Pub Date : 2026-02-04DOI: 10.1016/j.bbagrm.2026.195139
Melvin Prasad, Radhakrishna Shetty
Plants are immobile organisms, constantly exposed to a wide variety of environmental challenges, among these, drought, salinity and extreme temperatures are the most detrimental factors that significantly affect growth and productivity, leading to substantial annual crop losses worldwide. To respond and survive such challenges, plants have developed complex adaptive mechanisms involving gene regulation at multiple levels. Epigenetic modifications, such as DNA methylation, histone modification, RNA modification, and non-coding RNAs, play a significant role in modulating gene expressions without altering underlying DNA sequences. These modifications facilitate stress-induced gene activation or repression and contribute to the establishment of "stress memory", allowing plants to respond more effectively to repeated stresses. Recent advancements in gene editing technologies, particularly CRISPR/dCas9-based systems, have enabled researchers to target these epigenetic modifications with high precision. By fusing dCas9 (deactivated or dead Cas9) with effectors such as DNA methyltransferases or demethylases or histone acetyltransferases, researchers can modify epigenetic marks that influence gene expression at specific loci, enhancing stress resilience. Most promising techniques like SunTag system have further improved the efficiency of these tools. This review explores how environmental factors influence epigenetic changes and how the knowledge gained could be used for the development of stress resilient crops. These approaches offer a promising avenue for improving desirable traits and ensuring stable crop yields, thereby supporting global food security in a rapidly changing climate.
{"title":"Advancing crop resilience to environmental stresses: Insights from epigenetic modification and CRISPR/dCas9-based editing.","authors":"Melvin Prasad, Radhakrishna Shetty","doi":"10.1016/j.bbagrm.2026.195139","DOIUrl":"https://doi.org/10.1016/j.bbagrm.2026.195139","url":null,"abstract":"<p><p>Plants are immobile organisms, constantly exposed to a wide variety of environmental challenges, among these, drought, salinity and extreme temperatures are the most detrimental factors that significantly affect growth and productivity, leading to substantial annual crop losses worldwide. To respond and survive such challenges, plants have developed complex adaptive mechanisms involving gene regulation at multiple levels. Epigenetic modifications, such as DNA methylation, histone modification, RNA modification, and non-coding RNAs, play a significant role in modulating gene expressions without altering underlying DNA sequences. These modifications facilitate stress-induced gene activation or repression and contribute to the establishment of \"stress memory\", allowing plants to respond more effectively to repeated stresses. Recent advancements in gene editing technologies, particularly CRISPR/dCas9-based systems, have enabled researchers to target these epigenetic modifications with high precision. By fusing dCas9 (deactivated or dead Cas9) with effectors such as DNA methyltransferases or demethylases or histone acetyltransferases, researchers can modify epigenetic marks that influence gene expression at specific loci, enhancing stress resilience. Most promising techniques like SunTag system have further improved the efficiency of these tools. This review explores how environmental factors influence epigenetic changes and how the knowledge gained could be used for the development of stress resilient crops. These approaches offer a promising avenue for improving desirable traits and ensuring stable crop yields, thereby supporting global food security in a rapidly changing climate.</p>","PeriodicalId":55382,"journal":{"name":"Biochimica et Biophysica Acta-Gene Regulatory Mechanisms","volume":" ","pages":"195139"},"PeriodicalIF":3.1,"publicationDate":"2026-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146133677","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}
Background: Diabetic kidney disease (DKD) is a major microvascular complication of diabetes, characterized by abnormal mesangial cell (MC) proliferation, yet the underlying mechanisms remain unclear.
Methods: Using RNA-seq and qRT-PCR, Mov10 was identified as the most highly expressed splicing factor (SF) in high-glucose MCs among seven candidates (Mov10, Ssb, Rbm25, Fastk, Dek, Nsrp1, Cwc15). Functional assays (EdU, CCK-8) assessed MC proliferation, while qRT-PCR and Western blot measured inflammatory and fibrotic markers. RIP-seq, RNA-seq, and bioinformatics analyses were used to identify MOV10-binding sites, target genes, pathways, and alternative splicing (AS) events.
Results: Transcriptome analysis revealed extensive AS in DKD, with exon skipping being the most frequent. MOV10 knockdown suppressed MC proliferation and reduced inflammation and fibrosis, whereas MOV10 overexpression had opposite effects. RIP-seq showed MOV10 preferentially bound the ACGACG motif within CDS regions. MOV10 regulated AS of proliferation-related genes, including Tead1, Dcbld2, Slc9a5, Akap13, Tfdp2, and Trp53bp1, primarily via exon skipping.
Conclusions: This study identifies MOV10 as a novel DKD-associated splicing factor. By modulating AS of proliferation-related genes, MOV10 promotes mesangial proliferation, inflammation, and fibrosis, highlighting a potential therapeutic target in DKD.
{"title":"MOV10-mediated alternative splicing regulates mesangial cell proliferation in diabetic kidney disease.","authors":"Qijia Wang, Xinyu Chong, Handeng Liu, Rui Peng, Xuemei Peng, Xiaohui Liao, Yan Sun, Zheng Zhang","doi":"10.1016/j.bbagrm.2026.195138","DOIUrl":"10.1016/j.bbagrm.2026.195138","url":null,"abstract":"<p><strong>Background: </strong>Diabetic kidney disease (DKD) is a major microvascular complication of diabetes, characterized by abnormal mesangial cell (MC) proliferation, yet the underlying mechanisms remain unclear.</p><p><strong>Methods: </strong>Using RNA-seq and qRT-PCR, Mov10 was identified as the most highly expressed splicing factor (SF) in high-glucose MCs among seven candidates (Mov10, Ssb, Rbm25, Fastk, Dek, Nsrp1, Cwc15). Functional assays (EdU, CCK-8) assessed MC proliferation, while qRT-PCR and Western blot measured inflammatory and fibrotic markers. RIP-seq, RNA-seq, and bioinformatics analyses were used to identify MOV10-binding sites, target genes, pathways, and alternative splicing (AS) events.</p><p><strong>Results: </strong>Transcriptome analysis revealed extensive AS in DKD, with exon skipping being the most frequent. MOV10 knockdown suppressed MC proliferation and reduced inflammation and fibrosis, whereas MOV10 overexpression had opposite effects. RIP-seq showed MOV10 preferentially bound the ACGACG motif within CDS regions. MOV10 regulated AS of proliferation-related genes, including Tead1, Dcbld2, Slc9a5, Akap13, Tfdp2, and Trp53bp1, primarily via exon skipping.</p><p><strong>Conclusions: </strong>This study identifies MOV10 as a novel DKD-associated splicing factor. By modulating AS of proliferation-related genes, MOV10 promotes mesangial proliferation, inflammation, and fibrosis, highlighting a potential therapeutic target in DKD.</p>","PeriodicalId":55382,"journal":{"name":"Biochimica et Biophysica Acta-Gene Regulatory Mechanisms","volume":" ","pages":"195138"},"PeriodicalIF":3.1,"publicationDate":"2026-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146121221","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}
Pub Date : 2026-01-21DOI: 10.1016/j.bbagrm.2026.195137
Brigitta Veda Devani , Hye Su Moon , Ana Braza , Timoty Ekaputra , Audrey Christine , Jae Won Shim , Su Jung Song
Ten-eleven translocation 2 (Tet2) catalyzes the conversion of 5-methylcytosine to 5-hydroxymethylcytosine, facilitating active DNA demethylation. Although implicated in adipogenesis, its precise role remains controversial. Here, we investigated Tet2 function during early 3T3-L1 adipocyte differentiation, focusing on regulation of the imprinted gene Pref-1. Differentiation time-course experiments revealed that Tet2 protein, but not mRNA, was progressively reduced via proteasome-dependent degradation, contrasting with previous reports of Tet2 mRNA upregulation. Tet2 overexpression delayed lipid accumulation and reduced adipogenic marker expression, whereas knockdown had the opposite effect. Mechanistically, Tet2 positively regulated Pref-1 transcription by demethylating specific differentially methylated regions in its promoter and exon 6. Loss of Tet2 increased DNA methylation and decreased hydroxymethylation at these loci, leading to Pref-1 repression and derepression of C/EBPα and PPARγ. This stage-specific, proteasome-mediated downregulation of Tet2 integrates epigenetic and post-translational control to regulate adipocyte commitment. The Tet2–Pref-1 axis offers mechanistic insight into adipose tissue expansion and may represent a therapeutic target for obesity and imprinting-related disorders.
{"title":"Tet2-mediated Pref-1 activation delays adipocyte differentiation","authors":"Brigitta Veda Devani , Hye Su Moon , Ana Braza , Timoty Ekaputra , Audrey Christine , Jae Won Shim , Su Jung Song","doi":"10.1016/j.bbagrm.2026.195137","DOIUrl":"10.1016/j.bbagrm.2026.195137","url":null,"abstract":"<div><div>Ten-eleven translocation 2 (Tet2) catalyzes the conversion of 5-methylcytosine to 5-hydroxymethylcytosine, facilitating active DNA demethylation. Although implicated in adipogenesis, its precise role remains controversial. Here, we investigated Tet2 function during early 3T3-L1 adipocyte differentiation, focusing on regulation of the imprinted gene <em>Pref-1</em>. Differentiation time-course experiments revealed that Tet2 protein, but not mRNA, was progressively reduced via proteasome-dependent degradation, contrasting with previous reports of <em>Tet2</em> mRNA upregulation. Tet2 overexpression delayed lipid accumulation and reduced adipogenic marker expression, whereas knockdown had the opposite effect. Mechanistically, Tet2 positively regulated Pref-1 transcription by demethylating specific differentially methylated regions in its promoter and exon 6. Loss of Tet2 increased DNA methylation and decreased hydroxymethylation at these loci, leading to Pref-1 repression and derepression of C/EBPα and PPARγ. This stage-specific, proteasome-mediated downregulation of Tet2 integrates epigenetic and post-translational control to regulate adipocyte commitment. The Tet2–Pref-1 axis offers mechanistic insight into adipose tissue expansion and may represent a therapeutic target for obesity and imprinting-related disorders.</div></div>","PeriodicalId":55382,"journal":{"name":"Biochimica et Biophysica Acta-Gene Regulatory Mechanisms","volume":"1869 1","pages":"Article 195137"},"PeriodicalIF":3.1,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146041937","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}
Pub Date : 2026-01-15DOI: 10.1016/j.bbagrm.2026.195136
Sanghee Park , Taehyun Park , Dayoung Choi , Soeun Kim , Hyunjung Cho , Misu Lee
Hepatocellular carcinoma (HCC) is a highly lethal malignancy in which acquired resistance to sorafenib remains a major therapeutic challenge. To investigate mechanisms of resistance, we performed transcriptomic profiling of sorafenib-resistant HCC cells, which revealed enrichment of processes related to tumor progression, including mitotic regulation, chromatin remodeling, and apoptotic signaling. Notably, these cells displayed marked downregulation of tissue inhibitor of metalloproteinases-3 (TIMP3), a tumor suppressor known to regulate invasion and epithelial–mesenchymal transition (EMT). Functional studies showed that TIMP3 overexpression (OV) suppressed cell viability, stemness-associated proteins, and a key cell cycle regulator, while upregulating apoptosis-related proteins. Conversely, TIMP3 knockdown (KD) enhanced proliferation, stemness, and EMT. EMT markers were reduced in TIMP3-OV cells but increased with TIMP3-KD, consistent with spheroid sprouting assays, highlighting TIMP3 as a brake on aggressiveness. To explore upstream regulators, we integrated in silico predictions with validation, identifying miR-149-3p as a novel repressor of TIMP3. miR-149-3p overexpression reduced TIMP3 levels and promoted EMT and invasion, whereas inhibition of miR-149-3p restored TIMP3 expression and suppressed migration. Clinical analyses using TCGA datasets and HCC tissue microarrays confirmed significantly lower TIMP3 expression in tumors compared with normal liver tissue, and showed inverse correlations between TIMP3 and proliferative or stemness markers, including Ki67 and CD44. Collectively, these findings establish a mechanistic axis in which miR-149-3p–mediated suppression of TIMP3 promotes sorafenib resistance, EMT, and stemness in HCC. This work identifies TIMP3 as a pivotal determinant of tumor aggressiveness and suggests restoring TIMP3 or targeting downstream pathways as strategies to overcome resistance.
{"title":"miR-149-3p–mediated TIMP3 restoration suppresses tumor aggressiveness in sorafenib-resistant liver cancer cell","authors":"Sanghee Park , Taehyun Park , Dayoung Choi , Soeun Kim , Hyunjung Cho , Misu Lee","doi":"10.1016/j.bbagrm.2026.195136","DOIUrl":"10.1016/j.bbagrm.2026.195136","url":null,"abstract":"<div><div>Hepatocellular carcinoma (HCC) is a highly lethal malignancy in which acquired resistance to sorafenib remains a major therapeutic challenge. To investigate mechanisms of resistance, we performed transcriptomic profiling of sorafenib-resistant HCC cells, which revealed enrichment of processes related to tumor progression, including mitotic regulation, chromatin remodeling, and apoptotic signaling. Notably, these cells displayed marked downregulation of tissue inhibitor of metalloproteinases-3 (TIMP3), a tumor suppressor known to regulate invasion and epithelial–mesenchymal transition (EMT). Functional studies showed that TIMP3 overexpression (OV) suppressed cell viability, stemness-associated proteins, and a key cell cycle regulator, while upregulating apoptosis-related proteins. Conversely, TIMP3 knockdown (KD) enhanced proliferation, stemness, and EMT. EMT markers were reduced in TIMP3-OV cells but increased with TIMP3-KD, consistent with spheroid sprouting assays, highlighting TIMP3 as a brake on aggressiveness. To explore upstream regulators, we integrated in silico predictions with validation, identifying miR-149-3p as a novel repressor of TIMP3. miR-149-3p overexpression reduced TIMP3 levels and promoted EMT and invasion, whereas inhibition of miR-149-3p restored TIMP3 expression and suppressed migration. Clinical analyses using TCGA datasets and HCC tissue microarrays confirmed significantly lower TIMP3 expression in tumors compared with normal liver tissue, and showed inverse correlations between TIMP3 and proliferative or stemness markers, including Ki67 and CD44. Collectively, these findings establish a mechanistic axis in which miR-149-3p–mediated suppression of TIMP3 promotes sorafenib resistance, EMT, and stemness in HCC. This work identifies TIMP3 as a pivotal determinant of tumor aggressiveness and suggests restoring TIMP3 or targeting downstream pathways as strategies to overcome resistance.</div></div>","PeriodicalId":55382,"journal":{"name":"Biochimica et Biophysica Acta-Gene Regulatory Mechanisms","volume":"1869 1","pages":"Article 195136"},"PeriodicalIF":3.1,"publicationDate":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145994446","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}
Pub Date : 2026-01-12DOI: 10.1016/j.bbagrm.2026.195135
Sylwia Bloch , Natalia Lewandowska , Joanna Zwolenkiewicz-Nowak , Monika Mazur , Agnieszka Chylewska , Aleksandra M. Dąbrowska , Natalia Musiał , Paulina Czaplewska , Wojciech Wesołowski , Aleksandra Łukasiak , Mariusz Ferenc , Marcin Pietrzycki , Emilia Węglińska , Paulina Mach , Grzegorz Węgrzyn , Mikołaj Olejniczak , Bożena Nejman-Faleńczyk
The phage Φ24B-encoded small RNA (sRNA), named UpRoi1, was identified following the prophage induction. The UpRoi1 molecule is encoded in the antirepressor region of the phage genome and is notably small, consisting of only 30 nucleotides. This sRNA is comparable in size to microRNAs found in eukaryotic cells, and thus, unusual for prokaryotic sRNAs. Bioinformatic analysis revealed that UpRoi1 has multiple interaction sites within the phage and host genomes, suggesting its complex regulatory role. In turn, RNA-seq analyses confirmed that the UpRoi1 molecule has a broad impact on the host's gene expression and influences numerous biological processes, particularly those involved in bacterial motility. Furthermore, binding assays revealed that the UpRoi1 molecule may directly interact with the 5′ UTR of the phage antirepressor Roi mRNA as well as a bacterial transcript of the flgL gene encoding a protein associated with the structural unit of the bacterial flagellum. This affects both phage and host development, facilitating the switch of the phage to the lytic cycle. Besides, the RNA chaperone protein ProQ has been shown to bind the investigated sRNA with its target transcripts. Based on these results, we have found many similarities between UpRoi1 and herpesviral microRNAs, which is of high importance, because it justifies the occurrence of microRNA-type molecules in Shiga toxin-converting phages.
{"title":"UpRoi1 – the phage-derived microRNA-size non-coding RNA molecule regulating both phage and its bacterial host development","authors":"Sylwia Bloch , Natalia Lewandowska , Joanna Zwolenkiewicz-Nowak , Monika Mazur , Agnieszka Chylewska , Aleksandra M. Dąbrowska , Natalia Musiał , Paulina Czaplewska , Wojciech Wesołowski , Aleksandra Łukasiak , Mariusz Ferenc , Marcin Pietrzycki , Emilia Węglińska , Paulina Mach , Grzegorz Węgrzyn , Mikołaj Olejniczak , Bożena Nejman-Faleńczyk","doi":"10.1016/j.bbagrm.2026.195135","DOIUrl":"10.1016/j.bbagrm.2026.195135","url":null,"abstract":"<div><div>The phage Φ24<sub>B</sub>-encoded small RNA (sRNA), named UpRoi1, was identified following the prophage induction. The UpRoi1 molecule is encoded in the antirepressor region of the phage genome and is notably small, consisting of only 30 nucleotides. This sRNA is comparable in size to microRNAs found in eukaryotic cells, and thus, unusual for prokaryotic sRNAs. Bioinformatic analysis revealed that UpRoi1 has multiple interaction sites within the phage and host genomes, suggesting its complex regulatory role. In turn, RNA-seq analyses confirmed that the UpRoi1 molecule has a broad impact on the host's gene expression and influences numerous biological processes, particularly those involved in bacterial motility. Furthermore, binding assays revealed that the UpRoi1 molecule may directly interact with the 5′ UTR of the phage antirepressor Roi mRNA as well as a bacterial transcript of the <em>flgL</em> gene encoding a protein associated with the structural unit of the bacterial flagellum. This affects both phage and host development, facilitating the switch of the phage to the lytic cycle. Besides, the RNA chaperone protein ProQ has been shown to bind the investigated sRNA with its target transcripts. Based on these results, we have found many similarities between UpRoi1 and herpesviral microRNAs, which is of high importance, because it justifies the occurrence of microRNA-type molecules in Shiga toxin-converting phages.</div></div>","PeriodicalId":55382,"journal":{"name":"Biochimica et Biophysica Acta-Gene Regulatory Mechanisms","volume":"1869 1","pages":"Article 195135"},"PeriodicalIF":3.1,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145976535","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}
Pub Date : 2026-01-06DOI: 10.1016/j.bbagrm.2025.195134
Yasemin KALFA , Feyza Nur SAV , Meltem ALPER , Feray KOCKAR
Epigenetic silencing of ADAMTS-8 has been linked to increased tumor aggressiveness and poor prognosis; however, its transcriptional regulation in cancer remains largely undefined. Here, we comprehensively investigated the transcriptional regulation of ADAMTS-8 by SP1, which is associated with poor clinical outcomes in colorectal cancer (CRC). SP1 levels showed a marked upward trend in the clinical and molecular subtypes of CRC. Functional analyses demonstrated that SP1 overexpression in SW480 cells increased proliferation and migration; conversely, it significantly suppressed the ADAMTS-1 and ADAMTS-8 expressions. Furthermore, this suppressive effect was found to be reversible with Mitramycin A. Luciferase reporter assays confirmed the transcriptional repressive effect of SP1 on ADAMTS-8 promoter activity. ChIP-qPCR and EMSA demonstrated the specific binding of SP1 to the ADAMTS-8 promoter (−56/+17), indicating a direct regulatory mechanism. Clinical analyses revealed that ADAMTS-1 is significantly reduced in CRC, and low ADAMTS-1 levels are associated with poor survival. The regulatory relationship between SP1 and ADAMTS-8 was further examined in osteosarcoma, where SP1 expression was significantly elevated relative to osteoblasts, while ADAMTS-8 was markedly suppressed. The association of high ADAMTS-8 expression with better survival in the TCGA-SARC cohort supported its tumor-suppressive role in osteosarcoma. Consistently, qRT-PCR confirmed the inhibitory effect of SP1 on ADAMTS-8 in SAOS-2 cells.
Overall, our findings identify SP1 as a central negative regulator of ADAMTS-1 and ADAMTS-8, contributing to tumor progression in CRC and osteosarcoma. The SP1–ADAMTS axis represents a potentially important molecular network in cancer biology and may provide a basis for developing novel biomarkers or targeted therapeutic strategies.
{"title":"SP1 as a negative regulator of ADAMTS-8 in colorectal cancer: Evidence from functional and molecular analyses","authors":"Yasemin KALFA , Feyza Nur SAV , Meltem ALPER , Feray KOCKAR","doi":"10.1016/j.bbagrm.2025.195134","DOIUrl":"10.1016/j.bbagrm.2025.195134","url":null,"abstract":"<div><div>Epigenetic silencing of ADAMTS-8 has been linked to increased tumor aggressiveness and poor prognosis; however, its transcriptional regulation in cancer remains largely undefined. Here, we comprehensively investigated the transcriptional regulation of ADAMTS-8 by SP1, which is associated with poor clinical outcomes in colorectal cancer (CRC). SP1 levels showed a marked upward trend in the clinical and molecular subtypes of CRC. Functional analyses demonstrated that SP1 overexpression in SW480 cells increased proliferation and migration; conversely, it significantly suppressed the ADAMTS-1 and ADAMTS-8 expressions. Furthermore, this suppressive effect was found to be reversible with Mitramycin A. Luciferase reporter assays confirmed the transcriptional repressive effect of SP1 on ADAMTS-8 promoter activity. ChIP-qPCR and EMSA demonstrated the specific binding of SP1 to the ADAMTS-8 promoter (−56/+17), indicating a direct regulatory mechanism. Clinical analyses revealed that ADAMTS-1 is significantly reduced in CRC, and low ADAMTS-1 levels are associated with poor survival. The regulatory relationship between SP1 and ADAMTS-8 was further examined in osteosarcoma, where SP1 expression was significantly elevated relative to osteoblasts, while ADAMTS-8 was markedly suppressed. The association of high ADAMTS-8 expression with better survival in the TCGA-SARC cohort supported its tumor-suppressive role in osteosarcoma. Consistently, qRT-PCR confirmed the inhibitory effect of SP1 on ADAMTS-8 in SAOS-2 cells.</div><div>Overall, our findings identify SP1 as a central negative regulator of ADAMTS-1 and ADAMTS-8, contributing to tumor progression in CRC and osteosarcoma. The SP1–ADAMTS axis represents a potentially important molecular network in cancer biology and may provide a basis for developing novel biomarkers or targeted therapeutic strategies.</div></div>","PeriodicalId":55382,"journal":{"name":"Biochimica et Biophysica Acta-Gene Regulatory Mechanisms","volume":"1869 1","pages":"Article 195134"},"PeriodicalIF":3.1,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145936553","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}
Pub Date : 2025-12-16DOI: 10.1016/j.bbagrm.2025.195131
Eman A. Amr , Ola A. El-Feky , Nahla E. El-Ashmawy , Eman G. Khedr
Autophagy is a degradative process for recycling and breaking down cellular components, with several context-dependent functions in the development of tumors and resistance to therapy. Numerous clinical trials aiming to target autophagy in different tumors have been initiated as indicated by encouraging results from diverse preclinical investigations. Research on the connection between autophagosomes and the prognosis of different malignancies is now underway. The autophagy machinery itself may serve as a source of biomarkers for this purpose. Numerous research studies have established the association between autophagy-related genes (ATGs) and proteins (Atgs) in diverse types of cancer. Nonetheless, the outcomes of this association are still uncertain and the validation of reliable autophagy-related biomarkers is still lagging behind, owing to the paradoxical roles of autophagy in tumor biology and the scarcity of primary research studies. Herein, we explore recent developments, issues, and trends in the evaluation of clinically significant ATGs' and their encoded proteins' biomarker potential in human malignancies.
{"title":"Autophagy-related genes and encoded proteins' prognostic significance in various cancer types: A molecular perspective","authors":"Eman A. Amr , Ola A. El-Feky , Nahla E. El-Ashmawy , Eman G. Khedr","doi":"10.1016/j.bbagrm.2025.195131","DOIUrl":"10.1016/j.bbagrm.2025.195131","url":null,"abstract":"<div><div>Autophagy is a degradative process for recycling and breaking down cellular components, with several context-dependent functions in the development of tumors and resistance to therapy. Numerous clinical trials aiming to target autophagy in different tumors have been initiated as indicated by encouraging results from diverse preclinical investigations. Research on the connection between autophagosomes and the prognosis of different malignancies is now underway. The autophagy machinery itself may serve as a source of biomarkers for this purpose. Numerous research studies have established the association between autophagy-related genes (<em>ATG</em>s) and proteins (Atgs) in diverse types of cancer. Nonetheless, the outcomes of this association are still uncertain and the validation of reliable autophagy-related biomarkers is still lagging behind, owing to the paradoxical roles of autophagy in tumor biology and the scarcity of primary research studies. Herein, we explore recent developments, issues, and trends in the evaluation of clinically significant <em>ATGs'</em> and their encoded proteins' biomarker potential in human malignancies.</div></div>","PeriodicalId":55382,"journal":{"name":"Biochimica et Biophysica Acta-Gene Regulatory Mechanisms","volume":"1869 1","pages":"Article 195131"},"PeriodicalIF":3.1,"publicationDate":"2025-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145783781","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}
Pub Date : 2025-12-15DOI: 10.1016/j.bbagrm.2025.195133
Zulvikar Syambani Ulhaq , Mitsuyo Kishida
Aromatase is a key enzyme in estrogen biosynthesis, expressed in multiple tissues including the brain and retina. In teleost fish, Aromatase B (AroB), encoded by cyp19a1b, is brain-specific and highly expressed during early development, suggesting a role in neurogenesis. Here, we investigated the role of AroB in zebrafish eye development using morpholino (MO)-mediated knockdown. Injection of AroB MO into fertilized eggs reduced eye size (eye-to-body length ratio), decreased optic nerve diameter at 48 h post-fertilization (hpf), and increased apoptosis in the eye at 24 hpf. These defects were rescued by co-injection of AroB mRNA or treatment with 1 μM 17β-estradiol (E2). Functional assays revealed impaired visual background adaptation (VBA) at 5 days post-fertilization (dpf) and defective optomotor response (OMR) at 7 dpf in AroB morphants. Immunostaining with AroB antiserum confirmed a reduction in retinal AroB expression in knockdown larvae. To assess the role of estrogen receptors (ERs), embryos were exposed to selective antagonists. The ERα antagonist MPP had no effect on eye size, optic nerve diameter, or apoptosis. In contrast, the ERβ antagonist CYC reduced eye size and optic nerve diameter, while increasing apoptosis. The non-selective ER antagonist ICI also reduced eye size and elevated apoptosis, though it did not alter optic nerve diameter. Behaviorally, VBA was reduced by ICI and CYC, but not MPP; OMR was diminished by ICI and MPP, but unaffected by CYC. Together, these findings demonstrate that estrogen produced in the retina by AroB plays a critical role in zebrafish eye development, with its functions differentially mediated by distinct ER subtypes.
{"title":"Estrogen produced in the retina by brain aromatase plays a significant role in zebrafish eye development","authors":"Zulvikar Syambani Ulhaq , Mitsuyo Kishida","doi":"10.1016/j.bbagrm.2025.195133","DOIUrl":"10.1016/j.bbagrm.2025.195133","url":null,"abstract":"<div><div>Aromatase is a key enzyme in estrogen biosynthesis, expressed in multiple tissues including the brain and retina. In teleost fish, Aromatase B (AroB), encoded by <em>cyp19a1b</em>, is brain-specific and highly expressed during early development, suggesting a role in neurogenesis. Here, we investigated the role of AroB in zebrafish eye development using morpholino (MO)-mediated knockdown. Injection of AroB MO into fertilized eggs reduced eye size (eye-to-body length ratio), decreased optic nerve diameter at 48 h post-fertilization (hpf), and increased apoptosis in the eye at 24 hpf. These defects were rescued by co-injection of AroB mRNA or treatment with 1 μM 17β-estradiol (E<sub>2</sub>). Functional assays revealed impaired visual background adaptation (VBA) at 5 days post-fertilization (dpf) and defective optomotor response (OMR) at 7 dpf in AroB morphants. Immunostaining with AroB antiserum confirmed a reduction in retinal AroB expression in knockdown larvae. To assess the role of estrogen receptors (ERs), embryos were exposed to selective antagonists. The ERα antagonist MPP had no effect on eye size, optic nerve diameter, or apoptosis. In contrast, the ERβ antagonist CYC reduced eye size and optic nerve diameter, while increasing apoptosis. The non-selective ER antagonist ICI also reduced eye size and elevated apoptosis, though it did not alter optic nerve diameter. Behaviorally, VBA was reduced by ICI and CYC, but not MPP; OMR was diminished by ICI and MPP, but unaffected by CYC. Together, these findings demonstrate that estrogen produced in the retina by AroB plays a critical role in zebrafish eye development, with its functions differentially mediated by distinct ER subtypes.</div></div>","PeriodicalId":55382,"journal":{"name":"Biochimica et Biophysica Acta-Gene Regulatory Mechanisms","volume":"1869 1","pages":"Article 195133"},"PeriodicalIF":3.1,"publicationDate":"2025-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145776631","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}
Pub Date : 2025-12-15DOI: 10.1016/j.bbagrm.2025.195132
Xin-Rong Du , Yan Gao , Qin Zeng , Guo-Hui Zhang , Wei-Xin Liu
Post-translational modifications (PTMs) play a pivotal role in understanding male reproductive function, with an increasing number of PTMs being demonstrated to be associated with spermatogenesis and sperm function. The advancement of high-throughput molecular tools and the accumulation of bioinformatics data have significantly accelerated the discovery of novel PTMs. In this review, we highlight several newly identified PTMs, these modifications participate in spermatogenesis, sperm maturation, sperm motility in the female reproductive tract, capacitation, fertilization, as well as the regulation of Sertoli cell and epididymal functions. Furthermore, we discuss their involvement in the pathogenesis of various conditions, including asthenozoospermia, erectile dysfunction, and even testicular and prostate cancers, while exploring their potential clinical applications as therapeutic targets and biomarkers. Additionally, we provide insights into the cooperative or competitive interactions among different types of PTMs. A comprehensive understanding of PTM-mediated regulatory mechanisms in the male reproductive system will pave the way for developing novel and specific therapeutic strategies to treat male reproductive disorders. A systematic literature search was performed in PubMed, MEDLINE, EMBASE, and Web of Science Core Collection for studies published up to September 2025, using a combination of the term “male Reproductive System, sperm, fertilization, capacitation, disease” with keywords related to post-translational modifications, Eligible studies were limited to English-language publications that specifically examined the interaction between Male Reproductive System and novel PTMs, including “S-nitrosylation”, “crotonylation”, “2-hydroxyisobutyrylation”, “lactylation”, “polysialylation”, “myristoylation” and “SUMOylation”, including both original research and review articles. This review did not involve formal statistical analysis or meta-analytic techniques.
{"title":"Roles of novel post-translational modifications in the male reproductive system: From regulation of reproductive development to therapeutic potential","authors":"Xin-Rong Du , Yan Gao , Qin Zeng , Guo-Hui Zhang , Wei-Xin Liu","doi":"10.1016/j.bbagrm.2025.195132","DOIUrl":"10.1016/j.bbagrm.2025.195132","url":null,"abstract":"<div><div>Post-translational modifications (PTMs) play a pivotal role in understanding male reproductive function, with an increasing number of PTMs being demonstrated to be associated with spermatogenesis and sperm function. The advancement of high-throughput molecular tools and the accumulation of bioinformatics data have significantly accelerated the discovery of novel PTMs. In this review, we highlight several newly identified PTMs, these modifications participate in spermatogenesis, sperm maturation, sperm motility in the female reproductive tract, capacitation, fertilization, as well as the regulation of Sertoli cell and epididymal functions. Furthermore, we discuss their involvement in the pathogenesis of various conditions, including asthenozoospermia, erectile dysfunction, and even testicular and prostate cancers, while exploring their potential clinical applications as therapeutic targets and biomarkers. Additionally, we provide insights into the cooperative or competitive interactions among different types of PTMs. A comprehensive understanding of PTM-mediated regulatory mechanisms in the male reproductive system will pave the way for developing novel and specific therapeutic strategies to treat male reproductive disorders. A systematic literature search was performed in PubMed, MEDLINE, EMBASE, and Web of Science Core Collection for studies published up to September 2025, using a combination of the term “male Reproductive System, sperm, fertilization, capacitation, disease” with keywords related to post-translational modifications, Eligible studies were limited to English-language publications that specifically examined the interaction between Male Reproductive System and novel PTMs, including “S-nitrosylation”, “crotonylation”, “2-hydroxyisobutyrylation”, “lactylation”, “polysialylation”, “myristoylation” and “SUMOylation”, including both original research and review articles. This review did not involve formal statistical analysis or meta-analytic techniques.</div></div>","PeriodicalId":55382,"journal":{"name":"Biochimica et Biophysica Acta-Gene Regulatory Mechanisms","volume":"1869 1","pages":"Article 195132"},"PeriodicalIF":3.1,"publicationDate":"2025-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145776636","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}
Pub Date : 2025-11-23DOI: 10.1016/j.bbagrm.2025.195122
Linghuo Jiang , Liudan Wei , Yiying Gu , Peigen Jiang , Nathan Snyder , Xiufan Liao , Yiping Mo , Lingxin Pan , Chunyu Wei , Kyle W. Cunningham
Cmk2 is a homolog of mammalian calcium/calmodulin-dependent protein kinase II (CaMKII), and functions as a negative regulator of calcium signaling in yeast cells. Transcription of CMK2 gene is controlled by the zinc finger transcription factor Crz1 via a CDRE motif in the promoter. In this study, we have characterized the protein expression and phosphorylation of Cmk2. Purified Cmk2 proteins from yeast cells undergo autophosphorylation. Two forms of Cmk2 proteins, the slow-migrating (SM-Cmk2) and the fast-migrating (FM-Cmk2), were detected in response of yeast cells to calcium stress. In the absence of calcium stress, Cmk2 appears to be mainly in the form of SM-Cmk2. Deletion of CNB1 delays the calcium-induction of both forms, but only reduces the level of the calcium-induced FM-Cmk2. An extracellular calcium concentration of 200 mM results in maximal induction of both forms of Cmk2. Therefore, in addition to calcium/calcineurin signaling, expression of Cmk2 protein is controlled by additional factor(s). Furthermore, our mutational analysis indicates that the K76 residue of Cmk2 is required for the calcium-induction and steady-state expression levels of both FM-Cmk2 and SM-Cmk2. The S317 residue, the counterpart of the O-linked glycosylation site S279 in mammalian CaMKII, is also responsible for the calcium-induction of SM-Cmk2.
{"title":"Expression of two forms of the calcium/calmodulin-dependent protein kinase Cmk2 is differentially regulated in response to calcium stress in budding yeast","authors":"Linghuo Jiang , Liudan Wei , Yiying Gu , Peigen Jiang , Nathan Snyder , Xiufan Liao , Yiping Mo , Lingxin Pan , Chunyu Wei , Kyle W. Cunningham","doi":"10.1016/j.bbagrm.2025.195122","DOIUrl":"10.1016/j.bbagrm.2025.195122","url":null,"abstract":"<div><div>Cmk2 is a homolog of mammalian calcium/calmodulin-dependent protein kinase II (CaMKII), and functions as a negative regulator of calcium signaling in yeast cells. Transcription of <em>CMK2</em> gene is controlled by the zinc finger transcription factor Crz1 via a CDRE motif in the promoter. In this study, we have characterized the protein expression and phosphorylation of Cmk2. Purified Cmk2 proteins from yeast cells undergo autophosphorylation. Two forms of Cmk2 proteins, the <u>s</u>low-<u>m</u>igrating (SM-Cmk2) and the <u>f</u>ast-<u>m</u>igrating (FM-Cmk2), were detected in response of yeast cells to calcium stress. In the absence of calcium stress, Cmk2 appears to be mainly in the form of SM-Cmk2. Deletion of <em>CNB1</em> delays the calcium-induction of both forms, but only reduces the level of the calcium-induced FM-Cmk2. An extracellular calcium concentration of 200 mM results in maximal induction of both forms of Cmk2. Therefore, in addition to calcium/calcineurin signaling, expression of Cmk2 protein is controlled by additional factor(s). Furthermore, our mutational analysis indicates that the K76 residue of Cmk2 is required for the calcium-induction and steady-state expression levels of both FM-Cmk2 and SM-Cmk2. The S317 residue, the counterpart of the O-linked glycosylation site S279 in mammalian CaMKII, is also responsible for the calcium-induction of SM-Cmk2.</div></div>","PeriodicalId":55382,"journal":{"name":"Biochimica et Biophysica Acta-Gene Regulatory Mechanisms","volume":"1869 1","pages":"Article 195122"},"PeriodicalIF":3.1,"publicationDate":"2025-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145594782","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}
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