Biochimica et Biophysica Acta-Gene Regulatory Mechanisms最新文献

{"title":"Allelic variation within the major APOE CpG island affects its methylation in the brain of targeted replacement mice expressing human APOE","authors":"Johanna Rueter,&nbsp;Gerald Rimbach,&nbsp;Patricia Huebbe","doi":"10.1016/j.bbagrm.2023.194942","DOIUrl":"10.1016/j.bbagrm.2023.194942","url":null,"abstract":"<div><p></p><ul><li><span>•</span><span><p><span>The number of cytosine-phosphate-guanine (CpG) sites differs due to sequence variation in the human apolipoprotein E (</span><em>APOE</em>) gene.</p></span></li><li><span>•</span><span><p><em>APOE</em> DNA methylation is allele-dependently altered corresponding to the total number of CpG pairs in the brain of APOE targeted replacement mice (<em>APOE εpsilon 4</em> &gt; <em>εpsilon 3</em> &gt; <em>εpsilon 2</em>).</p></span></li><li><span>•</span><span><p>Binding of the methyl-CpG binding protein 2 to genomic <em>APOE</em> was in trend less pronounced in the brain of APOE4 mice.</p></span></li></ul></div>","PeriodicalId":55382,"journal":{"name":"Biochimica et Biophysica Acta-Gene Regulatory Mechanisms","volume":"1866 3","pages":"Article 194942"},"PeriodicalIF":4.7,"publicationDate":"2023-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10036791","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":"A novel endoplasmic reticulum adaptation is critical for the long-lived Caenorhabditis elegans rpn-10 proteasomal mutant","authors":"Meghna N. Chinchankar ,&nbsp;William B. Taylor ,&nbsp;Su-Hyuk Ko ,&nbsp;Ellen C. Apple ,&nbsp;Karl A. Rodriguez ,&nbsp;Lizhen Chen ,&nbsp;Alfred L. Fisher","doi":"10.1016/j.bbagrm.2023.194957","DOIUrl":"10.1016/j.bbagrm.2023.194957","url":null,"abstract":"<div><p><span><span>The loss of proteostasis due to reduced efficiency of </span>protein degradation pathways plays a key role in multiple age-related diseases and is a hallmark of the aging process. Paradoxically, we have previously reported that the </span><span><em>Caenorhabditis elegans</em><em> rpn-10(ok1865)</em></span><span> mutant, which lacks the RPN-10/RPN10/PSMD4 subunit of the 19S regulatory particle of the 26S proteasome<span>, exhibits enhanced cytosolic proteostasis, elevated stress resistance and extended lifespan, despite possessing reduced proteasome function. However, the response of this mutant against threats to endoplasmic reticulum (ER) homeostasis and proteostasis was unknown. Here, we find that the </span></span><em>rpn-10</em><span> mutant is highly ER stress<span> resistant compared to the wildtype. Under unstressed conditions, the ER unfolded protein response (UPR) is activated in the </span></span><em>rpn-10</em> mutant as signified by increased <em>xbp-1</em> splicing. This primed response appears to alter ER homeostasis through the upregulated expression of genes involved in ER protein quality control (ERQC), including those in the ER-associated protein degradation (ERAD) pathway. Pertinently, we find that ERQC is critical for the <em>rpn-10</em> mutant longevity. These changes also alter ER proteostasis, as studied using the <em>C. elegans</em><span> alpha-1 antitrypsin (AAT) deficiency model, which comprises an intestinal ER-localised transgenic reporter of an aggregation-prone form of AAT called ATZ. The </span><em>rpn-10</em> mutant shows a significant reduction in the accumulation of the ATZ reporter, thus indicating that its ER proteostasis is augmented. Via a genetic screen for suppressors of decreased ATZ aggregation in the <em>rpn-10</em> mutant, we then identified <em>ecps-2/H04D03.3</em><span>, a novel ortholog of the proteasome-associated adaptor and scaffold protein ECM29/ECPAS. We further show that </span><em>ecps-2</em> is required for improved ER proteostasis as well as lifespan extension of the <em>rpn-10</em> mutant. Thus, we propose that ECPS-2-proteasome functional interactions, alongside additional putative molecular processes, contribute to a novel ERQC adaptation which underlies the superior proteostasis and longevity of the <em>rpn-10</em> mutant.</p></div>","PeriodicalId":55382,"journal":{"name":"Biochimica et Biophysica Acta-Gene Regulatory Mechanisms","volume":"1866 3","pages":"Article 194957"},"PeriodicalIF":4.7,"publicationDate":"2023-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10528105/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10198101","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The fine-tuned crosstalk between lysine acetylation and the circadian rhythm","authors":"Honglv Jiang ,&nbsp;Xiaohui Wang ,&nbsp;Jingjing Ma ,&nbsp;Guoqiang Xu","doi":"10.1016/j.bbagrm.2023.194958","DOIUrl":"10.1016/j.bbagrm.2023.194958","url":null,"abstract":"<div><p><span><span>Circadian rhythm is a roughly 24-h wake and sleep cycle that almost all of the organisms on the earth follow when they execute their biological functions and physiological activities. The circadian clock is mainly regulated by the transcription-translation feedback loop (TTFL), consisting of the core clock proteins, including BMAL1, CLOCK, PERs, CRYs, and a series of accessory factors. The circadian clock and the downstream gene expression are not only controlled at the transcriptional and translational levels but also precisely regulated at the post-translational modification level. Recently, it has been discovered that CLOCK exhibits lysine acetyltransferase activities and could acetylate protein substrates. Core clock proteins are also acetylated, thereby altering their biological functions in the regulation of the expression of downstream genes. Studies have revealed that many </span>protein acetylation<span> events exhibit oscillation behavior. However, the biological function of acetylation on circadian rhythm has only begun to explore. This review will briefly introduce the acetylation and </span></span>deacetylation of the core clock proteins and summarize the proteins whose acetylation is regulated by CLOCK and circadian rhythm. Then, we will also discuss the crosstalk between lysine acetylation and the circadian clock or other post-translational modifications. Finally, we will briefly describe the possible future perspectives in the field.</p></div>","PeriodicalId":55382,"journal":{"name":"Biochimica et Biophysica Acta-Gene Regulatory Mechanisms","volume":"1866 3","pages":"Article 194958"},"PeriodicalIF":4.7,"publicationDate":"2023-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10412446","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":"Effect of CDK7 inhibitor on MYCN-amplified retinoblastoma","authors":"Hanyue Xu ,&nbsp;Lirong Xiao ,&nbsp;Yi Chen ,&nbsp;Yilin Liu ,&nbsp;Yifan Zhang ,&nbsp;Yuzhu Gao ,&nbsp;Shulei Man ,&nbsp;Naihong Yan ,&nbsp;Ming Zhang","doi":"10.1016/j.bbagrm.2023.194964","DOIUrl":"10.1016/j.bbagrm.2023.194964","url":null,"abstract":"<div><p>Retinoblastoma (RB) is a common malignancy that primarily affects pediatric populations. Although a well-known cause of RB is <em>RB1</em> mutation, <em>MYCN</em> amplification can also lead to the disease, which is a poor prognosis factor. Studies conducted in various tumor types have shown that <em>MYCN</em> inhibition is an effective approach to impede tumor growth. Various indirect approaches have been developed to overcome the difficulty of directly targeting MYCN, such as modulating the super enhancer (SE) upstream of <em>MYCN</em>. The drug used in this study to treat <em>MYCN</em>-amplified RB was THZ1, a CDK7 inhibitor that can effectively suppress transcription by interfering with the activity of SEs. The study findings confirmed the anticancer activity of THZ1 against RB in both in vitro and in vivo experiments. Therapy with THZ1 was found to affect numerous genes in RB according to the RNA-seq analysis. Moreover, the gene expression changes induced by THZ1 treatment were enriched in ribosome, endocytosis, cell cycle, apoptosis, etc. Furthermore, the combined analysis of ChIP-Seq and RNA-seq data suggested a potential role of SEs in regulating the expression of critical transcription factors, such as <em>MYCN</em>, <em>OTX2</em>, and <em>SOX4</em>. Moreover, ChIP–qPCR experiments were conducted to confirm the interaction between <em>MYCN</em> and SEs. In conclusion, THZ1 caused substantial changes in gene transcription in RB, resulting in inhibited cell proliferation, interference with the cell cycle, and increased apoptosis. The efficacy of THZ1 is positively correlated with the degree of <em>MYCN</em> amplification and is likely exerted by interfering with <em>MYCN</em> upstream SEs.</p></div>","PeriodicalId":55382,"journal":{"name":"Biochimica et Biophysica Acta-Gene Regulatory Mechanisms","volume":"1866 3","pages":"Article 194964"},"PeriodicalIF":4.7,"publicationDate":"2023-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10028379","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":"Quantitative proteomics revealed the transition of ergosterol biosynthesis and drug transporters processes during the development of fungal fluconazole resistance","authors":"Xinying Sui ,&nbsp;Xinyu Cheng ,&nbsp;Zhaodi Li ,&nbsp;Yonghong Wang ,&nbsp;Zhenpeng Zhang ,&nbsp;Ruyue Yan ,&nbsp;Lei Chang ,&nbsp;Yanchang Li ,&nbsp;Ping Xu ,&nbsp;Changzhu Duan","doi":"10.1016/j.bbagrm.2023.194953","DOIUrl":"10.1016/j.bbagrm.2023.194953","url":null,"abstract":"<div><p><span><span>Fungal infections and antifungal resistance are the increasing global public health concerns. Mechanisms of fungal resistance include alterations in drug-target interactions, detoxification by high expression of drug efflux transporters, and </span>permeability barriers<span> associated with biofilms. However, the systematic panorama and dynamic changes of the relevant biological processes<span> of fungal drug resistance acquisition remain limited. In this study, we developed a yeast model of resistance to prolonged fluconazole treatment and utilized the isobaric labels TMT (tandem mass tag)-based quantitative proteomics to analyze the </span></span></span>proteome<span> composition and changes in native, short-time fluconazole stimulated and drug-resistant strains. The proteome exhibited significant dynamic range at the beginning of treatment but returned to normal condition upon acquisition drug resistance. The sterol pathway responded strongly under a short time of fluconazole treatment, with increased transcript levels of most enzymes<span> facilitating greater protein expression. With the drug resistance acquisition, the sterol pathway returned to normal state, while the expression of efflux pump proteins increased obviously on the transcription level. Finally, multiple efflux pump proteins showed high expression in drug-resistant strain. Thus, families of sterol pathway and efflux pump proteins, which are closely associated with drug resistance mechanisms, may play different roles at different nodes in the process of drug resistance acquisition. Our findings uncover the relatively important role of efflux pump proteins in the acquisition of fluconazole resistance and highlight its potential as the vital antifungal targets.</span></span></p></div>","PeriodicalId":55382,"journal":{"name":"Biochimica et Biophysica Acta-Gene Regulatory Mechanisms","volume":"1866 3","pages":"Article 194953"},"PeriodicalIF":4.7,"publicationDate":"2023-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10027174","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 presence of an intron relieves gene repression caused by promoter-proximal four-bp specific sequences in yeast","authors":"Hiroki Kikuta ,&nbsp;Takahiro Aramaki ,&nbsp;Shingo Mabu ,&nbsp;Rinji Akada ,&nbsp;Hisashi Hoshida","doi":"10.1016/j.bbagrm.2023.194982","DOIUrl":"10.1016/j.bbagrm.2023.194982","url":null,"abstract":"<div><p>Introns can enhance gene expression in eukaryotic cells in a process called intron-mediated enhancement (IME). The levels of enhancement are affected not only by the intron sequence but also by coding sequences (CDSs). However, the parts of CDSs responsible for mediating IME have not yet been identified. In this study, we identified an IME-mediating sequence by analyzing three pairs of IME-sensitive and -insensitive CDSs in <span><em>Saccharomyces cerevisiae</em></span>. Expression of the CDSs y<em>CLuc</em>, yRo<em>GLU1</em>, and Km<em>BGA1</em><span> was enhanced by the presence of an intron (i.e., they were IME sensitive), but the expression of each corresponding codon-changed CDS, which encoded the identical amino acid sequence, was not enhanced (i.e., they were IME insensitive). Interestingly, the IME-insensitive CDSs showed higher expression levels that were like intron-enhanced expression of IME-sensitive CDSs, suggesting that expression of IME-sensitive CDSs was repressed. A four-nucleotide sequence (TCTT) located in the promoter-proximal position of either the untranslated or coding region was found to be responsible for repression in IME-sensitive CDSs, and repression caused by the TCTT sequence was relieved by the presence of an intron. Further, it was found that the expression of intron-containing yeast-native genes, </span><em>UBC4</em> and <em>MPT5</em><span>, was repressed by TCTT in the CDS but relieved by the introns. These results indicate that TCTT sequences in promoter-proximal positions repress gene expression and that introns play a role in relieving gene repression caused by sequences such as TCTT.</span></p></div>","PeriodicalId":55382,"journal":{"name":"Biochimica et Biophysica Acta-Gene Regulatory Mechanisms","volume":"1866 4","pages":"Article 194982"},"PeriodicalIF":4.7,"publicationDate":"2023-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10194516","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":"Fine tuning of the transcription juggernaut: A sweet and sour saga of acetylation and ubiquitination","authors":"Avik Ghosh ,&nbsp;Poushali Chakraborty ,&nbsp;Debabrata Biswas","doi":"10.1016/j.bbagrm.2023.194944","DOIUrl":"10.1016/j.bbagrm.2023.194944","url":null,"abstract":"<div><p><span>Among post-translational modifications of proteins, acetylation, phosphorylation, and ubiquitination are most extensively studied over the last several decades. Owing to their different target residues for modifications, cross-talk between phosphorylation with that of acetylation and ubiquitination is relatively less pronounced. However, since canonical acetylation and ubiquitination happen only on the lysine residues, an overlap of the same lysine residue being targeted for both acetylation and ubiquitination happens quite frequently and thus plays key roles in overall functional regulation predominantly through modulation of protein stability. In this review, we discuss the cross-talk of acetylation and ubiquitination in the regulation of protein stability for the functional regulation of cellular processes with an emphasis on transcriptional regulation. Further, we emphasize our understanding of the functional regulation of Super Elongation Complex (SEC)-mediated transcription, through regulation of stabilization by acetylation, </span>deacetylation<span> and ubiquitination and associated enzymes and its implication in human diseases.</span></p></div>","PeriodicalId":55382,"journal":{"name":"Biochimica et Biophysica Acta-Gene Regulatory Mechanisms","volume":"1866 3","pages":"Article 194944"},"PeriodicalIF":4.7,"publicationDate":"2023-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10392911","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":"Crystal structure of Tudor domain of TDRD3 in complex with a small molecule antagonist","authors":"Meixia Chen ,&nbsp;Zhuowen Wang ,&nbsp;Weiguo Li ,&nbsp;Yichang Chen ,&nbsp;Qin Xiao ,&nbsp;Xinci Shang ,&nbsp;Xiaolei Huang ,&nbsp;Zhengguo Wei ,&nbsp;Xinyue Ji ,&nbsp;Yanli Liu","doi":"10.1016/j.bbagrm.2023.194962","DOIUrl":"10.1016/j.bbagrm.2023.194962","url":null,"abstract":"<div><p><span><span>Tudor domain-containing protein 3 (TDRD3) is involved in regulating transcription and translation, promoting breast cancer progression, and modulating neurodevelopment and mental health, making it a promising therapeutic target for associated diseases. The </span>Tudor domain of TDRD3 is essential for its biological functions, and targeting this domain with potent and selective chemical probes may modulate its engagement with chromatin and related functions. Here we reported a study of TDRD3 antagonist following on our earlier work on the development of the SMN antagonist, Compound </span><strong>1</strong>, and demonstrated that TDRD3 can bind effectively to Compound <strong>2</strong>, a triple-ring analog of Compound <strong>1</strong>. Our structural analysis suggested that the triple-ring compound bound better to TDRD3 due to its smaller side chain at Y566 compared to W102 in SMN. We also revealed that adding a small hydrophobic group to the <em>N</em>-methyl site of Compound <strong>1</strong> can improve binding. These findings provide a path for identifying antagonists for single canonical Tudor domain-containing proteins such as TDRD3 and SMN.</p></div>","PeriodicalId":55382,"journal":{"name":"Biochimica et Biophysica Acta-Gene Regulatory Mechanisms","volume":"1866 3","pages":"Article 194962"},"PeriodicalIF":4.7,"publicationDate":"2023-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10412495","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":"UPS writes a new saga of SAGA","authors":"Priyanka Barman,&nbsp;Pritam Chakraborty,&nbsp;Rhea Bhaumik,&nbsp;Sukesh R. Bhaumik","doi":"10.1016/j.bbagrm.2023.194981","DOIUrl":"10.1016/j.bbagrm.2023.194981","url":null,"abstract":"<div><p>SAGA (<u>S</u>pt-<u>A</u>da-<u>G</u>cn5-<u>A</u><span><span>cetyltransferase), an evolutionarily conserved transcriptional co-activator among eukaryotes, is a large multi-subunit protein complex with two distinct </span>enzymatic activities, namely HAT (</span><u>H</u>istone <u>a</u>cetyl<u>t</u>ransferase) and DUB (<u>D</u>e-<u>ub</u><span>iquitinase), and is targeted to the promoter by the gene-specific activator proteins for histone covalent modifications and PIC (</span><u>P</u>re-<u>i</u>nitiation <u>c</u>omplex) formation in enhancing transcription (or gene activation). Targeting of SAGA to the gene promoter is further facilitated by the 19S RP (<u>R</u>egulatory <u>p</u><span>article) of the 26S proteasome<span> (that is involved in targeted degradation of protein via ubiquitylation) in a proteolysis-independent manner. Moreover, SAGA is also recently found to be regulated by the 26S proteasome in a proteolysis-dependent manner via the ubiquitylation of its Sgf73/ataxin-7 component that is required for SAGA's integrity and DUB activity (and hence transcription), and is linked to various diseases including neurodegenerative disorders and cancer. Thus, SAGA itself and its targeting to the active gene are regulated by the UPS (</span></span><u>U</u>biquitin-<u>p</u>roteasome <u>s</u>ystem) with implications in diseases.</p></div>","PeriodicalId":55382,"journal":{"name":"Biochimica et Biophysica Acta-Gene Regulatory Mechanisms","volume":"1866 4","pages":"Article 194981"},"PeriodicalIF":4.7,"publicationDate":"2023-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10261368","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":"2023-08-29","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}