Functional & Integrative Genomics最新文献

{"title":"Switching on survival: how rice outsmarts heat with a natural gene circuit","authors":"Mohammad Abubakar Yasin,&nbsp;Muhammad Waseem Sajjad,&nbsp;Rubab Zahra Naqvi,&nbsp;Imran Amin,&nbsp;Muhammad Arif","doi":"10.1007/s10142-025-01717-8","DOIUrl":"10.1007/s10142-025-01717-8","url":null,"abstract":"<div><p>Globally, the important economic and staple food crops face various abiotic and biotic factors that influence their growth and yield. Traditional breeding strategies have attempted to improve heat tolerance, but often face challenges as improving one trait compromises the other. In this context, a recent discovery by Li et al. shows how a tiny gene switch, regulated by NF-Y transcription factors (a highly conserved eukaryotic transcription factor) in the rice QT12 gene, not only helps the plant to escape the deadly grip of global heat waves but also protects yield and grain quality. In addition, Trait Regulatory Haplotypes (TRHs) associated with QT12 offer a cutting-edge breeding tool to incorporate heat tolerance traits into developing rice varieties, and it can be a powerful tool to mitigate the traditional breeding limitations. Understanding this circuit offers breeders a novel target for developing heat-resilient, high-quality rice cultivars, potentially adaptable to other cereals in the future.</p></div>","PeriodicalId":574,"journal":{"name":"Functional & Integrative Genomics","volume":"25 1","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145210612","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}

{"title":"Hypoxia-induced S100A10 promotes glioblastoma malignancy and chemoresistance by activating PI3K-AKT signaling pathway","authors":"Qingqing Yang,&nbsp;Yunlan Xi,&nbsp;Xuewei Huang,&nbsp;Wenzhe An,&nbsp;Cuiyun Sun,&nbsp;Qian Wang,&nbsp;Dan Hua,&nbsp;Wenjun Luo,&nbsp;Cuijuan Shi,&nbsp;Hongli Pan,&nbsp;Zhendong Jiang,&nbsp;Bingkun Wang,&nbsp;Xuebing Li,&nbsp;Shizhu Yu,&nbsp;Xuexia Zhou","doi":"10.1007/s10142-025-01693-z","DOIUrl":"10.1007/s10142-025-01693-z","url":null,"abstract":"<div><p>Glioblastoma (GBM) is the most frequent and lethal subtype of glioma that leads to unsatisfactory clinical outcomes. Hypoxia-induced chemoresistance exacerbates therapy. S100 calcium-binding protein A10 (S100A10) plays a crucial role in the oncogenesis of multiple human tumors. However, its role in to hypoxia-driven GBM progression and chemoresistance remains unclear. S100A10 was identified as a key gene because of its significant upregulation in GBM, hypoxia-treated GBM cells and temozolomide (TMZ)-resistant GBM cells. Public datasets, quantitative PCR (qPCR) and Western blot were performed to determine the levels of S100A10 in gliomas and cell lines. The clinical relevance, prognostic significance, and functional enrichment of S100A10 were fully assessed using open resources from the Chinese Glioma Genome Atlas (CGGA) and The Cancer Genome Atlas (TCGA). CCK8, 5-ethynyl-2’-deoxyuridine (EdU) incorporation, colony formation, annexin V staining, and flow cytometry assays were used to measure the proliferation, cell cycle, and apoptosis of GBM cells in vitro. Glycolysis potential was examined by determining lactate and pyruvate production. The interaction between hypoxia and S100A10 was assessed by qPCR and Western blot. Our study suggests that hypoxia-induced S100A10 expression facilitates proliferation and glycolysis and inhibits apoptosis by regulating the PI3K-AKT signaling pathway, which enhances TMZ resistance in GBM cells.</p></div>","PeriodicalId":574,"journal":{"name":"Functional & Integrative Genomics","volume":"25 1","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145197741","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}

{"title":"Cancer gene therapy: historical perspectives, current applications, and future directions","authors":"Jingyi Zeng,&nbsp;Jingwen Luo,&nbsp;Yingchun Zeng","doi":"10.1007/s10142-025-01712-z","DOIUrl":"10.1007/s10142-025-01712-z","url":null,"abstract":"<div><p>Gene therapy has emerged as a transformative approach in cancer treatment, leveraging genetic modifications to target malignancies with enhanced precision. Early efforts faced challenges such as inefficient vector delivery (&lt; 5% tumor transduction rates with first-generation adenoviruses), immune responses (neutralizing antibodies in ~ 30% of patients), and limited clinical efficacy (&lt; 10% objective response rates in 1990s trials). However, advancements in viral and non-viral vectors (e.g., AAVs achieving &gt; 50% transduction efficiency in solid tumors), alongside CRISPR-Cas9 (90% target gene knockout rates in preclinical models) and RNA interference technologies, have revolutionized the field. Presently, gene therapy strategies, including tumor suppressor gene restoration, oncogene silencing, and immune modulation, demonstrate promising clinical outcomes. Despite persistent hurdles like off-target effects and high costs, emerging innovations in personalized gene editing, oncolytic viruses, and combination therapies signal a paradigm shift in oncology. This review explores the evolution of gene therapy for cancer, highlighting key milestones, current applications, and future directions that could unlock its full therapeutic potential.</p></div>","PeriodicalId":574,"journal":{"name":"Functional & Integrative Genomics","volume":"25 1","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145184504","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}

{"title":"Genome-wide identification and analysis of paclobutrazol-resistance gene family in cotton and the positive role of GhPRE3 in salt stress and drought stress resistance","authors":"Shuaikang Geng,&nbsp;Jingjing Zhai,&nbsp;Bingkai Cui,&nbsp;Huiyun Shan,&nbsp;Zili Liu,&nbsp;Jiahui Li,&nbsp;Cong Wang,&nbsp;Yuling Liu,&nbsp;Pengtao Li,&nbsp;Quanwei Lu,&nbsp;Zihan Xiao,&nbsp;Xiaoping Pan,&nbsp;Renhai Peng,&nbsp;Yangyang Wei,&nbsp;Shoulin Hu","doi":"10.1007/s10142-025-01701-2","DOIUrl":"10.1007/s10142-025-01701-2","url":null,"abstract":"<div>\u0000 \u0000 <p>Compared with other transcription factors, much less studies have been performed on paclobutrazol-resistance (PRE), a subgroup of the extensive bHLH transcription factor gene family, and the research in cotton was also limited. By utilizing the PRE genes and their conserved domains identified in Arabidopsis, a total of 23, 22, 11, and 12 PRE genes were identified from two major cultivated cotton species and their two ancestors, respectively. The cotton PRE gene family was categorized into three subgroups based on evolutionary tree analysis. Motif and intron analyses indicated that the PRE gene has remained highly conserved throughout evolution. Collinearity analysis indicated that gene duplication, particularly through fragment replication, has significantly contributed to the expansion of the cotton PRE family. An exploration of the conserved elements within the PRE gene family uncovered numerous elements associated with plant stress resistance. Additionally, cotton transcriptome and qRT-PCR analysis showed that PRE genes were associated with a variety of abiotic stresses, including salt, drought, and cold treatments. Subcellular localization experiments indicated that the <i>GhPRE3</i> gene is associated with membrane proteins. Finally, we selected the <i>GhPRE3</i> gene for a VIGS experiment, which revealed that under salt stress and drought stress conditions, the wilting of leaves in the <i>GhPRE3-</i>silenced plants was significantly more severe than that observed in the control group, with T-AOC levels notably lower and MDA levels significantly higher. Overexpression of <i>GhPRE3</i> enhanced seed germination and root development in transgenic <i>Arabidopsis thaliana</i> under salt stress and drought stresses. This suggests that <i>GhPRE3</i> plays a positive regulatory role in cotton tolerance to salt and drought stressed, providing a reference for molecular genetic breeding of cotton with salt and drought tolerance.</p>\u0000 </div>","PeriodicalId":574,"journal":{"name":"Functional & Integrative Genomics","volume":"25 1","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12479684/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145184511","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}

{"title":"Dissecting the genomic landscape of ERD genes in alfalfa (Medicago sativa): the effect of melatonin and low selenium under salt stress","authors":"Muslim Qadir,&nbsp;Farhan Nabi,&nbsp;Jiaqin Shi,&nbsp;Zienab F.R. Ahmed,&nbsp;Irfan Ali Sabir","doi":"10.1007/s10142-025-01703-0","DOIUrl":"10.1007/s10142-025-01703-0","url":null,"abstract":"<div><p>The early response to dehydration (ERD) gene family plays a central role in abiotic stress regulation, plant development and defense mechanisms, particularly under dehydration conditions. However, the genomic characterization and functional roles of ERD genes in alfalfa (<i>Medicago sativa)</i> remain largely unexplored. This study aims to identify and analyze ERD genes in alfalfa to understand their evolutionary conservation and involvement in stress responses. A total of 27 ERD genes were identified and categorized into five distinct phylogenetic groups (Group˗1 to Group˗5) based on comparative analysis with homologs from <i>Glycine max</i>, <i>Medicago truncatula</i>, <i>Lotus japonicus</i> and <i>Arabidopsis thaliana.</i> Comprehensive analyses of gene structure, chromosomal localization, conserved protein motifs, <i>c</i>is-elements, synteny and transcriptomic profiles were conducted to uncover the structural and functional attributes of the MsERD genes. Notably, the results indicated that <i>MsERD2</i>, <i>MsERD15</i> and <i>MsERD27</i> were significantly overexpressed in response to low selenium concentrations and salt stress mediated by melatonin pathways. Evidence of segmental duplication and motif conservation implies evolutionary conservation and potential functional redundancy. Differential expression patterns in leaf tissues emphasize their roles in adaptive stress responses. This comprehensive genomic and expression study provides valuable insights into the molecular regulation of ERD genes in alfalfa. The findings underscore the potential roles of specific MsERD genes in abiotic stress tolerance and mineral homeostasis, highlighting potential targets for the genetic improvement of stress-resilient alfalfa cultivars.</p></div>","PeriodicalId":574,"journal":{"name":"Functional & Integrative Genomics","volume":"25 1","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145145351","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}

{"title":"Multi-omics based consensus subtypes, development of prognostic signature, and identification of INHBB as a potential therapeutic target in colorectal cancer","authors":"Xu Wang,&nbsp;Yuanmin Xu,&nbsp;Rui Sun,&nbsp;Sheng Wang,&nbsp;Xiang Wei","doi":"10.1007/s10142-025-01691-1","DOIUrl":"10.1007/s10142-025-01691-1","url":null,"abstract":"<div><p>This study aims to refine molecular subtypes via multi-omics data, develop a prognostic signature, and identify novel biomarkers in colorectal cancer (CRC). On the basis of the multi-omics data, the <i>MOVICS</i> R package was used to divide patients with CRC into three consensus subtypes (CSs). Among the 3 CSs, CS1 had higher immune scores, immune checkpoint expression, infiltration of immune cells, and sensitivity to chemotherapy drugs. Specific markers of CS1 were identified, and 101 combinations of machine learning methods were applied for calculating the consensus machine learning-based score (CMLS) and constructing the CMLS signature for predicting patient survival. CMLS showed high efficiency in predicting the outcome of patients across multiple CRC datasets, and the results demonstrated that CMLS was an independent prognostic factor in CRC. The high- and low-CMLS groups presented distinct immune landscapes. CMLS was linked to malignant cancer features, suggesting its potential as a predictor of malignant progression in diverse cancers. Among the genes used to calculate CMLS, the role of inhibin subunit beta B (INHBB) in CRC remains unexplored. Expression analysis of INHBB across different cancer types revealed its upregulation in CRC, which was further validated by western blot and immunohistochemistry (IHC) experiments. INHBB silencing significantly inhibited tumor cell proliferation and migration, decreased phosphorylated AKT and N-cadherin levels, and increased E-cadherin expression. INHBB potentially suppresses CRC development and progression by suppressing the AKT signaling pathway and the EMT process.</p></div>","PeriodicalId":574,"journal":{"name":"Functional & Integrative Genomics","volume":"25 1","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145145352","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}

{"title":"Joint multi-omics analysis reveals the response mechanism in rapeseed (Brassica Rapa L.) under low nitrogen stress","authors":"Yi Gong,&nbsp;Fang Huan,&nbsp;Saba Zafar,&nbsp;Aiman Hina,&nbsp;Fang Zhao,&nbsp;ZeJiang Qiu,&nbsp;Nazih Y. Rebouh,&nbsp;Aqsa Parvaiz,&nbsp;WeiHai Hou","doi":"10.1007/s10142-025-01713-y","DOIUrl":"10.1007/s10142-025-01713-y","url":null,"abstract":"<div><p>Nitrogen is fundamental macronutrient that regulates plant growth by modulating a wide array of physiological and metabolic processes. However, the excessive application of nitrogen fertilizers has led to substantial environmental concerns, emphasizing the need for sustainable nitrogen management in agriculture. In this study, an integrative analysis encompassing morphological, physiological, transcriptomic, and metabolomic approaches was employed to investigate the adaptive responses of <i>Brassica rapa</i> (rapeseed) under contrasting nitrogen regimes. Morphological assessments demonstrated significant enhancements in root length and surface area under low nitrogen conditions, while photosynthesis traits particularly chlorophyll content were markedly reduced, underscoring nitrogen`s essential role in photosynthetic efficiency. Enzymatic activity assays revealed tissue-specific responses: roots exhibited elevated enzymatic activities under nitrogen deficiency, indicative of compensatory nitrogen uptake strategies, whereas leaves showed a decline in enzymatic functions, reflecting Limited nitrogen availability. Transcriptomic profiling identified 1,481 and 1,917 differentially expressed genes (DEGs) in roots and leaves, respectively, which were primarily associated with photosynthesis, amino acid metabolism, and oxidative stress responses. These transcriptomic shifts were corroborated by metabolic profiling, which reveled significant alterations in metabolites involved in amino acid metabolism, phenylpropanoid biosynthesis, and energy production pathways. Integration of transcriptomic and metabolomic datasets through Weighted Gene Co-expression Network Analysis (WGCNA) identified key gene metabolite modules implicated in nitrogen stress adaptation. Quantitative RT-PCR validation of selected DEGs confirmed the RNA-Seq expression patterns, further substantiating the reliability of the transcriptomic data. Collectively, this comprehensive multi-omics investigation elucidates the molecular basis of <i>B. rapa</i>`s adaptation to nitrogen deficient conditions, providing valuable insights for enhancing nitrogen use efficiency and guiding sustainable crop management strategies.</p></div>","PeriodicalId":574,"journal":{"name":"Functional & Integrative Genomics","volume":"25 1","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145136048","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}

{"title":"Next-generation translational genomics for developing future crops","authors":"Udita Basu,&nbsp;Swarup K. Parida","doi":"10.1007/s10142-025-01704-z","DOIUrl":"10.1007/s10142-025-01704-z","url":null,"abstract":"<div><p>Advancements in translational genomics have revolutionized crop breeding, driving us from traditional breeding methods towards next-generation strategies that integrate genomic, transcriptomic, and phenotypic data to expedite crop improvement. There has been a shift from single genomes to pan-genomes, which better capture intraspecific diversity, and from bulk transcriptome analyses to single-cell transcriptomics, enabling cell-specific insights into gene regulation and functional genomics. Both high throughput genopyting and phenotyping approaches are now possible due to rapid technological advancement in the field of translational genomics. Large-scale phenotyping data from multi-environment field trials is now possible due to AI-enabled digital and drone-based scanning. In the era of artificial intelligence and machine learning we have developed flexible models to handle complex genetic architecture of trait regulation using various tools and approaches. These genetic and genomic resources are the foundation for generating novel, adaptable, and high-yielding varieties, accelerating trait discovery and mapping. This review explores the comprehensive landscape of modern translational genomics, highlighting key shifts and innovations that enhance our capacity to address agricultural challenges. Integrative pipelines that unify these next-generation approaches could facilitate faster, more precise, and sustainable crop improvement, ultimately meeting the growing demands for future-ready crops.</p></div>","PeriodicalId":574,"journal":{"name":"Functional & Integrative Genomics","volume":"25 1","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145129691","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}

{"title":"Comprehensive evolutionary, differential expression and VIGS analyses reveal the function of GhNST1 in regulating drought tolerance and early maturity in upland cotton","authors":"Xueli Zhang,&nbsp;Dandan Li,&nbsp;Xuefeng Guo,&nbsp;Qiwen Yang,&nbsp;Wenjuan Xu,&nbsp;Xiaoxue Yu,&nbsp;Junning Yang,&nbsp;Fuxiang Wang,&nbsp;Junji Su,&nbsp;Caixiang Wang","doi":"10.1007/s10142-025-01707-w","DOIUrl":"10.1007/s10142-025-01707-w","url":null,"abstract":"<div><p>NAC secondary wall thickening promoting factor 1 (<i>NST1</i>) is crucial for abiotic stress responses and plant growth and development. However, the study of the function of <i>GhNST1</i> in upland cotton is rather limited. Our study revealed that its promoter contains multiple cis-elements linked to hormones, stress, and development. Among various abiotic stresses (drought, heat, NaCl, and cold), <i>GhNST1</i> presented the strongest response to drought. The transcriptional level of <i>GhNST1</i> was higher in early-maturing varieties at the three-leaf stage compared to those of late-maturing varieties. VIGS experiments confirmed that <i>GhNST1</i> was essential for drought tolerance in cotton. The TRV:<i>GhNST1</i> presented a lower relative water content (RWC) and faster water loss rate (WLR) in isolated leaves than the TRV:00 plants. Under drought stress, the TRV:<i>GhNST1</i> plants presented more wilting leaves than did the control plants. The chlorophyll content, activities of superoxide dismutase (SOD) and peroxidase (POD) were lower, the contents of malondialdehyde (MDA), lignin and proline (Pro) were higher, 3,3'-diaminobenzidine (DAB) and nitroblue tetrazolium (NBT) staining was more intense, while the transcript levels of stress-responsive genes (<i>GhDREB2A</i>, <i>GhRD29A</i>, and <i>GhCBL3</i>) were significantly downregulated. Furthermore, the budding, flowering and boll-opening of the CLCrV:<i>GhNST1</i> plants occurred significantly later than those of the empty vector plants. In the CLCrV:<i>GhNST1</i> plants, the <i>GhAP1</i>, <i>GhFT</i> and <i>GhSOC1</i> expression levels were lower than those in the controls, whereas the <i>GhSVP</i> expression level was elevated. These findings provide critical information for further investigations into how <i>GhNST1</i> regulates both the early maturity and drought stress response in cotton.</p></div>","PeriodicalId":574,"journal":{"name":"Functional & Integrative Genomics","volume":"25 1","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145073977","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}

{"title":"Disrupting the epigenetic alliance: structural insights and therapeutic strategies targeting DNMT1–UHRF1","authors":"Emadeldin M. Kamel,&nbsp;Mohamed A. M. Ali,&nbsp;Ahmed A. Allam,&nbsp;Noha A. Ahmed,&nbsp;Adil Abalkhail,&nbsp;Faris F. Aba Alkhayl,&nbsp;Al Mokhtar Lamsabhi","doi":"10.1007/s10142-025-01708-9","DOIUrl":"10.1007/s10142-025-01708-9","url":null,"abstract":"<div><p>Maintenance DNA methylation relies on a coordinated partnership between DNMT1 and its chromatin cofactor UHRF1. UHRF1’s SRA domain flips 5-methylcytosine out of hemimethylated DNA, and UHRF1-installed ubiquitin marks on histone H3 (H3K18/K23Ub; H3Ub₂) and PAF15 (PAF15Ub₂) are recognized by the DNMT1 RFTS domain to relieve autoinhibition and license copying of parental methylation during S phase. Tumors often upregulate this axis to enforce promoter hypermethylation programs, whereas approved azanucleosides act via DNMT1 trapping and are associated with DNA-damage–linked toxicities. Over ~ 15 years of structural work—from the 2008 SRA–DNA complexes to a 2022 cryo-EM structure of DNMT1 engaged with hemimethylated DNA and H3Ub₂—has mapped two tractable sites: the UHRF1-SRA aromatic cage and the ubiquitin-binding surface on DNMT1’s RFTS. These insights catalyzed small-molecule discovery. The anthraquinone UM63 validated SRA-pocket engagement but intercalates into DNA; newer non-intercalating SRA-directed inhibitors AMSA-2 (hydroxyanthracene/anthrarobin) and MPB-7 (imidazoquinoline) retain low-micromolar potency. In cells, AMSA-2 and MPB-7 disrupt UHRF1/DNMT1 colocalization at replication foci and induce replication-coupled global hypomethylation, with preferential cytotoxicity in UHRF1-high cancer lines relative to non-transformed cells. Beyond SRA antagonism, DNMT1 can be down-regulated pharmacologically: the non-nucleoside inhibitor GSK-3,484,862 triggers proteasome-dependent DNMT1 degradation alongside hypomethylation, and the first DNMT1-targeting PROTAC (KW0113) achieves selective DNMT1 degradation and growth inhibition in AML models. Remaining hurdles include potency ceilings, nuclear exposure/pharmacokinetics, and adaptive chromatin rewiring upon DNMT1 inhibition; nonetheless, structure-guided optimization and degrader strategies outline a credible path to precision epigenetic therapeutics that directly disrupt the DNMT1–UHRF1 maintenance machinery.</p></div>","PeriodicalId":574,"journal":{"name":"Functional & Integrative Genomics","volume":"25 1","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145073909","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}