facilitate the development of molecular markers for further research and applications in medicine and agriculture.</p></div>","PeriodicalId":574,"journal":{"name":"Functional & Integrative Genomics","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142370672","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
This review analyzes the application of machine learning (ML) in oncological pharmacogenomics, focusing on customizing chemotherapy treatments. It explores how ML can analyze extensive genomic, proteomic, and other omics datasets to identify genetic patterns associated with drug responses. This, in turn, facilitates personalized therapies that are more effective and have fewer side effects. Recent studies have emphasized ML’s revolutionary role of ML in personalized oncology treatment by identifying genetic variability and understanding cancer pharmacodynamics. Integrating ML with electronic health records and clinical data shows promise in refining chemotherapy recommendations by considering the complex influencing factors. Although standard chemotherapy depends on population-based doses and treatment regimens, customized techniques use genetic information to tailor treatments for specific patients, potentially enhancing efficacy and reducing adverse effects.However, challenges, such as model interpretability, data quality, transparency, ethical issues related to data privacy, and health disparities, remain. Machine learning has been used to transform oncological pharmacogenomics by enabling personalized chemotherapy treatments. This review highlights ML’s potential of ML to enhance treatment effectiveness and minimize side effects through detailed genetic analysis. It also addresses ongoing challenges including improved model interpretability, data quality, and ethical considerations. The review concludes by emphasizing the importance of rigorous clinical trials and interdisciplinary collaboration in the ethical implementation of ML-driven personalized medicine, paving the way for improved outcomes in cancer patients and marking a new frontier in cancer treatment.
本综述分析了机器学习(ML)在肿瘤药物基因组学中的应用,重点关注定制化疗治疗。它探讨了机器学习如何分析广泛的基因组、蛋白质组和其他 omics 数据集,以确定与药物反应相关的遗传模式。这反过来又促进了更有效、副作用更小的个性化疗法。最近的研究强调了 ML 通过识别遗传变异和了解癌症药效学在个性化肿瘤治疗中的革命性作用。将 ML 与电子健康记录和临床数据相结合,通过考虑复杂的影响因素,在完善化疗建议方面大有可为。虽然标准化疗依赖于基于人群的剂量和治疗方案,但定制化技术利用基因信息为特定患者量身定制治疗方案,有可能提高疗效并减少不良反应。然而,模型的可解释性、数据质量、透明度、与数据隐私相关的伦理问题以及健康差异等挑战依然存在。机器学习已被用于改变肿瘤药物基因组学,实现个性化化疗。本综述强调了机器学习在通过详细的基因分析提高治疗效果和减少副作用方面的潜力。它还讨论了当前面临的挑战,包括提高模型的可解释性、数据质量和伦理考虑。综述最后强调了严格的临床试验和跨学科合作在以 ML 为驱动的个性化医疗的伦理实施中的重要性,为改善癌症患者的预后铺平了道路,并标志着癌症治疗进入了一个新的前沿领域。
{"title":"Machine learning in oncological pharmacogenomics: advancing personalized chemotherapy","authors":"Cigir Biray Avci, Bakiye Goker Bagca, Behrouz Shademan, Leila Sabour Takanlou, Maryam Sabour Takanlou, Alireza Nourazarian","doi":"10.1007/s10142-024-01462-4","DOIUrl":"10.1007/s10142-024-01462-4","url":null,"abstract":"<div><p>This review analyzes the application of machine learning (ML) in oncological pharmacogenomics, focusing on customizing chemotherapy treatments. It explores how ML can analyze extensive genomic, proteomic, and other omics datasets to identify genetic patterns associated with drug responses. This, in turn, facilitates personalized therapies that are more effective and have fewer side effects. Recent studies have emphasized ML’s revolutionary role of ML in personalized oncology treatment by identifying genetic variability and understanding cancer pharmacodynamics. Integrating ML with electronic health records and clinical data shows promise in refining chemotherapy recommendations by considering the complex influencing factors. Although standard chemotherapy depends on population-based doses and treatment regimens, customized techniques use genetic information to tailor treatments for specific patients, potentially enhancing efficacy and reducing adverse effects.However, challenges, such as model interpretability, data quality, transparency, ethical issues related to data privacy, and health disparities, remain. Machine learning has been used to transform oncological pharmacogenomics by enabling personalized chemotherapy treatments. This review highlights ML’s potential of ML to enhance treatment effectiveness and minimize side effects through detailed genetic analysis. It also addresses ongoing challenges including improved model interpretability, data quality, and ethical considerations. The review concludes by emphasizing the importance of rigorous clinical trials and interdisciplinary collaboration in the ethical implementation of ML-driven personalized medicine, paving the way for improved outcomes in cancer patients and marking a new frontier in cancer treatment.</p></div>","PeriodicalId":574,"journal":{"name":"Functional & Integrative Genomics","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142370674","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-02DOI: 10.1007/s10142-024-01461-5
Tam Thi Thanh Tran, Liem Huu Minh Le, Trang Thi Nguyen, Thanh Chi Nguyen, Trang Thi Huyen Hoang, Phat Tien Do, Huong Thi Mai To
{"title":"Correction to: QTL-seq identifies genomic region associated with the crown root development under Jasmonic acid response","authors":"Tam Thi Thanh Tran, Liem Huu Minh Le, Trang Thi Nguyen, Thanh Chi Nguyen, Trang Thi Huyen Hoang, Phat Tien Do, Huong Thi Mai To","doi":"10.1007/s10142-024-01461-5","DOIUrl":"10.1007/s10142-024-01461-5","url":null,"abstract":"","PeriodicalId":574,"journal":{"name":"Functional & Integrative Genomics","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142363926","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-30DOI: 10.1007/s10142-024-01460-6
Li Jin, Mengxiao Jiang, Jun Qian, Zhihua Ge, Feng Xu, Wenjie Liao
Lipoproteinassociated phospholipase A2 (Lp-PLA2), encoded by the phospholipase A2 group VII (Pla2g7) gene, has been pertinent to inflammatory responses. This study investigates the correlation between Lp-PLA2 and inflammatory injury in septic mice and explores its regulatory mechanism. Lp-PLA2 was found to be upregulated in the serum of septic mice induced by cecal ligation and puncture and in the culture supernatant of RAW264.7 cells following lipopolysaccharide and adenosine triphosphate treatments. The contents of Lp-PLA2 were positively correlated with increased concentrations of proinflammatory cytokines in patients with sepsis. Both animal and cellular models showed increased concentrations of proinflammatory cytokines. Spi-1 proto-oncogene (Spi1), highly expressed in these models, was found to activate Pla2g7 transcription. Knockdown of Pla2g7 or Spi1 reduced the proinflammatory cytokine production, mitigated organ damage in mice, and suppressed macrophage migration in vitro. Retinoblastoma binding protein 6 (Rbbp6), poorly expressed in both models, was found to reduce Spi1 protein stability through ubiquitination modification. Rbbp6 overexpression similarly suppressed inflammatory activation of RAW264.7 cells, which was counteracted by Pla2g7 or Spi1 upregulation. In summary, this study demonstrates that the Pla2g7 loss and Spi1 upregulation participate in inflammatory responses in sepsis by elevating the Lp-PLA2 levels.
{"title":"The role of lipoprotein‑associated phospholipase A2 in inflammatory response and macrophage infiltration in sepsis and the regulatory mechanisms","authors":"Li Jin, Mengxiao Jiang, Jun Qian, Zhihua Ge, Feng Xu, Wenjie Liao","doi":"10.1007/s10142-024-01460-6","DOIUrl":"10.1007/s10142-024-01460-6","url":null,"abstract":"<div><p>Lipoproteinassociated phospholipase A2 (Lp-PLA2), encoded by the phospholipase A2 group VII (<i>Pla2g7</i>) gene, has been pertinent to inflammatory responses. This study investigates the correlation between Lp-PLA2 and inflammatory injury in septic mice and explores its regulatory mechanism. Lp-PLA2 was found to be upregulated in the serum of septic mice induced by cecal ligation and puncture and in the culture supernatant of RAW264.7 cells following lipopolysaccharide and adenosine triphosphate treatments. The contents of Lp-PLA2 were positively correlated with increased concentrations of proinflammatory cytokines in patients with sepsis. Both animal and cellular models showed increased concentrations of proinflammatory cytokines. Spi-1 proto-oncogene (<i>Spi1</i>), highly expressed in these models, was found to activate <i>Pla2g7</i> transcription. Knockdown of <i>Pla2g7</i> or <i>Spi1</i> reduced the proinflammatory cytokine production, mitigated organ damage in mice, and suppressed macrophage migration in vitro. Retinoblastoma binding protein 6 (<i>Rbbp6</i>), poorly expressed in both models, was found to reduce Spi1 protein stability through ubiquitination modification. <i>Rbbp6</i> overexpression similarly suppressed inflammatory activation of RAW264.7 cells, which was counteracted by <i>Pla2g7</i> or <i>Spi1</i> upregulation. In summary, this study demonstrates that the <i>Pla2g7</i> loss and <i>Spi1</i> upregulation participate in inflammatory responses in sepsis by elevating the Lp-PLA2 levels.</p></div>","PeriodicalId":574,"journal":{"name":"Functional & Integrative Genomics","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142338903","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-28DOI: 10.1007/s10142-024-01459-z
Huma Hameed, Hafiz Shoaib Sarwar, Komel Younas, Muhammad Zaman, Muhammad Jamshaid, Ali Irfan, Maha Khalid, Muhammad Farhan Sohail
After COVID-19, a turning point in the way of pharmaceutical technology is gene therapy with beneficial potential to start a new medical era. However, commercialization of such pharmaceuticals would never be possible without the help of nanotechnology. Nanomedicine can fulfill the growing needs linked to safety, efficiency, and site-specific targeted delivery of Gene therapy-based pharmaceuticals. This review's goal is to investigate how nanomedicine may be used to transfer nucleic acids by getting beyond cellular and physicochemical barriers. Firstly, we provide a full description of types of gene therapy, their mechanism, translation, transcription, expression, type, and details of diseases with possible mechanisms that can only be treated with genes-based pharmaceuticals. Additionally, we also reviewed different types of physicochemical barriers, physiological and cellular barriers in nucleic acids (DNA/RNA) based drug delivery. Finally, we highlight the need and importance of cationic lipid-based nanomedicine/nanocarriers in gene-linked drug delivery and how nanotechnology can help to overcome the above-discussed barrier in gene therapy and their biomedical applications.