Biochimica et Biophysica Acta-Gene Regulatory Mechanisms最新文献_第2页

Effects of disease severity on RNA integrity measures in necrotising soft tissue infection as a possible source of research bias: An observational cohort study 疾病严重程度对坏死性软组织感染中RNA完整性测量的影响可能是研究偏倚的来源：一项观察性队列研究

IF 3.1 3区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et Biophysica Acta-Gene Regulatory Mechanisms

Pub Date : 2025-11-10 DOI: 10.1016/j.bbagrm.2025.195121

Julie Vinkel , Edoardo Saccenti , Bart Nijsse , Morten Hedetoft , Ole Hyldegaard

RNA sequencing is increasingly being employed in clinical studies. During data pre-processing, samples are typically excluded from further analysis based on quality metrics that assess the integrity of the intermediate genomic product. RNA degradation may occur during sample handling as well as necrosis, affecting tissues in people with necrotising soft tissue infections (NSTIs).

RNA integrity measured with RNA Quality Number (RQN) and Transcript Integrity Number (TIN) in infected tissue samples may be lower in severe cases of NSTI.

We analysed whole blood and infected tissue samples from 95 individuals with acute NSTI and evaluated RNA integrity using RQN and TIN. Using linear models, we examined their relationships with age, BMI, RNA quantity, Sequential Organ Failure Assessment (SOFA) score, plasma lactate level (blood), and tissue type (infected tissue).

In infected tissue samples, we discovered that for every 5-point increase in SOFA score, the RQN increased by 0.19 points, 95 % CI [0.15, 1.80], p = 0.022, but there was no influence on the TIN. In blood, we observed no associations between RQN and SOFA or raised lactate levels, nor between TIN and SOFA score or elevated lactate. In both tissues, we discovered a link between age and RNA integrity measurements, and that RQN was dependent on the RNA quantity extracted from samples.

We advocate using numerous integrity measures to evaluate RNA integrity. Samples should not be removed based on any integrity measures in data pre-processing. The biological and technological implications of eliminating samples should be assessed using the integrity metrics as covariates.

RNA测序越来越多地应用于临床研究。在数据预处理过程中，基于评估中间基因组产物完整性的质量指标，样品通常被排除在进一步分析之外。在样品处理和坏死过程中可能发生RNA降解，影响坏死性软组织感染（NSTIs）患者的组织。在严重的NSTI病例中，用RNA质量数（RQN）和转录本完整性数（TIN）测量感染组织样本的RNA完整性可能较低。我们分析了95例急性NSTI患者的全血和感染组织样本，并使用RQN和TIN评估RNA完整性。使用线性模型，我们检查了它们与年龄、BMI、RNA数量、顺序器官衰竭评估（SOFA）评分、血浆乳酸水平（血液）和组织类型（感染组织）的关系。在感染组织样本中，我们发现SOFA评分每增加5分，RQN增加0.19分，95 % CI [0.15, 1.80], p = 0.022，但对TIN没有影响。在血液中，我们观察到RQN与SOFA或升高的乳酸水平之间没有关联，TIN与SOFA评分或升高的乳酸水平之间也没有关联。在这两种组织中，我们发现年龄和RNA完整性测量之间存在联系，RQN依赖于从样本中提取的RNA数量。我们提倡使用多种完整性措施来评估RNA完整性。在数据预处理过程中，不应基于任何完整性措施去除样本。消除样本的生物学和技术意义应使用完整性指标作为协变量进行评估。

{"title":"Effects of disease severity on RNA integrity measures in necrotising soft tissue infection as a possible source of research bias: An observational cohort study","authors":"Julie Vinkel , Edoardo Saccenti , Bart Nijsse , Morten Hedetoft , Ole Hyldegaard","doi":"10.1016/j.bbagrm.2025.195121","DOIUrl":"10.1016/j.bbagrm.2025.195121","url":null,"abstract":"<div><div>RNA sequencing is increasingly being employed in clinical studies. During data pre-processing, samples are typically excluded from further analysis based on quality metrics that assess the integrity of the intermediate genomic product. RNA degradation may occur during sample handling as well as necrosis, affecting tissues in people with necrotising soft tissue infections (NSTIs).</div><div>RNA integrity measured with RNA Quality Number (RQN) and Transcript Integrity Number (TIN) in infected tissue samples may be lower in severe cases of NSTI.</div><div>We analysed whole blood and infected tissue samples from 95 individuals with acute NSTI and evaluated RNA integrity using RQN and TIN. Using linear models, we examined their relationships with age, BMI, RNA quantity, Sequential Organ Failure Assessment (SOFA) score, plasma lactate level (blood), and tissue type (infected tissue).</div><div>In infected tissue samples, we discovered that for every 5-point increase in SOFA score, the RQN increased by 0.19 points, 95 % CI [0.15, 1.80], <em>p</em> = 0.022, but there was no influence on the TIN. In blood, we observed no associations between RQN and SOFA or raised lactate levels, nor between TIN and SOFA score or elevated lactate. In both tissues, we discovered a link between age and RNA integrity measurements, and that RQN was dependent on the RNA quantity extracted from samples.</div><div>We advocate using numerous integrity measures to evaluate RNA integrity. Samples should not be removed based on any integrity measures in data pre-processing. The biological and technological implications of eliminating samples should be assessed using the integrity metrics as covariates.</div></div>","PeriodicalId":55382,"journal":{"name":"Biochimica et Biophysica Acta-Gene Regulatory Mechanisms","volume":"1868 4","pages":"Article 195121"},"PeriodicalIF":3.1,"publicationDate":"2025-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145508088","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Identification of a novel p65-p68 loop: A crucial determinant for p68 gene regulation in oncogenesis 新的p65-p68环的鉴定：肿瘤发生中p68基因调控的关键决定因素

IF 3.1 3区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et Biophysica Acta-Gene Regulatory Mechanisms

Pub Date : 2025-11-06 DOI: 10.1016/j.bbagrm.2025.195120

Mrinal K. Ghosh , Sunny Kumar , Veenita Khare , Siddik Sarkar , Shaheda Tabassum , Malini Basu

DEAD-box RNA helicase DDX5 (p68), located on chromosome 17, specifically at the 17q23.3 region), is overexpressed in most of the cancers, including colorectal cancer (CRC) and glioma, thereby gaining prominence as a potential biomarker. There is a paucity of research on the mechanisms of p68 gene regulation at the genetic level. RelA, (p65), belonging to the NF-κB signaling pathway plays a diversified role in accelerating oncogenesis. Here, we report for the first time a novel transcriptional positive feedback mechanism between p65 and p68 that drives oncogenesis in CRC and glioma. Using bioinformatics analysis, chromatin immunoprecipitation (ChIP), and luciferase reporter assays, we identified functional NF-κB binding sites in the p68 promoter region and demonstrated that p65 upregulates p68 expression. Functionally, increased p68 expression was associated with enhanced proliferation, migration, and invasion, established through in vitro as well as in vivo studies in glioma and CRC. Furthermore, the pharmacological inhibition of IKK (outside of the loop) via Bay-11 leads to the suppression of the “p65-p68 loop” and their oncogenic phenotypes. However, the analysis of patient-derived tumor samples revealed a positive correlation between p65 and p68, underscoring their clinical relevance. Hence, our findings elucidate novel transcriptional feedback “p65–68 loop” and its therapeutic potential in CRC and glioma.

DEAD-box RNA解旋酶DDX5 （p68）位于17号染色体上，特别是在17q23.3区域)，在大多数癌症中过表达，包括结直肠癌（CRC）和胶质瘤，因此作为一种潜在的生物标志物而受到重视。目前对p68基因在遗传水平上的调控机制研究较少。RelA, （p65）属于NF-κB信号通路，在加速肿瘤发生过程中发挥多种作用。在这里，我们首次报道了p65和p68之间的一种新的转录正反馈机制，该机制驱动结直肠癌和胶质瘤的肿瘤发生。通过生物信息学分析、染色质免疫沉淀（ChIP）和荧光素酶报告基因分析，我们确定了p68启动子区域的NF-κB结合位点，并证明p65上调了p68的表达。功能上，p68表达的增加与胶质瘤和结直肠癌的增殖、迁移和侵袭增强有关，这是通过体外和体内研究建立的。此外，通过Bay-11对IKK（环外）的药理学抑制导致“p65-p68环”及其致癌表型的抑制。然而，对患者来源的肿瘤样本的分析显示p65和p68之间呈正相关，强调了它们的临床相关性。因此，我们的研究结果阐明了新的转录反馈“p65-68环”及其在结直肠癌和胶质瘤中的治疗潜力。

{"title":"Identification of a novel p65-p68 loop: A crucial determinant for p68 gene regulation in oncogenesis","authors":"Mrinal K. Ghosh , Sunny Kumar , Veenita Khare , Siddik Sarkar , Shaheda Tabassum , Malini Basu","doi":"10.1016/j.bbagrm.2025.195120","DOIUrl":"10.1016/j.bbagrm.2025.195120","url":null,"abstract":"<div><div>DEAD-box RNA helicase DDX5 (p68), located on chromosome 17, specifically at the 17q23.3 region), is overexpressed in most of the cancers, including colorectal cancer (CRC) and glioma, thereby gaining prominence as a potential biomarker. There is a paucity of research on the mechanisms of p68 gene regulation at the genetic level. RelA, (p65), belonging to the NF-κB signaling pathway plays a diversified role in accelerating oncogenesis. Here, we report for the first time a novel transcriptional positive feedback mechanism between p65 and p68 that drives oncogenesis in CRC and glioma. Using bioinformatics analysis, chromatin immunoprecipitation (ChIP), and luciferase reporter assays, we identified functional NF-κB binding sites in the p68 promoter region and demonstrated that p65 upregulates p68 expression. Functionally, increased p68 expression was associated with enhanced proliferation, migration, and invasion, established through <em>in vitro</em> as well as <em>in vivo</em> studies in glioma and CRC. Furthermore, the pharmacological inhibition of IKK (outside of the loop) <em>via</em> Bay-11 leads to the suppression of the “p65-p68 loop” and their oncogenic phenotypes. However, the analysis of patient-derived tumor samples revealed a positive correlation between p65 and p68, underscoring their clinical relevance. Hence, our findings elucidate novel transcriptional feedback “p65–68 loop” and its therapeutic potential in CRC and glioma.</div></div>","PeriodicalId":55382,"journal":{"name":"Biochimica et Biophysica Acta-Gene Regulatory Mechanisms","volume":"1868 4","pages":"Article 195120"},"PeriodicalIF":3.1,"publicationDate":"2025-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145465735","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Heterogeneity of Acute Myeloid Leukemia patients explored through single-cell and single-sample gene regulatory networks 通过单细胞和单样本基因调控网络探讨急性髓系白血病患者的异质性。

IF 3.1 3区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et Biophysica Acta-Gene Regulatory Mechanisms

Pub Date : 2025-11-04 DOI: 10.1016/j.bbagrm.2025.195119

Leandro Fernandes, Edoardo Saccenti

Acute myeloid leukaemia (AML) is a genetically heterogeneous disease, driven by diverse mutations and epigenetic alterations that disrupt normal haematopoiesis. Understanding how this heterogeneity manifests at the gene regulatory level can provide insight into disease mechanisms and uncover potential targets for personalized treatment strategies.

In this study, single-cell RNA sequencing data from AML patients and healthy controls were used to infer patient gene regulatory networks (GRNs) for progenitor, monocyte, and dendritic cells. Consensus networks were constructed using four inference methods (ARACNE, CLR, MRNET, GENIE3). Additionally, single-sample single-cell networks were constructed using the LIONESS approach for all patients and cell types.

Dimensionality reduction applied to both network statistics and adjacency matrices of consensus networks revealed limited clustering, reflecting the biological heterogeneity of AML. Notably, dimensionality reduction and classification models based on single-cell networks achieved distinct patient clustering and perfect discrimination accuracy. This indicates that single-cell GRNs can capture patient-specific signatures of gene regulation.

Pathway enrichment analysis of highly connected and predictive genes highlighted distinct regulatory programs across cell types and individuals. These findings demonstrate the potential of GRNs from single-cell data to distinguish between patients and may serve as a foundation for the development of personalized biomarkers and therapeutics.

急性髓性白血病（AML）是一种遗传异质性疾病，由多种突变和表观遗传改变驱动，破坏正常的造血功能。了解这种异质性在基因调控水平上的表现，可以深入了解疾病机制，并发现个性化治疗策略的潜在靶点。在这项研究中，来自AML患者和健康对照的单细胞RNA测序数据被用来推断祖细胞、单核细胞和树突状细胞的患者基因调控网络（grn）。采用ARACNE、CLR、MRNET、GENIE3四种推理方法构建共识网络。此外，使用LIONESS方法为所有患者和细胞类型构建单样本单细胞网络。将降维应用于网络统计和共识网络的邻接矩阵显示有限的聚类，反映了AML的生物学异质性。值得注意的是，基于单细胞网络的降维和分类模型实现了明显的患者聚类和完美的识别精度。这表明单细胞grn可以捕获基因调控的患者特异性特征。通路富集分析高度连接和预测基因强调不同细胞类型和个体的不同调控程序。这些发现证明了单细胞数据中grn区分患者的潜力，并可能为个性化生物标志物和治疗方法的开发奠定基础。

{"title":"Heterogeneity of Acute Myeloid Leukemia patients explored through single-cell and single-sample gene regulatory networks","authors":"Leandro Fernandes, Edoardo Saccenti","doi":"10.1016/j.bbagrm.2025.195119","DOIUrl":"10.1016/j.bbagrm.2025.195119","url":null,"abstract":"<div><div>Acute myeloid leukaemia (AML) is a genetically heterogeneous disease, driven by diverse mutations and epigenetic alterations that disrupt normal haematopoiesis. Understanding how this heterogeneity manifests at the gene regulatory level can provide insight into disease mechanisms and uncover potential targets for personalized treatment strategies.</div><div>In this study, single-cell RNA sequencing data from AML patients and healthy controls were used to infer patient gene regulatory networks (GRNs) for progenitor, monocyte, and dendritic cells. Consensus networks were constructed using four inference methods (ARACNE, CLR, MRNET, GENIE3). Additionally, single-sample single-cell networks were constructed using the LIONESS approach for all patients and cell types.</div><div>Dimensionality reduction applied to both network statistics and adjacency matrices of consensus networks revealed limited clustering, reflecting the biological heterogeneity of AML. Notably, dimensionality reduction and classification models based on single-cell networks achieved distinct patient clustering and perfect discrimination accuracy. This indicates that single-cell GRNs can capture patient-specific signatures of gene regulation.</div><div>Pathway enrichment analysis of highly connected and predictive genes highlighted distinct regulatory programs across cell types and individuals. These findings demonstrate the potential of GRNs from single-cell data to distinguish between patients and may serve as a foundation for the development of personalized biomarkers and therapeutics.</div></div>","PeriodicalId":55382,"journal":{"name":"Biochimica et Biophysica Acta-Gene Regulatory Mechanisms","volume":"1868 4","pages":"Article 195119"},"PeriodicalIF":3.1,"publicationDate":"2025-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145460726","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

TET enzymes: Involvement in cancer development and therapeutical perspectives TET酶：参与癌症的发展和治疗前景。

IF 3.1 3区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et Biophysica Acta-Gene Regulatory Mechanisms

Pub Date : 2025-10-16 DOI: 10.1016/j.bbagrm.2025.195118

Tarik Aanniz , Meriem El Fessikh , Jihane Touhtouh , Sara Aboulaghras , Nasreddine El Omari , Asaad Khalid , Ashraf N. Abdalla , Mohammed Amanullah , Bey Hing Goh , Learn-Han Lee , Abdelhakim Bouyahya

The TET family of enzymes is essential for the dynamic regulation of DNA methylation and the epigenetic landscape of human genomes. Their ability to oxidize 5-methylcytosine (5mC) into various hydroxymethylated derivatives facilitates active DNA demethylation and serves as a critical regulatory mechanism in normal cellular processes. Dysregulation of TET proteins has been implicated in multiple types of cancer, highlighting their significance in tumorigenesis and their potential for therapeutic targeting. The functionality of TET proteins continues to be widely studied across various tissues and contexts. Their role as novel drug targets in cancer therapy is attracting increasing attention. Understanding how TET enzymes contribute to epigenetic alterations could provide new insights into cancer prevention and treatment, potentially extending the window of effective therapeutic intervention. This review aims to explore the diverse roles and regulatory mechanisms of TET proteins, examine how their dysregulation promotes cancer progression, and underscore the potential of TET enzymes as druggable targets for anticancer therapy.

TET家族的酶对于DNA甲基化和人类基因组的表观遗传景观的动态调控是必不可少的。它们将5-甲基胞嘧啶（5mC）氧化成各种羟甲基化衍生物的能力促进了活跃的DNA去甲基化，并在正常细胞过程中起着关键的调节作用。TET蛋白的失调与多种类型的癌症有关，突出了它们在肿瘤发生中的重要性和它们在治疗靶向方面的潜力。TET蛋白的功能继续在各种组织和环境中被广泛研究。它们作为新型药物靶点在癌症治疗中的作用越来越受到人们的关注。了解TET酶如何促进表观遗传改变可以为癌症预防和治疗提供新的见解，可能扩大有效治疗干预的窗口。本综述旨在探讨TET蛋白的多种作用和调控机制，研究其失调如何促进癌症进展，并强调TET酶作为抗癌药物靶点的潜力。

{"title":"TET enzymes: Involvement in cancer development and therapeutical perspectives","authors":"Tarik Aanniz , Meriem El Fessikh , Jihane Touhtouh , Sara Aboulaghras , Nasreddine El Omari , Asaad Khalid , Ashraf N. Abdalla , Mohammed Amanullah , Bey Hing Goh , Learn-Han Lee , Abdelhakim Bouyahya","doi":"10.1016/j.bbagrm.2025.195118","DOIUrl":"10.1016/j.bbagrm.2025.195118","url":null,"abstract":"<div><div>The TET family of enzymes is essential for the dynamic regulation of DNA methylation and the epigenetic landscape of human genomes. Their ability to oxidize 5-methylcytosine (5mC) into various hydroxymethylated derivatives facilitates active DNA demethylation and serves as a critical regulatory mechanism in normal cellular processes. Dysregulation of TET proteins has been implicated in multiple types of cancer, highlighting their significance in tumorigenesis and their potential for therapeutic targeting. The functionality of TET proteins continues to be widely studied across various tissues and contexts. Their role as novel drug targets in cancer therapy is attracting increasing attention. Understanding how TET enzymes contribute to epigenetic alterations could provide new insights into cancer prevention and treatment, potentially extending the window of effective therapeutic intervention. This review aims to explore the diverse roles and regulatory mechanisms of TET proteins, examine how their dysregulation promotes cancer progression, and underscore the potential of TET enzymes as druggable targets for anticancer therapy.</div></div>","PeriodicalId":55382,"journal":{"name":"Biochimica et Biophysica Acta-Gene Regulatory Mechanisms","volume":"1868 4","pages":"Article 195118"},"PeriodicalIF":3.1,"publicationDate":"2025-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145318950","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The cAMP receptor protein, SyCRP1 acts as a transcriptional repressor of CO2-concentrating mechanism genes at high inorganic carbon levels in Synechocystis PCC 6803 聚囊藻（Synechocystis PCC 6803）中，cAMP受体蛋白SyCRP1作为高无机碳水平下co2富集机制基因的转录抑制因子。

IF 3.1 3区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et Biophysica Acta-Gene Regulatory Mechanisms

Pub Date : 2025-10-02 DOI: 10.1016/j.bbagrm.2025.195117

Suraj Chauhan , N. Prakash Prabhu , Martin Hagemann , Sue Lin-Chao , Jogadhenu S.S. Prakash

Cyanobacteria utilize a CO₂-concentrating mechanism (CCM) to enhance photosynthetic efficiency by accumulating CO₂ around RuBisCO, a process crucial for adapting to fluctuating environmental CO₂ levels. While the upregulation of CCM genes under low inorganic carbon (C_i) conditions is known, the precise C_i sensing and regulatory mechanisms governing CCM gene expression remain incompletely understood. We show that a membrane-bound SyCRP1 senses high C_i levels through cAMP binding to its low- and high-affinity sites. We demonstrate its interaction with membrane lipids and liposomes, and a subsequent reversal of its membrane localization upon cAMP binding. Comprehensive ChIP-seq analysis reveals direct binding of SyCRP1 to regulatory elements of core CCM genes. Our findings establish SyCRP1 as a key transcriptional repressor of these genes under high C_i conditions, significantly advancing our understanding of the molecular mechanisms governing CCM genes' expression in cyanobacteria.

蓝藻利用二氧化碳浓缩机制（CCM）通过在RuBisCO周围积累二氧化碳来提高光合效率，这一过程对于适应环境中波动的二氧化碳水平至关重要。虽然已知CCM基因在低无机碳（Ci）条件下的上调，但CCM基因表达的精确Ci感知和调控机制仍不完全清楚。我们发现，膜结合的SyCRP1通过cAMP结合到其低和高亲和力位点来感知高Ci水平。我们证明了它与膜脂和脂质体的相互作用，以及随后在cAMP结合时其膜定位的逆转。综合ChIP-seq分析显示SyCRP1与核心CCM基因的调控元件直接结合。我们的研究结果表明，SyCRP1在高Ci条件下是这些基因的关键转录抑制因子，这极大地促进了我们对蓝藻中CCM基因表达的分子机制的理解。

{"title":"The cAMP receptor protein, SyCRP1 acts as a transcriptional repressor of CO2-concentrating mechanism genes at high inorganic carbon levels in Synechocystis PCC 6803","authors":"Suraj Chauhan , N. Prakash Prabhu , Martin Hagemann , Sue Lin-Chao , Jogadhenu S.S. Prakash","doi":"10.1016/j.bbagrm.2025.195117","DOIUrl":"10.1016/j.bbagrm.2025.195117","url":null,"abstract":"<div><div>Cyanobacteria utilize a CO<sub>2</sub>-concentrating mechanism (CCM) to enhance photosynthetic efficiency by accumulating CO<sub>2</sub> around RuBisCO, a process crucial for adapting to fluctuating environmental CO<sub>2</sub> levels. While the upregulation of CCM genes under low inorganic carbon (C<sub>i</sub>) conditions is known, the precise C<sub>i</sub> sensing and regulatory mechanisms governing CCM gene expression remain incompletely understood. We show that a membrane-bound SyCRP1 senses high C<sub>i</sub> levels through cAMP binding to its low- and high-affinity sites. We demonstrate its interaction with membrane lipids and liposomes, and a subsequent reversal of its membrane localization upon cAMP binding. Comprehensive ChIP-seq analysis reveals direct binding of SyCRP1 to regulatory elements of core CCM genes. Our findings establish SyCRP1 as a key transcriptional repressor of these genes under high C<sub>i</sub> conditions, significantly advancing our understanding of the molecular mechanisms governing CCM genes' expression in cyanobacteria.</div></div>","PeriodicalId":55382,"journal":{"name":"Biochimica et Biophysica Acta-Gene Regulatory Mechanisms","volume":"1868 4","pages":"Article 195117"},"PeriodicalIF":3.1,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145226313","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Transcriptional activation of the PKLR gene by novel erythroid-specific regulatory elements 新的红细胞特异性调控元件对plklr基因转录激活的影响。

IF 3.1 3区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et Biophysica Acta-Gene Regulatory Mechanisms

Pub Date : 2025-09-16 DOI: 10.1016/j.bbagrm.2025.195116

Yea Woon Kim , Jin Kang , AeRi Kim

The pyruvate kinase L/R (PKLR) gene encodes the L- and R-type isoforms of pyruvate kinase, which catalyze the final step of glycolysis in mammals. The L-type isozyme is mainly found in liver cells, whereas the R-type isozyme is produced specifically in erythroid cells. To investigate the transcriptional activation of the PKLR gene for the R-type isozyme, we analyzed chromatin features—including DNase I sensitivity, histone modifications, and enhancer–promoter interactions—in erythroid K562 and non-erythroid HUVEC cells. Putative regulatory elements, including a promoter and two enhancers, were identified near the PKLR locus in K562 cells. Depletion of H3K4me1 and H3K27ac, histone marks associated with active enhancers, through mutation of histone methyltransferases led to a marked reduction in PKLR transcription, while transcription of a nearby gene remained stable. These regulatory elements were highly occupied by the erythroid-specific transcription factors GATA1 and TAL1. Loss of either factors disrupted local H3K27ac and reduced the recruitment of chromatin-looping factors, resulting in decreased PKLR transcription. Furthermore, CRISPR/Cas9-mediated deletion of the putative regulatory elements significantly diminished PKLR transcription, demonstrating their functional importance. Collectively, these findings highlight the essential role of these regulatory elements in activating PKLR transcription in erythroid cells and emphasize the requirement of erythroid-specific factors for their function.

丙酮酸激酶L/R （PKLR）基因编码丙酮酸激酶的L型和R型同工型，在哺乳动物中催化糖酵解的最后一步。l型同工酶主要存在于肝细胞中，而r型同工酶仅在红细胞中产生。为了研究PKLR基因对r型同工酶的转录激活，我们分析了红系K562和非红系HUVEC细胞的染色质特征，包括DNase I敏感性、组蛋白修饰和增强子-启动子相互作用。在K562细胞的pkr位点附近发现了可能的调控元件，包括一个启动子和两个增强子。与活性增强子相关的组蛋白标记H3K4me1和H3K27ac通过组蛋白甲基转移酶突变导致PKLR转录显著减少，而附近基因的转录保持稳定。这些调控元件被红系特异性转录因子GATA1和TAL1高度占据。任何一个因子的缺失都会破坏局部H3K27ac，减少染色质环因子的募集，导致pkr转录减少。此外，CRISPR/ cas9介导的缺失显著降低了PKLR转录，证明了它们在功能上的重要性。总的来说，这些发现强调了这些调控元件在激活红细胞plklr转录中的重要作用，并强调了红细胞特异性因子对其功能的要求。

{"title":"Transcriptional activation of the PKLR gene by novel erythroid-specific regulatory elements","authors":"Yea Woon Kim , Jin Kang , AeRi Kim","doi":"10.1016/j.bbagrm.2025.195116","DOIUrl":"10.1016/j.bbagrm.2025.195116","url":null,"abstract":"<div><div>The pyruvate kinase L/R (PKLR) gene encodes the L- and R-type isoforms of pyruvate kinase, which catalyze the final step of glycolysis in mammals. The L-type isozyme is mainly found in liver cells, whereas the R-type isozyme is produced specifically in erythroid cells. To investigate the transcriptional activation of the PKLR gene for the R-type isozyme, we analyzed chromatin features—including DNase I sensitivity, histone modifications, and enhancer–promoter interactions—in erythroid K562 and non-erythroid HUVEC cells. Putative regulatory elements, including a promoter and two enhancers, were identified near the PKLR locus in K562 cells. Depletion of H3K4me1 and H3K27ac, histone marks associated with active enhancers, through mutation of histone methyltransferases led to a marked reduction in PKLR transcription, while transcription of a nearby gene remained stable. These regulatory elements were highly occupied by the erythroid-specific transcription factors GATA1 and TAL1. Loss of either factors disrupted local H3K27ac and reduced the recruitment of chromatin-looping factors, resulting in decreased PKLR transcription. Furthermore, CRISPR/Cas9-mediated deletion of the putative regulatory elements significantly diminished PKLR transcription, demonstrating their functional importance. Collectively, these findings highlight the essential role of these regulatory elements in activating PKLR transcription in erythroid cells and emphasize the requirement of erythroid-specific factors for their function.</div></div>","PeriodicalId":55382,"journal":{"name":"Biochimica et Biophysica Acta-Gene Regulatory Mechanisms","volume":"1868 4","pages":"Article 195116"},"PeriodicalIF":3.1,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145087956","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

RNA-protein interaction techniques - A historical and comparative analysis rna -蛋白质相互作用技术-历史和比较分析。

IF 3.1 3区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et Biophysica Acta-Gene Regulatory Mechanisms

Pub Date : 2025-09-11 DOI: 10.1016/j.bbagrm.2025.195115

Sourabh Chakrabarty , Sayan Roy , Soumyadip Sarkar , Kusum K. Singh

RNAs intricately orchestrate a myriad of molecular and cellular processes. This includes mRNAs which serve as the essential blueprints for protein synthesis and the non-coding RNAs which act as versatile regulators, influencing gene expression, RNA stability, and even protein function. Over the past few decades, a diverse array of RNA- and protein-centric methodologies have emerged to discern and elucidate the identities of RNA binding proteins (RBPs) and RNAs engaged in RNA-Protein interactions (RPI). The selection of an appropriate method is paramount, given the distinctive advantages and limitations inherent to each technique, in order to effectively address specific biological inquiries. This review spans the spectrum of techniques employed in RNA-Protein interaction studies, ranging from time-honored methods like Electrophoretic Mobility Shift Assay (EMSA) to contemporary approaches such as CRISPR-based RNA-Protein interaction profiling (CBRIP). This review aims not only to list methods but also to provide historical background, discuss the strengths and weaknesses of each approach, and highlight their current applications. Furthermore, it consolidates methodologies tailored to characterize RNA-protein interactions based on their distinct purposes.

rna复杂地协调着无数的分子和细胞过程。这包括作为蛋白质合成基本蓝图的mrna和作为多种调节因子，影响基因表达、RNA稳定性甚至蛋白质功能的非编码RNA。在过去的几十年里，出现了一系列以RNA和蛋白质为中心的方法来辨别和阐明RNA结合蛋白（rbp）和参与RNA-蛋白质相互作用（RPI）的RNA的身份。考虑到每种技术的独特优势和固有局限性，为了有效地处理特定的生物学调查，选择适当的方法是至关重要的。这篇综述涵盖了rna -蛋白质相互作用研究中使用的技术范围，从历史悠久的方法，如电泳迁移转移测定（EMSA）到现代方法，如基于crispr的rna -蛋白质相互作用分析（CBRIP）。本文不仅列出了各种方法，而且还提供了历史背景，讨论了每种方法的优缺点，并强调了它们目前的应用。此外，它还根据rna -蛋白质相互作用的不同目的，整合了专门用于表征它们的方法。

{"title":"RNA-protein interaction techniques - A historical and comparative analysis","authors":"Sourabh Chakrabarty , Sayan Roy , Soumyadip Sarkar , Kusum K. Singh","doi":"10.1016/j.bbagrm.2025.195115","DOIUrl":"10.1016/j.bbagrm.2025.195115","url":null,"abstract":"<div><div>RNAs intricately orchestrate a myriad of molecular and cellular processes. This includes mRNAs which serve as the essential blueprints for protein synthesis and the non-coding RNAs which act as versatile regulators, influencing gene expression, RNA stability, and even protein function. Over the past few decades, a diverse array of RNA- and protein-centric methodologies have emerged to discern and elucidate the identities of RNA binding proteins (RBPs) and RNAs engaged in RNA-Protein interactions (RPI). The selection of an appropriate method is paramount, given the distinctive advantages and limitations inherent to each technique, in order to effectively address specific biological inquiries. This review spans the spectrum of techniques employed in RNA-Protein interaction studies, ranging from time-honored methods like Electrophoretic Mobility Shift Assay (EMSA) to contemporary approaches such as CRISPR-based RNA-Protein interaction profiling (CBRIP). This review aims not only to list methods but also to provide historical background, discuss the strengths and weaknesses of each approach, and highlight their current applications. Furthermore, it consolidates methodologies tailored to characterize RNA-protein interactions based on their distinct purposes.</div></div>","PeriodicalId":55382,"journal":{"name":"Biochimica et Biophysica Acta-Gene Regulatory Mechanisms","volume":"1868 4","pages":"Article 195115"},"PeriodicalIF":3.1,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145058811","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The Catsper3 promoter activity is regulated by the cAMP-Response Element Modulator tau (CREMτ) and the cAMP-Response Element Binding protein 1A (CREBA) transcription factors Catsper3启动子活性受cAMP-Response Element Modulator tau （CREMτ）和cAMP-Response Element Binding protein 1A （CREBA）转录因子调控

IF 3.1 3区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et Biophysica Acta-Gene Regulatory Mechanisms

Pub Date : 2025-08-25 DOI: 10.1016/j.bbagrm.2025.195114

Diego Eduardo Sánchez-Jasso , Sergio Federico López-Guzmán , Javier Hernández-Sánchez , Rosa María Bermúdez-Cruz , Norma Oviedo

Catsper3 has been shown to be essential for the proper functioning of CatSper calcium channel, sperm hyperactivation and egg fertilization. Although its function and physiological relevance to male fertility have been characterized, nothing is known about its regulation at the transcriptional level. Here, we identified the murine Catsper3 promoter and evaluated the role of CREBA and CREMτ transcription factors (TF) on its regulation. Cloning of a predicted Catsper3 promoter region and further deletion analysis indicates that Catsper3 core promoter is located at −157 to +152 relative to the transcription start site (TSS). Mutation of a TATA box and a Downstream Promoter Element (DPE) did not alter the promoter activity, indicating that this promoter is TATA and DPE independent. Exogenous expression of CREBA and CREMτ increase the Catsper3 promoter activity in the presence of the +268 to +439 region, where two CRE sites were predicted, and mutation of both CRE sites prevents the transactivation by both TFs, suggesting that CREMτ and CREBA may use these sites to promote Catsper3 transcription. Finally, binding of CREBA and CREMτ to both CRE sites was confirmed in vitro by EMSA and ChIP-qPCR assays demonstrated an enrichment of CREBA and CREMτ at the Catsper3 promoter in vivo in the testis but not in liver, indicating its tissue-specific binding. Altogether, these results strongly suggest that Catsper3 gene has a TATA-less, DPE independent promoter encompassed by −157 to +152 region around TSS and that Catsper3 gene expression is directly regulated through two CRE sites by CREBA and CREMτ.

Catsper3已被证明对Catsper3钙通道的正常运作、精子过度激活和卵子受精至关重要。虽然其功能和与男性生育能力的生理相关性已被表征，但其在转录水平上的调控尚不清楚。在此，我们鉴定了小鼠Catsper3启动子，并评估了CREBA和CREMτ转录因子（TF）在其调控中的作用。克隆预测的Catsper3启动子区域和进一步的缺失分析表明，相对于转录起始位点（TSS）， Catsper3核心启动子位于- 157至+152。TATA盒子和下游启动子元件（DPE）的突变没有改变启动子的活性，表明该启动子与TATA和DPE无关。CREBA和CREMτ的外源表达增加了+268至+439区域存在的Catsper3启动子活性，其中预测了两个CRE位点，两个CRE位点的突变阻止了两个tf的反激活，这表明CREMτ和CREBA可能利用这些位点促进Catsper3转录。最后，通过体外EMSA和ChIP-qPCR分析证实CREBA和CREMτ与两个CRE位点的结合表明，体内睾丸中Catsper3启动子处的CREBA和CREMτ富集，而肝脏中没有，表明其组织特异性结合。总之，这些结果强烈表明，Catsper3基因具有一个TATA-less， DPE独立的启动子，包含在TSS周围的- 157至+152区域，并且Catsper3基因的表达由CREBA和CREMτ通过两个CRE位点直接调节。

{"title":"The Catsper3 promoter activity is regulated by the cAMP-Response Element Modulator tau (CREMτ) and the cAMP-Response Element Binding protein 1A (CREBA) transcription factors","authors":"Diego Eduardo Sánchez-Jasso , Sergio Federico López-Guzmán , Javier Hernández-Sánchez , Rosa María Bermúdez-Cruz , Norma Oviedo","doi":"10.1016/j.bbagrm.2025.195114","DOIUrl":"10.1016/j.bbagrm.2025.195114","url":null,"abstract":"<div><div>Catsper3 has been shown to be essential for the proper functioning of CatSper calcium channel, sperm hyperactivation and egg fertilization. Although its function and physiological relevance to male fertility have been characterized, nothing is known about its regulation at the transcriptional level. Here, we identified the murine <em>Catsper3</em> promoter and evaluated the role of CREBA and CREMτ transcription factors (TF) on its regulation. Cloning of a predicted <em>Catsper3</em> promoter region and further deletion analysis indicates that <em>Catsper3</em> core promoter is located at −157 to +152 relative to the transcription start site (TSS). Mutation of a TATA box and a Downstream Promoter Element (DPE) did not alter the promoter activity, indicating that this promoter is TATA and DPE independent. Exogenous expression of CREBA and CREMτ increase the <em>Catsper3</em> promoter activity in the presence of the +268 to +439 region, where two CRE sites were predicted, and mutation of both CRE sites prevents the transactivation by both TFs, suggesting that CREMτ and CREBA may use these sites to promote <em>Catsper3</em> transcription. Finally, binding of CREBA and CREMτ to both CRE sites was confirmed <em>in vitro</em> by EMSA and ChIP-qPCR assays demonstrated an enrichment of CREBA and CREMτ at the <em>Catsper3</em> promoter <em>in vivo</em> in the testis but not in liver, indicating its tissue-specific binding. Altogether, these results strongly suggest that <em>Catsper3</em> gene has a TATA-less, DPE independent promoter encompassed by −157 to +152 region around TSS and that <em>Catsper3</em> gene expression is directly regulated through two CRE sites by CREBA and CREMτ.</div></div>","PeriodicalId":55382,"journal":{"name":"Biochimica et Biophysica Acta-Gene Regulatory Mechanisms","volume":"1868 4","pages":"Article 195114"},"PeriodicalIF":3.1,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144919682","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Expression of CMK2 is controlled by the general stress-response transcriptional factor Msn2 through a single STRE site in budding yeast 在出芽酵母中，CMK2的表达受一般应激反应转录因子Msn2通过一个单一的STRE位点控制。

IF 3.1 3区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et Biophysica Acta-Gene Regulatory Mechanisms

Pub Date : 2025-08-13 DOI: 10.1016/j.bbagrm.2025.195107

Linghuo Jiang , Yiying Gu , Liudan Wei , Jinrong Feng , Lingxin Pan , Xiufan Liao , Yiping Mo , Chunyu Wei

Mammalian calcium/calmodulin-dependent protein kinase II (CaMKII) is a memory molecule in the brain, and regulates fatty acids and lipid metabolism. As a yeast homolog of CaMKII, Cmk2 is a negative feed-back regulator of calcium signaling in Saccharomyces cerevisiae. Previous systemic studies have shown that 42 transcription factors (TFs) are involved in the control of CMK2 expression under various conditions other than calcium stress, but only one, Crz1, is reported to directly regulate CMK2 expression in response to calcium stress. Here, we show that other 26 TFs, Adr1, Aft2, Cad1, Cst6, Cup2, Dal81, Dal82, Flo8, Gcr2, Haa1, Hfi1, Msn2, Oaf1, Pho4, Ppr1, Rfx1, Rgm1, Rpn4, Sfp1, SIp3, Smp1, Spt10, Stp1, Sum1, Swi4 and Tup1, are involved in the positive control of CMK2 transcription, with 10 of them being calcium stress-specific. In contrast, other four TFs, Hir2, Rph1, Sin3 and Uga3, negatively regulates CMK2 transcription independent of calcium stress. Therefore, multiple TFs directly or indirectly control the transcription of CMK2 in yeast cells. EMSA and ChIP analysis demonstrate that the general stress-responsive Msn2 directly controls the expression of CMK2 through one STRE site, 5′ C₋₁₅₅CCCT 3′, in its promoter. Our genetic study indicates that Crz1 is epistatic to Msn2 in controlling CMK2 expression and the calcium sensitivity of yeast cells in response to calcium stress. This work provides important clues to the study on the regulation of CaMKII expression in mammalian cells.

哺乳动物钙/钙调素依赖性蛋白激酶II （CaMKII）是大脑中的一种记忆分子，调节脂肪酸和脂质代谢。作为CaMKII的酵母同源物，cm2是酿酒酵母钙信号的负反馈调节因子。先前的系统研究表明，在钙胁迫以外的各种条件下，42种转录因子（tf）参与控制CMK2的表达，但据报道只有一种转录因子Crz1在钙胁迫下直接调节CMK2的表达。在这里，我们发现了Adr1、Aft2、Cad1、Cst6、Cup2、Dal81、Dal82、Flo8、Gcr2、Haa1、Hfi1、Msn2、Oaf1、Pho4、Ppr1、Rfx1、Rgm1、Rpn4、Sfp1、SIp3、Smp1、Spt10、Stp1、Sum1、Swi4和Tup1等26个tf参与CMK2转录的阳性控制，其中10个是钙胁迫特异性的。相反，其他四个tf， Hir2, Rph1， Sin3和Uga3，负调控CMK2转录，不依赖于钙胁迫。因此，多种TFs直接或间接地控制酵母细胞中CMK2的转录。EMSA和ChIP分析表明，一般应激响应的Msn2通过启动子中的一个STRE位点5‘ C-155CCCT 3’直接控制cm2的表达。我们的遗传研究表明，Crz1在控制酵母细胞对钙胁迫的CMK2表达和钙敏感性方面是上位性的。这项工作为研究CaMKII在哺乳动物细胞中的表达调控提供了重要线索。

{"title":"Expression of CMK2 is controlled by the general stress-response transcriptional factor Msn2 through a single STRE site in budding yeast","authors":"Linghuo Jiang , Yiying Gu , Liudan Wei , Jinrong Feng , Lingxin Pan , Xiufan Liao , Yiping Mo , Chunyu Wei","doi":"10.1016/j.bbagrm.2025.195107","DOIUrl":"10.1016/j.bbagrm.2025.195107","url":null,"abstract":"<div><div>Mammalian calcium/calmodulin-dependent protein kinase II (CaMKII) is a memory molecule in the brain, and regulates fatty acids and lipid metabolism. As a yeast homolog of CaMKII, Cmk2 is a negative feed-back regulator of calcium signaling in <em>Saccharomyces cerevisiae</em>. Previous systemic studies have shown that 42 transcription factors (TFs) are involved in the control of <em>CMK2</em> expression under various conditions other than calcium stress, but only one, Crz1, is reported to directly regulate <em>CMK2</em> expression in response to calcium stress. Here, we show that other 26 TFs, Adr1, Aft2, Cad1, Cst6, Cup2, Dal81, Dal82, Flo8, Gcr2, Haa1, Hfi1, Msn2, Oaf1, Pho4, Ppr1, Rfx1, Rgm1, Rpn4, Sfp1, SIp3, Smp1, Spt10, Stp1, Sum1, Swi4 and Tup1, are involved in the positive control of <em>CMK2</em> transcription, with 10 of them being calcium stress-specific. In contrast, other four TFs, Hir2, Rph1, Sin3 and Uga3, negatively regulates <em>CMK2</em> transcription independent of calcium stress. Therefore, multiple TFs directly or indirectly control the transcription of <em>CMK2</em> in yeast cells. EMSA and ChIP analysis demonstrate that the general stress-responsive Msn2 directly controls the expression of <em>CMK2</em> through one STRE site, 5′ C<sub>−155</sub>CCCT 3′, in its promoter. Our genetic study indicates that Crz1 is epistatic to Msn2 in controlling <em>CMK2</em> expression and the calcium sensitivity of yeast cells in response to calcium stress. This work provides important clues to the study on the regulation of CaMKII expression in mammalian cells.</div></div>","PeriodicalId":55382,"journal":{"name":"Biochimica et Biophysica Acta-Gene Regulatory Mechanisms","volume":"1868 4","pages":"Article 195107"},"PeriodicalIF":3.1,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144859964","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A putative PIWIL/piRNA–OTX2 network: An emerging model for epigenetic regulation of cancer stemness in retinoblastoma PIWIL/piRNA-OTX2网络：视网膜母细胞瘤肿瘤干细胞的表观遗传调控新模型

IF 2.6 3区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et Biophysica Acta-Gene Regulatory Mechanisms

Pub Date : 2025-07-19 DOI: 10.1016/j.bbagrm.2025.195106

Rupa Roy , Subbulakshmi Chidambaram

Recent findings underscore the critical role of PIWIL/piRNA pathways in cancer, extending their known functions beyond reproductive biology. Retinoblastoma (RB), a rare pediatric retinal tumor, is primarily driven by RB1 gene loss but also involves significant epigenetic alterations. Our previous studies revealed that PIWIL4 is significantly upregulated in RB, and its knockdown disrupts the expression of stemness-associated factors, including OTX2, SOX2, and NANOG. In this review, we have proposed that PIWIL/piRNA complexes might recruit epigenetic modifiers to cis-regulatory modules (CRMs) of the OTX2 gene, modulating chromatin accessibility and transcription factor binding. Aberrant PIWIL4 expression may dysregulate OTX2 expression, impacting stemness-maintaining factors and activating oncogenic pathways, including Wnt/β-catenin signaling, mediated by TSPAN12, EphA2, and ZNF proteins. This conceptual framework positions the PIWIL/piRNA-OTX2 axis as a potential regulator of CSC dynamics, linking it to epigenetic modifications, transcription factor interactions, and neuronal differentiation in RB. Targeting this axis could disrupt stemness-associated pathways and oncogenic signaling, offering new therapeutic strategies to mitigate tumor progression and recurrence in RB and other cancers with similar molecular mechanisms.

最近的研究结果强调了PIWIL/piRNA通路在癌症中的关键作用，将其已知功能扩展到生殖生物学之外。视网膜母细胞瘤（RB）是一种罕见的儿童视网膜肿瘤，主要由RB1基因缺失驱动，但也涉及显著的表观遗传改变。我们之前的研究表明，PIWIL4在RB中显著上调，其下调会破坏OTX2、SOX2和NANOG等stemness相关因子的表达。在这篇综述中，我们提出PIWIL/piRNA复合物可能将表观遗传修饰因子募集到OTX2基因的顺式调控模块（CRMs）中，调节染色质可及性和转录因子结合。PIWIL4的异常表达可能会使OTX2的表达失调，影响干细胞维持因子，激活由TSPAN12、EphA2和ZNF蛋白介导的Wnt/β-catenin信号通路。这一概念框架将PIWIL/piRNA-OTX2轴定位为CSC动力学的潜在调节因子，将其与RB的表观遗传修饰、转录因子相互作用和神经元分化联系起来。靶向该轴可能会破坏干细胞相关通路和致癌信号，为减轻RB和其他具有类似分子机制的癌症的肿瘤进展和复发提供新的治疗策略。

{"title":"A putative PIWIL/piRNA–OTX2 network: An emerging model for epigenetic regulation of cancer stemness in retinoblastoma","authors":"Rupa Roy , Subbulakshmi Chidambaram","doi":"10.1016/j.bbagrm.2025.195106","DOIUrl":"10.1016/j.bbagrm.2025.195106","url":null,"abstract":"<div><div>Recent findings underscore the critical role of PIWIL/piRNA pathways in cancer, extending their known functions beyond reproductive biology. Retinoblastoma (RB), a rare pediatric retinal tumor, is primarily driven by RB1 gene loss but also involves significant epigenetic alterations. Our previous studies revealed that PIWIL4 is significantly upregulated in RB, and its knockdown disrupts the expression of stemness-associated factors, including OTX2, SOX2, and NANOG. In this review, we have proposed that PIWIL/piRNA complexes might recruit epigenetic modifiers to cis-regulatory modules (CRMs) of the OTX2 gene, modulating chromatin accessibility and transcription factor binding. Aberrant PIWIL4 expression may dysregulate OTX2 expression, impacting stemness-maintaining factors and activating oncogenic pathways, including Wnt/β-catenin signaling, mediated by TSPAN12, EphA2, and ZNF proteins. This conceptual framework positions the PIWIL/piRNA-OTX2 axis as a potential regulator of CSC dynamics, linking it to epigenetic modifications, transcription factor interactions, and neuronal differentiation in RB. Targeting this axis could disrupt stemness-associated pathways and oncogenic signaling, offering new therapeutic strategies to mitigate tumor progression and recurrence in RB and other cancers with similar molecular mechanisms.</div></div>","PeriodicalId":55382,"journal":{"name":"Biochimica et Biophysica Acta-Gene Regulatory Mechanisms","volume":"1868 3","pages":"Article 195106"},"PeriodicalIF":2.6,"publicationDate":"2025-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144683636","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0