Clinical Epigenetics最新文献

{"title":"Differential effect of histone H3.3 depletion on retroviral repression in embryonic stem cells.","authors":"Ayellet Tal,&nbsp;Jose David Aguilera,&nbsp;Igor Bren,&nbsp;Carmit Strauss,&nbsp;Sharon Schlesinger","doi":"10.1186/s13148-023-01499-5","DOIUrl":"https://doi.org/10.1186/s13148-023-01499-5","url":null,"abstract":"<p><strong>Background: </strong>Integration of retroviruses into the host genome can impair the genomic and epigenomic integrity of the cell. As a defense mechanism, epigenetic modifications on the proviral DNA repress retroviral sequences in mouse embryonic stem cells (ESC). Here, we focus on the histone 3 variant H3.3, which is abundant in active transcription zones, as well as centromeres and heterochromatinized repeat elements, e.g., endogenous retroviruses (ERV).</p><p><strong>Results: </strong>To understand the involvement of H3.3 in the epigenetic silencing of retroviral sequences in ESC, we depleted the H3.3 genes in ESC and transduced the cells with GFP-labeled MLV pseudovirus. This led to altered retroviral repression and reduced Trim28 recruitment, which consequently led to a loss of heterochromatinization in proviral sequences. Interestingly, we show that H3.3 depletion has a differential effect depending on which of the two genes coding for H3.3, H3f3a or H3f3b, are knocked out. Depletion of H3f3a resulted in a transient upregulation of incoming retroviral expression and ERVs, while the depletion of H3f3b did not have the same effect and repression was maintained. However, the depletion of both genes resulted in a stable activation of the retroviral promoter. These findings suggest that H3.3 is important for regulating retroviral gene expression in mouse ESC and provide evidence for a distinct function of the two H3.3 genes in this regulation. Furthermore, we show that Trim28 is needed for depositing H3.3 in retroviral sequences, suggesting a functional interaction between Trim28 recruitment and H3.3 loading.</p><p><strong>Conclusions: </strong>Identifying the molecular mechanisms by which H3.3 and Trim28 interact and regulate retroviral gene expression could provide a deeper understanding of the fundamental processes involved in retroviral silencing and the general regulation of gene expression, thus providing new answers to a central question of stem cell biology.</p>","PeriodicalId":48652,"journal":{"name":"Clinical Epigenetics","volume":null,"pages":null},"PeriodicalIF":5.7,"publicationDate":"2023-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10176700/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9474812","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Time to relapse in chronic lymphocytic leukemia and DNA-methylation-based biological age.","authors":"Drew R Nannini,&nbsp;Rene Cortese,&nbsp;Peter Egwom,&nbsp;Senthilnathan Palaniyandi,&nbsp;Gerhard C Hildebrandt","doi":"10.1186/s13148-023-01496-8","DOIUrl":"https://doi.org/10.1186/s13148-023-01496-8","url":null,"abstract":"<p><p>Chronic lymphocytic leukemia (CLL) is a mature B cell neoplasm with a predilection for older individuals. While previous studies have identified epigenetic signatures associated with CLL, whether age-related DNA methylation changes modulate CLL relapse remains elusive. In this study, we examined the association between epigenetic age acceleration and time to CLL relapse in a publicly available dataset. DNA methylation profiling of 35 CLL patients prior to initiating chemoimmunotherapy was performed using the Infinium HumanMethylation450 BeadChip. Four epigenetic age acceleration metrics (intrinsic epigenetic age acceleration [IEAA], extrinsic epigenetic age acceleration [EEAA], PhenoAge acceleration [PhenoAA], and GrimAge acceleration [GrimAA]) were estimated from blood DNA methylation levels. Linear, quantile, and logistic regression and receiver operating characteristic curve analyses were conducted to assess the association between each epigenetic age metric and time to CLL relapse. EEAA (p = 0.011) and PhenoAA (p = 0.046) were negatively and GrimAA (p = 0.040) was positively associated with time to CLL relapse. Simultaneous assessment of EEAA and GrimAA in male patients distinguished patients who relapsed early from patients who relapsed later (p = 0.039). No associations were observed with IEAA. These findings suggest epigenetic age acceleration prior to chemoimmunotherapy initiation is associated with time to CLL relapse. Our results provide novel insight into the association between age-related DNA methylation changes and CLL relapse and may serve has biomarkers for treatment relapse, and potentially, treatment selection.</p>","PeriodicalId":48652,"journal":{"name":"Clinical Epigenetics","volume":null,"pages":null},"PeriodicalIF":5.7,"publicationDate":"2023-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10170738/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9528913","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CRISPR-Cas9 knockout screen identifies novel treatment targets in childhood high-grade glioma.","authors":"Anna Wenger,&nbsp;Ida Karlsson,&nbsp;Teresia Kling,&nbsp;Helena Carén","doi":"10.1186/s13148-023-01498-6","DOIUrl":"https://doi.org/10.1186/s13148-023-01498-6","url":null,"abstract":"<p><strong>Background: </strong>Brain tumours are the leading cause of cancer-related death in children, and there is no effective treatment. A growing body of evidence points to deregulated epigenetics as a tumour driver, particularly in paediatric cancers as they have relatively few genomic alterations, and key driver mutations have been identified in histone 3 (H3). Cancer stem cells (CSC) are implicated in tumour development, relapse and therapy resistance and thus particularly important to target. We therefore aimed to identify novel epigenetic treatment targets in CSC derived from H3-mutated high-grade glioma (HGG) through a CRISPR-Cas9 knockout screen.</p><p><strong>Results: </strong>The knockout screen identified more than 100 novel genes essential for the growth of CSC derived from paediatric HGG with H3K27M mutation. We successfully validated 12 of the 13 selected hits by individual knockout in the same two CSC lines, and for the top six hits we included two additional CSC lines derived from H3 wild-type paediatric HGG. Knockout of these genes led to a significant decrease in CSC growth, and altered stem cell and differentiation markers.</p><p><strong>Conclusions: </strong>The screen robustly identified essential genes known in the literature, but also many novel genes essential for CSC growth in paediatric HGG. Six of the novel genes (UBE2N, CHD4, LSM11, KANSL1, KANSL3 and EED) were validated individually thus demonstrating their importance for CSC growth in H3-mutated and wild-type HGG. These genes should be further studied and evaluated as novel treatment targets in paediatric HGG.</p>","PeriodicalId":48652,"journal":{"name":"Clinical Epigenetics","volume":null,"pages":null},"PeriodicalIF":5.7,"publicationDate":"2023-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10170782/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9844994","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Risk assessment of assisted reproductive technology and parental age at childbirth for the development of uniparental disomy-mediated imprinting disorders caused by aneuploid gametes.","authors":"Kaori Hara-Isono,&nbsp;Keiko Matsubara,&nbsp;Akie Nakamura,&nbsp;Shinichiro Sano,&nbsp;Takanobu Inoue,&nbsp;Sayaka Kawashima,&nbsp;Tomoko Fuke,&nbsp;Kazuki Yamazawa,&nbsp;Maki Fukami,&nbsp;Tsutomu Ogata,&nbsp;Masayo Kagami","doi":"10.1186/s13148-023-01494-w","DOIUrl":"https://doi.org/10.1186/s13148-023-01494-w","url":null,"abstract":"<p><strong>Background: </strong>Our previous study suggested that assisted reproductive technology (ART) may be a possible risk factor for the development of epimutation-mediated imprinting disorders (epi-IDs) for mothers aged ≥ 30 years. However, whether ART or advanced parental age facilitates the development of uniparental disomy-mediated IDs (UPD-IDs) has not yet been investigated.</p><p><strong>Results: </strong>We enrolled 130 patients with aneuploid UPD-IDs including various IDs confirmed by molecular studies and obtained ART data of the general population and patients with epi-IDs from a robust nationwide database and our previous report, respectively. We compared the proportion of ART-conceived livebirths and maternal childbearing age between patients with UPD-IDs and the general population or patients with epi-IDs. The proportion of ART-conceived livebirths in patients with aneuploid UPD-IDs was consistent with that in the general population of maternal age ≥ 30 years and was lower than that in the patients with epi-IDs, although there was no significant difference. The maternal childbearing age of patients with aneuploid UPD-IDs was skewed to the increased ages with several cases exceeding the 97.5th percentile of maternal childbearing age of the general population and significantly higher than that of patients with epi-IDs (P < 0.001). In addition, we compared the proportion of ART-conceived livebirths and parental age at childbirth between patients with UPD-IDs caused by aneuploid oocytes (oUPD-IDs) and that by aneuploid sperm (sUPD-IDs). Almost all ART-conceived livebirths were identified in patients with oUPD-IDs, and both maternal age and paternal age at childbirth were significantly higher in patients with oUPD-IDs than in patients with sUPD-IDs. Because maternal age and paternal age were strongly correlated (r_s = 0.637, P < 0.001), higher paternal age in oUPD-IDs was explained by the higher maternal age in this group.</p><p><strong>Conclusions: </strong>Different from the case of epi-IDs, ART itself is not likely to facilitate the development of aneuploid UPD-IDs. We demonstrated that advanced maternal age can be a risk factor for the development of aneuploid UPD-IDs, particularly oUPD-IDs.</p>","PeriodicalId":48652,"journal":{"name":"Clinical Epigenetics","volume":null,"pages":null},"PeriodicalIF":5.7,"publicationDate":"2023-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10163687/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9467610","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SOCS1 methylation level is associated with prognosis in patients with acute-on-chronic hepatitis B liver failure.","authors":"Feng Li,&nbsp;Ying Zhang,&nbsp;Zhao-Hui Wang,&nbsp;Shuai Gao,&nbsp;Yu-Chen Fan,&nbsp;Kai Wang","doi":"10.1186/s13148-023-01495-9","DOIUrl":"https://doi.org/10.1186/s13148-023-01495-9","url":null,"abstract":"<p><strong>Background: </strong>Glucocorticoids could greatly improve the prognosis of patients with acute-on-chronic hepatitis B liver failure (ACHBLF). Suppressor of cytokine signaling (SOCS) 1 methylation has been shown to be associated with mortality in ACHBLF.</p><p><strong>Methods: </strong>Eighty patients with ACHBLF were divided into group glucocorticoid (GC) and group conservative medical (CM). Sixty patients with chronic hepatitis B (CHB), and Thirty healthy controls (HCs) served as control group. SOCS1 methylation levels in peripheral mononuclear cells (PBMCs) was detected by MethyLight.</p><p><strong>Results: </strong>SOCS1 methylation levels were significantly higher in patients with ACHBLF than those with CHB and HCs (P < 0.01, respectively). Nonsurvivors showed significantly higher SOCS1 methylation levels (P < 0.05) than survivors in both GC and CM groups in ACHBLF patients. Furthermore, the survival rates of the SOCS1 methylation-negative group were significantly higher than that of the methylation-positive group at 1 month (P = 0.014) and 3 months (P = 0.003) follow-up. Meanwhile, GC group and CM group had significantly lower mortality at 3 months, which may be related to application of glucocorticoid. In the SOCS1 methylation-positive group, the 1-month survival rate was significantly improved, which may be related to GC treatment (P = 0.020). However, no significant difference could be observed between the GC group and CM group in the methylation-negative group (P = 0.190).</p><p><strong>Conclusions: </strong>GC treatment could decrease the mortality of ACHBLF and SOCS1 methylation levels might serve as prognostic marker for favorable response to glucocorticoid treatment.</p>","PeriodicalId":48652,"journal":{"name":"Clinical Epigenetics","volume":null,"pages":null},"PeriodicalIF":5.7,"publicationDate":"2023-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10163770/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9844989","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"E3 ubiquitin ligase RNF180 prevents excessive PCDH10 methylation to suppress the proliferation and metastasis of gastric cancer cells by promoting ubiquitination of DNMT1.","authors":"Nannan Zhang,&nbsp;Xiaoliang Gao,&nbsp;Qiangqiang Yuan,&nbsp;Xin Fu,&nbsp;Pengliang Wang,&nbsp;Fenglin Cai,&nbsp;Hui Liu,&nbsp;Jing Zhang,&nbsp;Han Liang,&nbsp;Yongzhan Nie,&nbsp;Jingyu Deng","doi":"10.1186/s13148-023-01492-y","DOIUrl":"https://doi.org/10.1186/s13148-023-01492-y","url":null,"abstract":"<p><strong>Background: </strong>Downregulation of certain tumor-suppressor genes (TSGs) by aberrant methylation of CpG islands in the promoter region contributes a great deal to the oncogenesis and progression of several cancers, including gastric cancer (GC). Protocadherin 10 (PCDH10) is a newly identified TSG in various cancers and is downregulated in GC; however, the specific mechanisms of PCDH10 in GC remain elusive. Here, we elucidated a novel epigenetic regulatory signaling pathway involving the E3 ubiquitin ligase RNF180 and DNA methyltransferase 1 (DNMT1), responsible for modulating PCDH10 expression by affecting its promoter methylation.</p><p><strong>Results: </strong>We revealed that PCDH10 was downregulated in GC cells and tissues, and low PCDH10 expression was correlated with lymph node metastasis and poor prognosis in patients with GC. Additionally, PCDH10 overexpression suppressed GC cell proliferation and metastasis. Mechanistically, DNMT1-mediated promoter hypermethylation resulted in decreased expression of PCDH10 in GC tissues and cells. Further analysis revealed that RNF180 can bind directly to DNMT1 and was involved in DNMT1 degradation via ubiquitination. Additionally, a positive correlation was found between RNF180 and PCDH10 expression and an inverse association between DNMT1 and PCDH10 expression showed considerable prognostic significance.</p><p><strong>Conclusion: </strong>Our data showed that RNF180 overexpression upregulated PCDH10 expression via ubiquitin-dependent degradation of DNMT1, thus suppressing GC cell proliferation, indicating that the RNF180/DNMT1/PCDH10 axis could be a potential therapeutic target for GC treatment.</p>","PeriodicalId":48652,"journal":{"name":"Clinical Epigenetics","volume":null,"pages":null},"PeriodicalIF":5.7,"publicationDate":"2023-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10163782/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9495762","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The impact of epigenetic landscape on ovarian cells in infertile older women undergoing IVF procedures.","authors":"Giulia Sgueglia,&nbsp;Salvatore Longobardi,&nbsp;Domenico Valerio,&nbsp;Maria Rosaria Campitiello,&nbsp;Nicola Colacurci,&nbsp;Cinzia Di Pietro,&nbsp;Rosalia Battaglia,&nbsp;Thomas D'Hooghe,&nbsp;Lucia Altucci,&nbsp;Carmela Dell'Aversana","doi":"10.1186/s13148-023-01490-0","DOIUrl":"https://doi.org/10.1186/s13148-023-01490-0","url":null,"abstract":"<p><p>The constant decline in fertility and older reproductive age is the major cause of low clinical pregnancy rates in industrialised countries. Epigenetic mechanisms impact on proper embryonic development in women undergoing in vitro fertilisation (IVF) protocols. Here, we describe the main epigenetic modifications that may influence female reproduction and could affect IVF success.</p>","PeriodicalId":48652,"journal":{"name":"Clinical Epigenetics","volume":null,"pages":null},"PeriodicalIF":5.7,"publicationDate":"2023-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10161563/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9828100","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Epigenetic priming improves salvage chemotherapy in diffuse large B-cell lymphoma via endogenous retrovirus-induced cGAS-STING activation.","authors":"Jun Liu,&nbsp;Suji Min,&nbsp;Dongchan Kim,&nbsp;Jihyun Park,&nbsp;Eunchae Park,&nbsp;Youngil Koh,&nbsp;Dong-Yeop Shin,&nbsp;Tae Kon Kim,&nbsp;Ja Min Byun,&nbsp;Sung-Soo Yoon,&nbsp;Junshik Hong","doi":"10.1186/s13148-023-01493-x","DOIUrl":"https://doi.org/10.1186/s13148-023-01493-x","url":null,"abstract":"<p><strong>Background: </strong>Although most patients with diffuse large B-cell lymphoma (DLBCL) achieve complete remission after first-line rituximab-containing immunochemotherapy, up to 40% of patients relapse and require salvage therapy. Among those patients, a substantial proportion remain refractory to salvage therapy due to insufficient efficacy or intolerance of toxicities. A hypomethylating agent, 5-azacytidine, showed a chemosensitizing effect when primed before chemotherapy in lymphoma cell lines and newly diagnosed DLBCL patients. However, its potential to improve outcomes of salvage chemotherapy in DLBCL has not been investigated.</p><p><strong>Results: </strong>In this study, we demonstrated the mechanism of 5-azacytidine priming as a chemosensitizer in a platinum-based salvage regimen. This chemosensitizing effect was associated with endogenous retrovirus (ERV)-induced viral mimicry responses via the cGAS-STING axis. We found deficiency of cGAS impaired the chemosensitizing effect of 5-azacytidine. Furthermore, combining vitamin C and 5-azacytidine to synergistically activate STING could be a potential remedy for insufficient priming induced by 5-azacytidine alone.</p><p><strong>Conclusions: </strong>Taken together, the chemosensitizing effect of 5-azacytidine could be exploited to overcome the limitations of the current platinum-containing salvage chemotherapy in DLBCL and the status of cGAS-STING has the potential to predict the efficacy of 5-azacytidine priming.</p>","PeriodicalId":48652,"journal":{"name":"Clinical Epigenetics","volume":null,"pages":null},"PeriodicalIF":5.7,"publicationDate":"2023-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10155448/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9467596","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Epigenetic reactivation of tumor suppressor genes with CRISPRa technologies as precision therapy for hepatocellular carcinoma.","authors":"Agustin Sgro,&nbsp;Joseph Cursons,&nbsp;Charlene Waryah,&nbsp;Eleanor A Woodward,&nbsp;Momeneh Foroutan,&nbsp;Ruqian Lyu,&nbsp;George C T Yeoh,&nbsp;Peter J Leedman,&nbsp;Pilar Blancafort","doi":"10.1186/s13148-023-01482-0","DOIUrl":"https://doi.org/10.1186/s13148-023-01482-0","url":null,"abstract":"<p><strong>Background: </strong>Epigenetic silencing of tumor suppressor genes (TSGs) is a key feature of oncogenesis in hepatocellular carcinoma (HCC). Liver-targeted delivery of CRISPR-activation (CRISPRa) systems makes it possible to exploit chromatin plasticity, by reprogramming transcriptional dysregulation.</p><p><strong>Results: </strong>Using The Cancer Genome Atlas HCC data, we identify 12 putative TSGs with negative associations between promoter DNA methylation and transcript abundance, with limited genetic alterations. All HCC samples harbor at least one silenced TSG, suggesting that combining a specific panel of genomic targets could maximize efficacy, and potentially improve outcomes as a personalized treatment strategy for HCC patients. Unlike epigenetic modifying drugs lacking locus selectivity, CRISPRa systems enable potent and precise reactivation of at least 4 TSGs tailored to representative HCC lines. Concerted reactivation of HHIP, MT1M, PZP, and TTC36 in Hep3B cells inhibits multiple facets of HCC pathogenesis, such as cell viability, proliferation, and migration.</p><p><strong>Conclusions: </strong>By combining multiple effector domains, we demonstrate the utility of a CRISPRa toolbox of epigenetic effectors and gRNAs for patient-specific treatment of aggressive HCC.</p>","PeriodicalId":48652,"journal":{"name":"Clinical Epigenetics","volume":null,"pages":null},"PeriodicalIF":5.7,"publicationDate":"2023-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10149030/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9528871","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characterization of molecular subtypes based on chromatin regulators and identification of the role of NPAS2 in lung adenocarcinoma.","authors":"Yongbiao Huang,&nbsp;Lingyan Xiao,&nbsp;Motuma Yigezu Daba,&nbsp;Duo Xu,&nbsp;Yuan Wang,&nbsp;Long Li,&nbsp;Qian Li,&nbsp;Bo Liu,&nbsp;Wan Qin,&nbsp;Huixian Zhang,&nbsp;Xianglin Yuan","doi":"10.1186/s13148-023-01486-w","DOIUrl":"https://doi.org/10.1186/s13148-023-01486-w","url":null,"abstract":"<p><strong>Background: </strong>Chromatin regulators (CRs) are critical epigenetic modifiers and have been reported to play critical roles during the progression of various tumors, but their role in lung adenocarcinoma (LUAD) has not been comprehensively studied.</p><p><strong>Methods: </strong>Differential expression and univariate Cox regression analyses were conducted to identify the prognostic CRs. Consensus clustering was applied to classify the subtypes of LUAD based on prognostic CRs. LASSO-multivariate Cox regression method was used for construction of a prognostic signature and development of chromatin regulator-related gene index (CRGI). The capacity of CRGI to distinguish survival was evaluated via Kaplan-Meier method in multiple datasets. Relationship between CRGI and tumor microenvironment (TME) was evaluated. Additionally, clinical variables and CRGI were incorporated to create a nomogram. The role of the prognostic gene NPAS2 in LUAD was elucidated via clinical samples validation and a series of in vitro and in vivo experiments.</p><p><strong>Results: </strong>Two subtypes of LUAD were classified based on 46 prognostic CRs via consensus clustering which had significantly different survival and TME. A prognostic signature consisting of six CRs (MOCS, PBK, CBX3, A1CF, NPAS2, and CTCFL) was developed and proved to be an effective survival predictor in multiple independent datasets. The prognostic signature was also demonstrated to be an indicator of TME and sensitivity to immunotherapy and chemotherapy. The nomogram was suggested to be a simple tool that can predict survival accurately. Clinical samples show that NPAS2 is highly expressed in LUAD tissues, and in vitro and in vivo experiments demonstrated that inhibition of NPAS2 impeded malignant progression of LUAD cells.</p><p><strong>Conclusions: </strong>Our study comprehensively unveiled the functions of CRs in LUAD, developed a classifier to predict survival and response to treatments, and suggested that NPAS2 promoted LUAD progression for the first time.</p>","PeriodicalId":48652,"journal":{"name":"Clinical Epigenetics","volume":null,"pages":null},"PeriodicalIF":5.7,"publicationDate":"2023-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10149025/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9528414","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}