Biochimica et Biophysica Acta-Gene Regulatory Mechanisms最新文献

{"title":"Isolation and characterisation of promoters from mouse genome to drive post-meiotic germ cell-specific robust gene expression for functional genomics studies","authors":"Abhishek Das ,&nbsp;Srimoyee Koner ,&nbsp;Subeer S. Majumdar ,&nbsp;Nirmalya Ganguli","doi":"10.1016/j.bbagrm.2023.194994","DOIUrl":"10.1016/j.bbagrm.2023.194994","url":null,"abstract":"<div><p><span>The generation of spermatozoa from developing germ cells through mitotic and meiotic divisions is a highly regulated and complex process. Any defect in this process, may lead to subfertility/infertility. The role of different transcripts (mRNA/miRNA/lncRNA) in regulation of the pre-meiotic, meiotic, and post-meiotic stages of spermatogenesis<span> are being proposed based on various multiomics based approaches. Such differential gene-expression is regulated by promoter elements that are activated in a stage specific manner. To determine the role of these differentially expressed transcripts in the process of meiosis, a robust post-meiotic germ cell specific promoter is required. In the present study, we have isolated and characterized the expression of the mouse Proacrosin, SP10, and ELP<span> promoters for driving post-meiotic germ cell specific gene-expression. Promoter regions of all these 3 genes were isolated and cloned to generate mammalian expression vector. The transgene expression in post-meiotic germ cells was assessed in mice using the testicular electroporation method </span></span></span><em>in vitro</em> as well as <em>in vivo</em><span>, using above promoters. It was also validated in goat seminiferous tubules, </span><em>in vitro</em>. We have also carried out a comparative analysis of the strength of these promoters to confirm their robustness that indicated Proacrosin to be the most robust promoter that can be useful for diving post-meiotic germ cells specific gene-expression. These promoters can be used to alter gene-expression specifically in post-meiotic germ cells for deciphering the role(s) of germ cell genes in spermatogenic progression or for expressing various genome editing tools for engineering the germ cell genome to understand basis of subfertility/infertility.</p></div>","PeriodicalId":55382,"journal":{"name":"Biochimica et Biophysica Acta-Gene Regulatory Mechanisms","volume":"1867 1","pages":"Article 194994"},"PeriodicalIF":4.7,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"92157398","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}

{"title":"N/C-degron pathways and inhibitor development for PROTAC applications","authors":"Zhibin Wu,&nbsp;Yunyuan Huang,&nbsp;Ke Liu,&nbsp;Jinrong Min","doi":"10.1016/j.bbagrm.2023.194952","DOIUrl":"10.1016/j.bbagrm.2023.194952","url":null,"abstract":"<div><p>Ubiquitination is a fascinating post-translational modification that has received continuous attention since its discovery. In this review, we first provide a concise overview of the E3 ubiquitin ligases, delving into classification, characteristics and mechanisms of ubiquitination. We then specifically examine the ubiquitination pathways mediated by the N/C-degrons, discussing their unique features and substrate recognition mechanisms. Finally, we offer insights into the current state of development pertaining to inhibitors that target the N/C-degron pathways, as well as the promising advances in the field of PROTAC (PROteolysis TArgeting Chimeras). Overall, this review offers a comprehensive understanding of the rapidly-evolving field of ubiquitin biology.</p></div>","PeriodicalId":55382,"journal":{"name":"Biochimica et Biophysica Acta-Gene Regulatory Mechanisms","volume":"1867 1","pages":"Article 194952"},"PeriodicalIF":4.7,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10247291","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}

{"title":"The functions of FOXP transcription factors and their regulation by post-translational modifications","authors":"Congwen Gao ,&nbsp;Honglin Zhu ,&nbsp;Peng Gong ,&nbsp;Chen Wu ,&nbsp;Xingzhi Xu ,&nbsp;Xuefei Zhu","doi":"10.1016/j.bbagrm.2023.194992","DOIUrl":"10.1016/j.bbagrm.2023.194992","url":null,"abstract":"<div><p><span><span>The forkhead box subfamily P (FOXP) of transcription factors, consisting of FOXP1, </span>FOXP2, </span>FOXP3<span><span>, and FOXP4, is involved in the regulation of multisystemic functioning. Disruption of the transcriptional activity of FOXP proteins leads to neurodevelopmental disorders and immunological diseases, as well as the suppression or promotion of carcinogenesis. The transcriptional activities of FOXP proteins are directly or indirectly regulated by diverse post-translational modifications, including phosphorylation, ubiquitination, </span>SUMOylation<span><span>, acetylation, O-GlcNAcylation, and </span>methylation. Here, we discuss how post-translational modifications modulate the multiple functions of FOXP proteins and examine the implications for tumorigenesis and cancer therapy.</span></span></p></div>","PeriodicalId":55382,"journal":{"name":"Biochimica et Biophysica Acta-Gene Regulatory Mechanisms","volume":"1866 4","pages":"Article 194992"},"PeriodicalIF":4.7,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41156288","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}

{"title":"ETS2 overexpression ameliorates cartilage injury in osteoarthritis by the ETS2/miR-155/STAT1/DNMT1 feedback loop pathway","authors":"Shuxiang Chen ,&nbsp;Xiaotong Zhu ,&nbsp;Wenhuan Ou ,&nbsp;Le Kang ,&nbsp;Jian Situ ,&nbsp;Zhipeng Liao ,&nbsp;Li Huang ,&nbsp;Weizhong Qi ,&nbsp;Songjia Ni","doi":"10.1016/j.bbagrm.2023.194965","DOIUrl":"10.1016/j.bbagrm.2023.194965","url":null,"abstract":"<div><p><span><span><span>Osteoarthritis (OA) is the most common irreversible chronic joint dysfunction disease, which is pathologically characterized by disturbance of articular cartilage homeostasis leading to subsequent inflammatory response and cartilage extracellular matrix (ECM) degradation. Increasing evidence has demonstrated the dysregulation of transcription factors play crucial roles in the occurrence and development of osteoarthritis (OA), but the potential functions and mechanism of most transcription factors in OA has not been completely illuminated. In this study, we identified that transcription factor V-ets erythroblastosis virus E26 </span>oncogene homolog 2 (ETS2) was significantly down-regulated in OA cartilage and IL-1β-induced OA </span>chondrocytes<span>. Functional experiments in vitro demonstrated that the overexpressed ETS2 strikingly enhanced proliferation, outstandingly suppressed apoptosis, and dramatically reduced inflammation and ECM degradation in IL-1β-induced OA chondrocytes, whereas the knockdown of ETS2 led to the opposite effects. Further in vivo studies<span> have shown that up-regulated ETS2 dramatically ameliorates cartilage injury in DMM-induced OA mice. Mechanical studies have disclosed that DNMT1-mediated downregulation of ETS2 dramatically promotes STAT1 by inhibiting miR-155 transcription, and increased STAT1 initiates a feedback loop that may enhance DNMT1-mediated hypermethylation of ETS2 to inhibit ETS2 expression, thus forming a DNMT1/ETS2/miR-155/STAT1 feedback loop that inhibits MAPK </span></span></span>signaling pathways and aggravates OA cartilage injury. In all, our results revealed that overexpression of ETS2 markedly ameliorated OA cartilage injury through the ETS2/miR-155/STAT1/DNMT1 feedback loop, providing a new perspective on the pathogenesis and therapeutic strategies for OA.</p></div>","PeriodicalId":55382,"journal":{"name":"Biochimica et Biophysica Acta-Gene Regulatory Mechanisms","volume":"1866 4","pages":"Article 194965"},"PeriodicalIF":4.7,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10386661","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}

{"title":"Protein post-translational modifications: A key factor in colorectal cancer resistance mechanisms","authors":"Bo Bi ,&nbsp;Miaojuan Qiu ,&nbsp;Peng Liu ,&nbsp;Qiang Wang ,&nbsp;Yingfei Wen ,&nbsp;You Li ,&nbsp;Binbin Li ,&nbsp;Yongshu Li ,&nbsp;Yulong He ,&nbsp;Jing Zhao","doi":"10.1016/j.bbagrm.2023.194977","DOIUrl":"10.1016/j.bbagrm.2023.194977","url":null,"abstract":"<div><p>Colorectal cancer (CRC) is one of the leading causes of cancer-related death. Despite advances in treatment, drug resistance remains a critical impediment. Post-translational modifications (PTMs) regulate protein stability, localization, and activity, impacting vital cellular processes. Recent research has highlighted the essential role of PTMs in the development of CRC resistance. This review summarizes recent advancements in understanding PTMs' roles in CRC resistance, focusing on the latest discoveries. We discuss the functional impact of PTMs on signaling pathways and molecules involved in CRC resistance, progress in drug development, and potential therapeutic targets. We also summarize the primary enrichment methods for PTMs. Finally, we discuss current challenges and future directions, including the need for more comprehensive PTM analysis methods and PTM-targeted therapies. This review identifies potential therapeutic interventions for addressing medication resistance in CRC, proposes prospective therapeutic options, and gives an overview of the function of PTMs in CRC resistance.</p></div>","PeriodicalId":55382,"journal":{"name":"Biochimica et Biophysica Acta-Gene Regulatory Mechanisms","volume":"1866 4","pages":"Article 194977"},"PeriodicalIF":4.7,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10494009","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}

{"title":"Post-translational modifications of lysine-specific demethylase 1","authors":"Dongha Kim ,&nbsp;Hye Jin Nam ,&nbsp;Sung Hee Baek","doi":"10.1016/j.bbagrm.2023.194968","DOIUrl":"10.1016/j.bbagrm.2023.194968","url":null,"abstract":"<div><p>Lysine-specific demethylase 1 (LSD1) is crucial for regulating gene expression by catalyzing the demethylation of mono- and di-methylated histone H3 lysine 4 (H3K4) and lysine 9 (H3K9) and non-histone proteins through the amine oxidase activity with FAD⁺ as a cofactor. It interacts with several protein partners, which potentially contributes to its diverse substrate specificity. Given its pivotal role in numerous physiological and pathological conditions, the function of LSD1 is closely regulated by diverse post-translational modifications (PTMs), including phosphorylation, ubiquitination, methylation, and acetylation. In this review, we aim to provide a comprehensive understanding of the regulation and function of LSD1 following various PTMs. Specifically, we will focus on the impact of PTMs on LSD1 function in physiological and pathological contexts and discuss the potential therapeutic implications of targeting these modifications for the treatment of human diseases.</p></div>","PeriodicalId":55382,"journal":{"name":"Biochimica et Biophysica Acta-Gene Regulatory Mechanisms","volume":"1866 4","pages":"Article 194968"},"PeriodicalIF":4.7,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10082073","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}

{"title":"The versatility of the proteasome in gene expression and silencing: Unraveling proteolytic and non-proteolytic functions","authors":"Hyesu Lee ,&nbsp;Sungwook Kim ,&nbsp;Daeyoup Lee","doi":"10.1016/j.bbagrm.2023.194978","DOIUrl":"10.1016/j.bbagrm.2023.194978","url":null,"abstract":"<div><p><span>The 26S proteasome consists of a 20S core particle and a 19S regulatory particle and critically regulates gene expression and silencing through both proteolytic and non-proteolytic functions. The 20S core particle mediates </span>proteolysis<span><span>, while the 19S regulatory particle performs non-proteolytic functions. The proteasome plays a role in regulating gene expression in euchromatin<span> by modifying histones, activating transcription, initiating and terminating transcription, mRNA export, and maintaining </span></span>transcriptome<span><span> integrity. In gene silencing, the proteasome modulates the heterochromatin formation, spreading, and </span>subtelomere silencing by degrading specific proteins and interacting with anti-silencing factors such as Epe1, Mst2, and Leo1. This review discusses the proteolytic and non-proteolytic functions of the proteasome in regulating gene expression and gene silencing-related heterochromatin formation. This article is part of a special issue on the regulation of gene expression and genome integrity by the ubiquitin-proteasome system.</span></span></p></div>","PeriodicalId":55382,"journal":{"name":"Biochimica et Biophysica Acta-Gene Regulatory Mechanisms","volume":"1866 4","pages":"Article 194978"},"PeriodicalIF":4.7,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10118733","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}

{"title":"Role of clusterin gene 3’-UTR polymorphisms and promoter hypomethylation in the pathogenesis of pseudoexfoliation syndrome and pseudoexfoliation glaucoma","authors":"Ramani Shyam Kapuganti ,&nbsp;Lipsa Sahoo ,&nbsp;Pranjya Paramita Mohanty ,&nbsp;Bushra Hayat ,&nbsp;Sucheta Parija ,&nbsp;Debasmita Pankaj Alone","doi":"10.1016/j.bbagrm.2023.194980","DOIUrl":"10.1016/j.bbagrm.2023.194980","url":null,"abstract":"<div><p><span><span>Pseudoexfoliation (PEX) is a multifactorial age-related disease characterized by the deposition of extracellular fibrillar aggregates in the anterior ocular tissues. This study aims to identify the genetic<span> and epigenetic contribution of </span></span>clusterin<span> (CLU) in PEX pathology. CLU is a molecular chaperone upregulated in PEX and genetically associated with the disease. Sequencing of a 2.9 kb region encompassing the previously associated rs2279590 in 250 control and 313 PEX [(207 pseudoexfoliation syndrome (PEXS) and 106 pseudoexfoliation glaucoma (PEXG)] individuals identified three single nucleotide polymorphisms (SNPs), rs9331942, rs9331949 and rs9331950, in the 3’-UTR of </span></span><em>CLU</em><span> of which rs9331942 and rs9331949 were found to be significantly associated with PEXS and PEXG as risk factors. Following in silico analysis, in vitro luciferase<span> reporter assays in human embryonic kidney cells revealed that risk alleles at rs9331942 and rs9331949 bind to miR-223 and miR-1283, respectively, suggesting differential regulation of clusterin in the presence of risk alleles at the SNPs. Further, through bisulfite sequencing, we also identified that </span></span><em>CLU</em><span><span> promoter is hypomethylated in DNA from blood and lens capsules of PEX patients compared to controls that correlated with decreased expression of </span>DNA methyltransferase<span> 1 (DNMT1). Promoter demethylation of </span></span><em>CLU</em> using DNMT inhibitor, 5′-aza-dC, in human lens epithelial cells increased CLU expression. Chromatin immunoprecipitation assays showed that the demethylated <em>CLU</em> promoter provides increased access to the transcription factor, Sp1, which might lead to enhanced expression of CLU. In conclusion, this study highlights the different molecular mechanisms of clusterin regulation in pseudoexfoliation pathology.</p></div>","PeriodicalId":55382,"journal":{"name":"Biochimica et Biophysica Acta-Gene Regulatory Mechanisms","volume":"1866 4","pages":"Article 194980"},"PeriodicalIF":4.7,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10235128","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}

{"title":"N6-methyladenosine (m6A) methylation in kidney diseases: Mechanisms and therapeutic potential","authors":"Yuting Sun ,&nbsp;De Jin ,&nbsp;Ziwei Zhang ,&nbsp;Hangyu Ji ,&nbsp;Xuedong An ,&nbsp;Yuehong Zhang ,&nbsp;Cunqing Yang ,&nbsp;Wenjie Sun ,&nbsp;Yuqing Zhang ,&nbsp;Yingying Duan ,&nbsp;Xiaomin Kang ,&nbsp;Linlin Jiang ,&nbsp;Xuefei Zhao ,&nbsp;Fengmei Lian","doi":"10.1016/j.bbagrm.2023.194967","DOIUrl":"10.1016/j.bbagrm.2023.194967","url":null,"abstract":"<div><p>The N6-methyladenosine (m6A) modification is regulated by methylases, commonly referred to as “writers,” and demethylases, known as “erasers,” leading to a dynamic and reversible process. Changes in m6A levels have been implicated in a wide range of cellular processes, including nuclear RNA export, mRNA metabolism, protein translation, and RNA splicing, establishing a strong correlation with various diseases. Both physiologically and pathologically, m6A methylation plays a critical role in the initiation and progression of kidney disease. The methylation of m6A may also facilitate the early diagnosis and treatment of kidney diseases, according to accumulating research. This review aims to provide a comprehensive overview of the potential role and mechanism of m6A methylation in kidney diseases, as well as its potential application in the treatment of such diseases. There will be a thorough examination of m6A methylation mechanisms, paying particular attention to the interplay between m6A writers, m6A erasers, and m6A readers. Furthermore, this paper will elucidate the interplay between various kidney diseases and m6A methylation, summarize the expression patterns of m6A in pathological kidney tissues, and discuss the potential therapeutic benefits of targeting m6A in the context of kidney diseases.</p></div>","PeriodicalId":55382,"journal":{"name":"Biochimica et Biophysica Acta-Gene Regulatory Mechanisms","volume":"1866 4","pages":"Article 194967"},"PeriodicalIF":4.7,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9993758","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}

{"title":"The mechanism of UP1 binding and unfolding of human telomeric DNA G-quadruplex","authors":"Xiaobin Ling ,&nbsp;Yuqi Yao ,&nbsp;Lei Ding ,&nbsp;Jinbiao Ma","doi":"10.1016/j.bbagrm.2023.194985","DOIUrl":"10.1016/j.bbagrm.2023.194985","url":null,"abstract":"<div><p><span><span><span>The human telomere contains multiple copies of the </span>DNA sequence d(TTAGGG) which can fold into higher order intramolecular G-quadruplexes and regulate the maintenance of </span>telomere length<span><span> and chromosomal integrity. The nucleic acid binding protein heteronuclear </span>ribonucleoprotein<span> A1 (hnRNP A1) and its N-terminus proteolytic product UP1 have been shown to efficiently bind and unfold telomeric DNA G-quadruplex. However, the understanding of the molecular mechanism of the UP1 binding and unfolding telomeric G-quadruplexes is still limited. Here, we performed biochemical and biophysical characterizations of UP1 binding and unfolding of human telomeric DNA G-quadruplex d[AGGG(TTAGGG)</span></span></span>₃<span><span><span><span>], and in combination of systematic site-direct mutagenesis of two tandem </span>RNA recognition motifs<span> (RRMs) in UP1, revealed that RRM1 is responsible for initial binding and unfolding, whereas </span></span>RRM2<span> assists RRM1 to complete the unfolding of G-quadruplex. Isothermal titration calorimetry (ITC) and </span></span>circular dichroism (CD) studies of the interactions between UP1 and DNA G-quadruplex variants indicate that the “TAG” binding motif in Loop2 of telomeric G-quadruplex is critical for UP1 recognition and G-quadruplex unfolding initiation. Together we depict a model for molecular mechanism of hnRNP A1 (UP1) binding and unfolding of the human telomeric DNA G-quadruplex.</span></p></div>","PeriodicalId":55382,"journal":{"name":"Biochimica et Biophysica Acta-Gene Regulatory Mechanisms","volume":"1866 4","pages":"Article 194985"},"PeriodicalIF":4.7,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10634108","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}