Functional & Integrative Genomics最新文献

{"title":"Regulatory dynamics of Nanog in chondrocyte dedifferentiation: role of KLF4/p53 and p38/AKT signaling","authors":"Young Seok Eom,&nbsp;Song Ja Kim","doi":"10.1007/s10142-025-01572-7","DOIUrl":"10.1007/s10142-025-01572-7","url":null,"abstract":"<div><p>Homeobox protein Nanog, a member of the transcription factor family, plays a crucial role in maintaining the pluripotency and self-renewal of embryonic stem cells. Due to its diverse activities, Nanog has been identified in multiple cell types, including embryonic stem cells (ESCs) and cancer stem cells (CSCs). However, its molecular mechanism in chondrocytes remains unclear. In this study, we explored the effects of Nanog on chondrocytes and its interaction with chondrocyte-specific proteins. Chondrocytes were transfected with a Nanog cDNA vector, resulting in reduced expression of the chondrogenic markers Type II collagen and SOX9, as confirmed by western blot, RT-PCR, and immunofluorescence. Following siRNA transfection, the dedifferentiation effect of Nanog was reversed, restoring Type II collagen and SOX9 expression. We also discovered that the mechanism by which Nanog affects chondrocytes is closely linked to p53 and KLF4. Overexpression of KLF4 induced the phosphorylation of p53, and phospho-p53 directly inhibited Nanog expression. Moreover, the p53 activator Nutlin-3 A accelerated Nanog degradation, while the p53 inhibitor Pifithrin-α stabilized Nanog. Stabilized Nanog continued to promote chondrocyte dedifferentiation. Additional experiments were performed to identify the signaling pathways involved in Nanog-induced chondrocyte dedifferentiation. Our results showed that Nanog overexpression in chondrocytes significantly impacted the p38 kinase and AKT signaling pathways. Inhibition of p38 and AKT with SB203580 and LY294002 reduced Nanog expression and partially restored Type II collagen levels. Conversely, activation with anisomycin(ANS) and 740 Y-P enhanced Nanog expression, further reducing Type II collagen levels. To investigate Nanog’s role in early development in vivo, we injected Nanog expression vectors into zebrafish embryos. The injected zebrafish exhibited structural defects in craniofacial cartilage, confirming Nanog’s involvement in chondrocyte differentiation. These findings suggest that Nanog induces chondrocyte dedifferentiation, and this process can be modulated via the p53/KLF4 and p38/AKT pathways.</p></div>","PeriodicalId":574,"journal":{"name":"Functional & Integrative Genomics","volume":"25 1","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143583426","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 of F-box-LRR gene family and the functional analysis of CsFBXL13 transcription factor in tea plants","authors":"Xiangya Dou,&nbsp;Siyi Xie,&nbsp;Jinbo Wang,&nbsp;Xiaohua Shen,&nbsp;Shuoqian Liu,&nbsp;Na Tian","doi":"10.1007/s10142-025-01569-2","DOIUrl":"10.1007/s10142-025-01569-2","url":null,"abstract":"<div><p>This study focused on the identification and functional analysis of the F-box-LRR (FBXL) protein family in tea tree (<i>Camellia sinensis</i>), aiming to reveal its role in spring bud germination and environmental adaptation. Thirty-seven members of the tea tree F-box-LRR gene family were identified and systematically analyzed for their chromosomal localization, gene structure, conserved motifs, and cis-acting elements by bioinformatics methods. It was found that these genes were distributed on 14 chromosomes, with strong conserved and inter-gene covariance characteristics. Cis-acting element analysis showed that the F-box-LRR family members were associated with signals such as low temperature, gibberellin and growth hormone, which may play a key role in spring low-temperature germination. In addition, the study verified that the CsWRKY40 transcription factor directly binds to the promoter region of the <i>CsFBXL13</i> gene and significantly activates its expression by subcellular localization, yeast one-hybridization and dual luciferase assays, revealing the important function of the CsWRKY40-<i>CsFBXL13</i> regulatory axis in low-temperature response and spring bud germination in tea tree. This study not only expands the understanding of the F-box-LRR protein family, but also provides potential molecular targets for improving the resistance and productivity of tea tree through molecular breeding.</p></div>","PeriodicalId":574,"journal":{"name":"Functional & Integrative Genomics","volume":"25 1","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s10142-025-01569-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143581227","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":"Transcriptomic profiling reveals mechanism, therapeutic potential, and prognostic value of cancer stemness characteristic in nasopharyngeal carcinoma","authors":"Jin-Wei Chen,&nbsp;Run-Nan Shen,&nbsp;Jiang-Quan Zhu,&nbsp;Ying-Hang Wang,&nbsp;Liang-Min Fu,&nbsp;Yu-Hang Chen,&nbsp;Jia-Zheng Cao,&nbsp;Jin-Huan Wei,&nbsp;Jun-Hang Luo,&nbsp;Jia-Ying Li,&nbsp;Cheng-Peng Gui","doi":"10.1007/s10142-025-01561-w","DOIUrl":"10.1007/s10142-025-01561-w","url":null,"abstract":"<div><p>Nasopharyngeal carcinoma (NPC) recurrence, distant metastasis, and drug resistance remain significant obstacles in clinical prognosis. Cancer stemness is hypothesized to be a key contributor, though direct evidence is sparse. We utilized bioinformatics and machine learning techniques on single-cell RNA-seq and bulk transcriptomic datasets, complemented by basic experiments, to investigate stemness-based characteristics in NPC. Our analysis identified two potential developmental trajectories of nasopharyngeal cancer cells, each exhibiting varying levels of stemness. We subsequently identified and validated a cancer stemness-related signature (STEM-signature). Single-cell profiling revealed enrichment of LAYN + CD8 + , CTLA4 + CD4 + , CXCL13 + CD4 + T cells, tumor-associated macrophages, and CD14 + monocytes in NPC patients with high stemness. NicheNet analysis suggested these immune cells regulate cancer stemness. Bulk transcriptomic analysis corroborated these findings, indicating a poor therapeutic response in high-stemness NPC. We predicted 13 potential drugs and identified 13 stemness-related miRNAs for NPC with high stemness. A Least Absolute Shrinkage and Selection Operator (LASSO) Cox regression model, based on this miRNA signature, predicted overall survival with an AUC of 0.71 and 0.72 in validation and testing sets, respectively. The miRNA-based stemness signature outperformed previous established signatures. Multivariate Cox regression analysis indicated that our prognostic signature could serve as an independent prognostic factor (p &lt; 0.001). Basic experiments showed that miR-300, miR-361-5p, miR-1246, and miR-1290 enhanced the stemness characteristics of NPC cells, promoting proliferation, invasion, and migration. These findings suggest that these four stemness-related miRNAs could serve as therapeutic targets, potentially improving therapeutic responses by targeting stemness-related genes.</p></div>","PeriodicalId":574,"journal":{"name":"Functional & Integrative Genomics","volume":"25 1","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143571144","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":"Transcriptome analysis of the hypothalamus and testes in Brandt’s Vole: new insights into mechanisms of photoperiodic plasticity in postnatal testicular development","authors":"Lewen Wang,&nbsp;Yaqi Ying,&nbsp;Ning Li,&nbsp;Ying Song,&nbsp;Lijuan Zhao,&nbsp;Hong Sun,&nbsp;Zhenlong Wang,&nbsp;Xiao-Hui Liu,&nbsp;Dawei Wang","doi":"10.1007/s10142-025-01562-9","DOIUrl":"10.1007/s10142-025-01562-9","url":null,"abstract":"<div><p>Postnatal gonadal development is regulated by photoperiod via the hypothalamus, especially in seasonal breeding small rodents. However, the precise molecular mechanisms remain unclear. In this study, we conducted a comparative analysis of the transcriptomes of the hypothalamus and testes in 10-week-old male Brandt’s voles born under long (LP, 16L:8D) and short photoperiod (SP, 8L:16D) conditions. Results indicate that the SP group exhibited significantly smaller testes with spermatogenesis halted before meiosis, identifying 129 differentially expressed genes (DEGs) in the hypothalamus and 21,673 DEGs in the testes. In the hypothalamus, genes involved in the thyroid hormone and retinoic acid (RA) pathway were notably altered under SP conditions, including decreased <i>Tshb</i> and <i>Cga</i> expression, increased <i>Dio3</i>, and reduced <i>Crabp1</i> and <i>Lrat</i>, highlighting their key roles in SP signaling. In the testes, downregulated genes were significantly enriched in male reproduction-related GO terms and metabolic KEGG pathways, such as steroid hormone biosynthesis and retinol metabolism. Key genes for testosterone synthesis (e.g. <i>Star</i>, <i>Cyp11a1</i>) and RA synthesis (e.g. <i>Rdh10</i>, <i>Rdh11</i>) were downregulated, while those linked to RA degradation (<i>Cyp26b1</i>) and undifferentiated spermatogonia maintenance (e.g. <i>Gdnf</i>, <i>Gfra1</i>) were upregulated. These findings outline a molecular microenvironment that favors the preservation of undifferentiated spermatogonia over their differentiation from the hypothalamus to the testes. This study firstly provides valuable insights into the transcriptomic basis of SP-inhibited testicular development in Brandt’s voles.</p></div>","PeriodicalId":574,"journal":{"name":"Functional & Integrative Genomics","volume":"25 1","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143564457","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":"Pan-cancer investigation regarding the prognostic predictive and immunological regulation functions of PGK1 and experimental validation in esophageal squamous cell carcinoma","authors":"Junru Chen,&nbsp;Xun Wu,&nbsp;Hongtao Luo,&nbsp;Dandan Wang,&nbsp;Meng Dong,&nbsp;Yuhang Wang,&nbsp;Yuhong Ou,&nbsp;Shilong Sun,&nbsp;Zhiqiang Liu,&nbsp;Qiuning Zhang,&nbsp;Quanlin Guan","doi":"10.1007/s10142-025-01555-8","DOIUrl":"10.1007/s10142-025-01555-8","url":null,"abstract":"<div><p>Phosphoglycerate kinase 1 (PGK1), a pivotal enzyme in the glycolysis pathway, contributes to tumor progression through diverse biological activities like cell metabolism, angiogenesis, proliferation, and epithelial-mesenchymal transformation (EMT). Although PGK1 has been intensively researched in specific cancer types, its overarching significance in pan-cancer contexts remains underexplored. This study leveraged various public database resources, including the Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), Tumor Immune Estimation Resource (TIMER2.0), and cBioPortal, to analyze the gene expression, gene alteration characteristics, prognostic value, subcellular localization, biological function, immune characteristics, and drug sensitivity of PGK1 in 33 different cancer types. R software was used to visualize these data. Furthermore, the effects of PGK1 on the proliferation, apoptosis, migration, and invasion of esophageal squamous cell carcinoma (ESCC) cells were also examined in vitro using 5-ethynyl-2′-deoxyuridine (EdU) incorporation assay, CCK-8 assay, Annexin V-FITC/PI assay, migration assay, and invasion assay. The findings suggested that PGK1 is upregulated in various cancer types and closely associated with poor prognosis. In terms of functional enrichment analysis, PGK1 primarily plays a role in glycolysis, hypoxia, EMT, and immune-related pathways. Furthermore, PGK1 is highly expressed in immune and malignant cells in the tumor microenvironment. Notably, PGK1 expression varied significantly among immune cells with distinct activation states. The results of experiments in vitro showed that PGK1 was significantly upregulated in ESCC cells, and its knockdown led to significant inhibition of proliferation, migration, and invasion while increasing cell apoptosis; conversely, overexpression promoted proliferation, migration, and invasion while reducing apoptosis. PGK1 can serve as a prognostic biomarker and therapy target for various cancers, and it may be a promising focal point of immunological studies.</p></div>","PeriodicalId":574,"journal":{"name":"Functional & Integrative Genomics","volume":"25 1","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143554147","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":"Polycomb repressive complex 2 (PRC2) pathway’s role in cancer cell plasticity and drug resistance","authors":"Pouya Goleij,&nbsp;Mohammad Mahdi Heidari,&nbsp;Mohammad Amin Khazeei Tabari,&nbsp;Mahboube Hadipour,&nbsp;Aryan Rezaee,&nbsp;Alireza Javan,&nbsp;Pantea Majma Sanaye,&nbsp;Danaé S. Larsen,&nbsp;Maria Daglia,&nbsp;Haroon Khan","doi":"10.1007/s10142-025-01563-8","DOIUrl":"10.1007/s10142-025-01563-8","url":null,"abstract":"<div><p>Polycomb Repressive Complex 2 (PRC2) is a central regulator of gene expression via the trimethylation of histone H3 on lysine 27. This epigenetic modification plays a crucial role in maintaining cell identity and controlling differentiation, while its dysregulation is closely linked to cancer progression. PRC2 silences tumor suppressor genes, promoting cell proliferation, metastasis, epithelial-mesenchymal transition, and cancer stem cell plasticity. Enhancement of zeste homolog 2 (EZH2) overexpression or gain-of-function mutations have been observed in several cancers, including lymphoma, breast, and prostate cancers, driving aggressive tumor behavior and drug resistance. In addition to EZH2, other PRC2 components, such as embryonic ectoderm development (EED) and suppressor of zeste 12, are essential for complex stability and function. EED, in particular, enhances EZH2 activity and has emerged as a therapeutic target. Inhibitors like MAK683 and EED226 disrupt EED’s ability to maintain PRC2 activity, thereby reducing H3K27me3 levels and reactivating tumor suppressor genes. Valemetostat, a dual inhibitor of both EZH2 and EED, has shown promising results in aggressive cancers like diffuse large B-cell lymphoma and small-cell lung cancer, underlining the therapeutic potential of targeting multiple PRC2 components. PRC2’s role extends beyond gene repression, as it contributes to metabolic reprogramming in tumors, regulating glycolysis and lipid synthesis to fuel cancer growth. Furthermore, PRC2 is implicated in chemoresistance, particularly by modulating DNA damage response and immune evasion. Tazemetostat, a selective EZH2 inhibitor, has demonstrated significant clinical efficacy in EZH2-mutant cancers, such as non-Hodgkin lymphomas and epithelioid sarcoma. However, the compensatory function of enhancer of zeste homolog 1 (EZH1) in some cancers requires dual inhibition strategies, as seen with agents like UNC1999 and Tulmimetostat, which target both EZH1 and EZH2. Given PRC2’s multifaceted role in cancer biology, its inhibition represents a promising avenue for therapeutic intervention. The continued development of PRC2 inhibitors and exploration of their use in combination with standard chemotherapy or immunotherapy has great potential for improving patient outcomes in cancers driven by PRC2 dysregulation.</p><h3>Graphical abstract</h3><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":574,"journal":{"name":"Functional & Integrative Genomics","volume":"25 1","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143564407","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":"Molecular signatures that translate across omics layers and crops under high aluminium and low phosphorus stress facilitate the identification of reliable molecular targets for genotyping in lentil","authors":"Kadiyala Kavya,&nbsp;Noren Singh Konjengbam,&nbsp;M James,&nbsp;Mayank Rai,&nbsp;Wricha Tyagi,&nbsp;Ajay Kumar Mahato","doi":"10.1007/s10142-025-01542-z","DOIUrl":"10.1007/s10142-025-01542-z","url":null,"abstract":"<div><p>Aluminium toxicity and phosphorus deficiency are co-existing characteristics of low pH stress that significantly affect the grain yield of crops. The increasing acidity of Indian soils potentially limits the cultivable area for lentil (<i>Lens culinaris</i>), the third most widely consumed pulse. Breeding for tolerance requires an understanding of interdependent biological responses, but the molecular characterization of integrated tolerance remains elusive. Therefore, this study aimed to integrate high aluminium and low phosphorus stress responsive associations across the genomics, transcriptomics, proteomics, and metabolomics of multiple crop species. The overlapping molecular signatures were fine mapped to 23 candidates that serve multiple regulatory roles crucial for cellular homeostasis. Most of these genes have not been adequately discussed in the context of soil acidity tolerance. Thus, a multi-omics guided regulatory framework was developed to provide new insights into tolerance mechanisms. In silico genotyping of 29 lentil genotypes across 588 genes related to transomics loci yielded seven nonsynonymous and three synonymous variants likely associated with their differential response to stress. The results suggest comprehensive genotyping of multi-omics specific targets to identify potential candidates for marker-trait association studies. In conclusion, data-driven exploratory analysis of multi-omics variants highlights potential biomarkers as targets for genetically improving complex biological traits.</p></div>","PeriodicalId":574,"journal":{"name":"Functional & Integrative Genomics","volume":"25 1","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143553897","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":"N-glycosylation of GSTO1 promotes cervical cancer migration and invasion through JAK/STAT3 pathway activation","authors":"Panpan Yu,&nbsp;Zouyu Zhao,&nbsp;Qianyu Sun,&nbsp;Bowen Diao,&nbsp;Chongfeng Sun,&nbsp;Yan Wang,&nbsp;Hui Qiao,&nbsp;Hong Li,&nbsp;Ping Yang","doi":"10.1007/s10142-025-01565-6","DOIUrl":"10.1007/s10142-025-01565-6","url":null,"abstract":"<div><p>Protein glycosylation is strongly associated with tumor progression. Glutathione S-transferase omega 1 (GSTO1) is a member of the glutathione S-transferase family. The significance of GSTO1 N-glycosylation in the progression of cervical cancer (CC) has remained elusive. In this study, we investigated the functional significance of GSTO1 N-glycosylation in CC progression. We employed immunohistochemistry to detect the relative expression of evaluating the link between GSTO1 in CC and benign tissues and the overall survival (OS) and progression-free survival (PFS) in CC patients.In vitro and in vivo experiments to detect CC cell proliferation or metastatic ability after GSTO1 downregulation. NetNGly1.0 Server database predicts potential N-glycosylation modification sites of GSTO1 (Asn55, Asn135, Asn190). Investigating GSTO1 N-glycosylation’s function in cellular migration, invasion and epithelial–mesenchymal transition (EMT), we mutated the N-glycosylation sites of GSTO1 through lentivirus-based insertional mutagenesis. Detection of signalling pathways associated with N-glycosylation-modified GSTO1 by enrichment analysis and Western blot. Compared to normal cervical tissue, CC tissue showed significantly higher GSTO1 expression. Further, high GSTO1 levels were a poor predictor of OS and PFS. Both cell and animal experiments suggested that down-regulation of GSTO1 inhibited cell proliferation and metastasis. Glycosylation modification of targeted mutant GSTO1 at positions 55, 135 and 190 significantly inhibits migration and invasion of CC cells. GSTO1 N-glycosylation fixed point mutation inhibits EMT process in CC cells. Mechanistically, N-glycosylated GSTO1 promoted the expression of JAK/STAT3 pathway related markers. GSTO1 N-glycosylation is associated with CC progression and may promote EMT via JAK/STAT3 signaling.</p><h3>Graphical abstract</h3>\u0000<div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":574,"journal":{"name":"Functional & Integrative Genomics","volume":"25 1","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143533127","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":"Aberrant DNA methylation as a key modulator of cell death pathways: insights into cancer progression and other diseases","authors":"Ambreen Zahoor,&nbsp;Rafia Khazer,&nbsp;Insha Mehraj,&nbsp;Ubaid Gani,&nbsp;Falah Fayaz,&nbsp;Firdous A. Khanday,&nbsp;Sahar Saleem Bhat","doi":"10.1007/s10142-025-01552-x","DOIUrl":"10.1007/s10142-025-01552-x","url":null,"abstract":"<div><p>Cell death plays a significant role in the physiology of all living organisms, and its disruption is the underlying cause of various diseases. Previously, it was assumed that apoptosis and necrosis were the only means of cell death. Recent discoveries of alternative cell death pathways highlighted a complicated interplay between cell death regulation and its role in numerous human pathologies. DNA methylation is a universal epigenetic mechanism characterized by the covalent addition of a methyl group to cytosine in CpG dinucleotides. Alterations in DNA methylation patterns lead to the dysregulation of multiple cell death pathways. DNA methylome studies on cell death pathways have improved our understanding of the mechanism of various types of cell death, such as apoptosis, pyroptosis, necroptosis, ferroptosis, anoikis, autophagy, and cuproptosis. The irregular DNA methylation patterns of genes encoding proteins linked to multiple cell death pathways could underlie resistance to cell death. Dysregulation of cell death is linked to ailments in humans, such as cancer. However, unlike genetic alterations, DNA methylation is reversible, making it extremely interesting for therapeutics considering the potential use of DNA methyltransferase inhibitors. Furthermore, tumor microenvironment and genetic heterogeneity of cancers may influence the methylation-dependent regulation of cell death, contributing to tumor progression and therapeutic resistance. Understanding how DNA methylation influences cell death pathways may illuminate the underlying causes of cancer. This review explores the significance of the DNA methylation patterns of key genes involved in cell death pathways, emphasizing their connections and identifying potential gaps that could be exploited for developing epigenetic therapies targeting cancer.</p></div>","PeriodicalId":574,"journal":{"name":"Functional & Integrative Genomics","volume":"25 1","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143527613","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":"AZD7648 (DNA-PKcs inhibitor): a two-edged sword for editing genomes","authors":"Muhammad Waseem Sajjad,&nbsp;Ifrah Imran,&nbsp;Fatima Muzamil,&nbsp;Rubab Zahra Naqvi,&nbsp;Imran Amin","doi":"10.1007/s10142-025-01560-x","DOIUrl":"10.1007/s10142-025-01560-x","url":null,"abstract":"<div><p>Clustered regularly interspaced short palindromic repeats (CRISPR-Cas9) has been the most practical technique in genome editing for the last decade. Its molecular mechanism includes steps that occur in a sequence, starting from a break in a double strand to repair. After a double-strand break in the DNA strand, the repairing of DNA done via Homology-Directed Repair (HDR) is considered important in different organisms as it is ideal for precise genome editing and the reduction of unintended mutations. Still, it is mostly dominated by the Non-Homologous End Joining (NHEJ) pathway. A recent study by Cullot et al. published in <i>Nature Biotechnology</i> showed interesting features of AZD7648 (a DNA-PKcs inhibitor) that increase the probability of HDR event while DNA repairing (Cullot et al. 2024).</p></div>","PeriodicalId":574,"journal":{"name":"Functional & Integrative Genomics","volume":"25 1","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s10142-025-01560-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143521675","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}