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Differential effect of histone H3.3 depletion on retroviral repression in embryonic stem cells. 组蛋白H3.3缺失对胚胎干细胞逆转录病毒抑制的差异效应。
IF 5.7 2区 医学 Q1 Medicine Pub Date : 2023-05-11 DOI: 10.1186/s13148-023-01499-5
Ayellet Tal, Jose David Aguilera, Igor Bren, Carmit Strauss, Sharon Schlesinger

Background: 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).

Results: 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.

Conclusions: 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.

背景:逆转录病毒整合到宿主基因组中会损害细胞基因组和表观基因组的完整性。作为一种防御机制,前病毒DNA的表观遗传修饰抑制小鼠胚胎干细胞(ESC)中的逆转录病毒序列。在这里,我们关注的是组蛋白3变体H3.3,它在活性转录区、着丝粒和异染色质重复元件(如内源性逆转录病毒(ERV))中丰富。结果:为了了解H3.3在ESC逆转录病毒序列的表观遗传沉默中的作用,我们在ESC中去除H3.3基因,并用gfp标记的MLV假病毒转导细胞。这导致逆转录病毒抑制的改变和Trim28募集的减少,从而导致原病毒序列中异染色化的缺失。有趣的是,我们发现H3.3缺失会产生不同的影响,这取决于编码H3.3的两个基因(H3f3a或H3f3b)中哪一个被敲除。H3f3a的缺失导致传入的逆转录病毒表达和erv的短暂上调,而H3f3b的缺失没有同样的效果,并且抑制得以维持。然而,这两个基因的缺失导致了逆转录病毒启动子的稳定激活。这些发现表明H3.3对于调节小鼠ESC中逆转录病毒基因的表达是重要的,并提供了两个H3.3基因在这种调节中的不同功能的证据。此外,我们发现Trim28是在逆转录病毒序列中沉积H3.3所必需的,这表明Trim28的募集和H3.3装载之间存在功能上的相互作用。结论:确定H3.3和Trim28相互作用和调控逆转录病毒基因表达的分子机制,可以更深入地了解逆转录病毒沉默和基因表达的一般调控的基本过程,从而为干细胞生物学的核心问题提供新的答案。
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引用次数: 0
Time to relapse in chronic lymphocytic leukemia and DNA-methylation-based biological age. 慢性淋巴细胞白血病复发时间与dna甲基化的生物学年龄。
IF 5.7 2区 医学 Q1 Medicine Pub Date : 2023-05-10 DOI: 10.1186/s13148-023-01496-8
Drew R Nannini, Rene Cortese, Peter Egwom, Senthilnathan Palaniyandi, Gerhard C Hildebrandt

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.

慢性淋巴细胞白血病(CLL)是一种成熟的B细胞肿瘤,多发于老年人。虽然以前的研究已经确定了与CLL相关的表观遗传特征,但与年龄相关的DNA甲基化变化是否会调节CLL复发仍然难以捉摸。在这项研究中,我们在一个公开的数据集中研究了表观遗传年龄加速与CLL复发时间之间的关系。使用Infinium HumanMethylation450 BeadChip对35名CLL患者进行了化疗免疫治疗前的DNA甲基化分析。根据血液DNA甲基化水平估计了四种表观遗传年龄加速指标(内在表观遗传年龄加速[IEAA]、外在表观遗传年龄加速[EEAA]、表型年龄加速[PhenoAA]和GrimAA])。进行线性、分位数和逻辑回归以及受试者工作特征曲线分析,以评估每个表观遗传年龄指标与CLL复发时间之间的关系。EEAA (p = 0.011)和PhenoAA (p = 0.046)与CLL复发时间呈负相关,GrimAA (p = 0.040)与CLL复发时间呈正相关。同时评估男性患者的EEAA和GrimAA可区分早期复发患者和晚期复发患者(p = 0.039)。未观察到与IEAA相关。这些发现表明,化疗免疫治疗开始前的表观遗传年龄加速与CLL复发的时间有关。我们的研究结果为年龄相关的DNA甲基化变化与CLL复发之间的关系提供了新的见解,并可能为治疗复发和潜在的治疗选择提供生物标志物。
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引用次数: 2
CRISPR-Cas9 knockout screen identifies novel treatment targets in childhood high-grade glioma. CRISPR-Cas9敲除筛选确定儿童高级别胶质瘤的新治疗靶点。
IF 5.7 2区 医学 Q1 Medicine Pub Date : 2023-05-09 DOI: 10.1186/s13148-023-01498-6
Anna Wenger, Ida Karlsson, Teresia Kling, Helena Carén

Background: 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.

Results: 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.

Conclusions: 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.

背景:脑肿瘤是儿童癌症相关死亡的主要原因,目前尚无有效的治疗方法。越来越多的证据表明,不受管制的表观遗传学是肿瘤的驱动因素,特别是在儿科癌症中,因为它们的基因组改变相对较少,并且在组蛋白3 (H3)中发现了关键的驱动突变。肿瘤干细胞(CSC)与肿瘤的发展、复发和治疗抵抗有关,因此特别重要。因此,我们旨在通过CRISPR-Cas9敲除筛选,在h3突变的高级别胶质瘤(HGG)衍生的CSC中确定新的表观遗传治疗靶点。结果:基因敲除筛选确定了100多个新基因,这些基因对H3K27M突变的儿童HGG衍生的CSC生长至关重要。我们成功地在相同的两种CSC系中通过单个敲除验证了13个选定的hit中的12个,并且对于前6个hit,我们包括了来自H3野生型儿科HGG的另外两个CSC系。敲除这些基因导致CSC生长显著下降,并改变干细胞和分化标志物。结论:筛选有力地确定了文献中已知的必要基因,但也发现了许多对儿童HGG中CSC生长至关重要的新基因。六个新基因(UBE2N, CHD4, LSM11, KANSL1, KANSL3和EED)分别被验证,从而证明它们对h3突变和野生型HGG中CSC生长的重要性。这些基因作为儿科HGG的新治疗靶点有待进一步研究和评估。
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引用次数: 0
Risk assessment of assisted reproductive technology and parental age at childbirth for the development of uniparental disomy-mediated imprinting disorders caused by aneuploid gametes. 辅助生殖技术和父母分娩年龄对由非整倍体配子引起的单亲二体介导的印迹疾病发展的风险评估。
IF 5.7 2区 医学 Q1 Medicine Pub Date : 2023-05-06 DOI: 10.1186/s13148-023-01494-w
Kaori Hara-Isono, Keiko Matsubara, Akie Nakamura, Shinichiro Sano, Takanobu Inoue, Sayaka Kawashima, Tomoko Fuke, Kazuki Yamazawa, Maki Fukami, Tsutomu Ogata, Masayo Kagami

Background: 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.

Results: 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 (rs = 0.637, P < 0.001), higher paternal age in oUPD-IDs was explained by the higher maternal age in this group.

Conclusions: 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.

背景:我们之前的研究表明,辅助生殖技术(ART)可能是年龄≥30岁的母亲发生上皮突变介导的印迹障碍(epi-IDs)的一个可能的危险因素。然而,ART或父母年龄的提高是否促进了单亲二体介导的id (upd - id)的发展尚未被研究。结果:我们招募了130名非整倍体upd - id患者,包括分子研究证实的各种id,并分别从强大的全国数据库和我们之前的报告中获得了普通人群和epi- id患者的ART数据。我们比较了upd - id患者与普通人群或epi- id患者的art受孕活产比例和产妇生育年龄。非整倍体upd - id患者art受孕的活产比例与年龄≥30岁的一般人群一致,低于epi- id患者,但差异无统计学意义。非整倍体upd - id患者的产妇生育年龄偏大,有多例超过一般人群产妇生育年龄的97.5%,显著高于epi- id患者(P = 0.637, P)。结论:与epi- id病例不同,ART本身不太可能促进非整倍体upd - id的发生。我们证明,高龄产妇可能是非整倍体upd - id,特别是oupd - id发展的危险因素。
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引用次数: 0
SOCS1 methylation level is associated with prognosis in patients with acute-on-chronic hepatitis B liver failure. SOCS1甲基化水平与急性慢性乙型肝炎肝衰竭患者的预后相关
IF 5.7 2区 医学 Q1 Medicine Pub Date : 2023-05-06 DOI: 10.1186/s13148-023-01495-9
Feng Li, Ying Zhang, Zhao-Hui Wang, Shuai Gao, Yu-Chen Fan, Kai Wang

Background: 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.

Methods: 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.

Results: 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).

Conclusions: GC treatment could decrease the mortality of ACHBLF and SOCS1 methylation levels might serve as prognostic marker for favorable response to glucocorticoid treatment.

背景:糖皮质激素可显著改善急性慢性乙型肝炎肝衰竭(ACHBLF)患者的预后。细胞因子信号传导抑制因子(SOCS) 1甲基化已被证明与ACHBLF的死亡率相关。方法:80例ACHBLF患者分为糖皮质激素组(GC)和保守用药组(CM)。60例慢性乙型肝炎(CHB)患者和30例健康对照(hc)作为对照组。MethyLight检测外周单核细胞(peripheral mononuclear cells, PBMCs)中SOCS1甲基化水平。结果:ACHBLF患者的SOCS1甲基化水平明显高于CHB和hc患者(P结论:GC治疗可降低ACHBLF的死亡率,SOCS1甲基化水平可作为糖皮质激素治疗反应良好的预后指标。
{"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}
引用次数: 0
E3 ubiquitin ligase RNF180 prevents excessive PCDH10 methylation to suppress the proliferation and metastasis of gastric cancer cells by promoting ubiquitination of DNMT1. E3泛素连接酶RNF180通过促进DNMT1的泛素化,阻止PCDH10过度甲基化,抑制胃癌细胞的增殖和转移。
IF 5.7 2区 医学 Q1 Medicine Pub Date : 2023-05-05 DOI: 10.1186/s13148-023-01492-y
Nannan Zhang, Xiaoliang Gao, Qiangqiang Yuan, Xin Fu, Pengliang Wang, Fenglin Cai, Hui Liu, Jing Zhang, Han Liang, Yongzhan Nie, Jingyu Deng

Background: 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.

Results: 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.

Conclusion: 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.

背景:启动子区CpG岛的异常甲基化导致某些肿瘤抑制基因(TSGs)的下调,在包括胃癌(GC)在内的几种癌症的发生和进展中起着重要作用。原钙粘蛋白10 (PCDH10)是在多种癌症中新发现的TSG,在胃癌中下调;然而,PCDH10在GC中的具体机制尚不清楚。在这里,我们阐明了一个新的表观遗传调控信号通路,涉及E3泛素连接酶RNF180和DNA甲基转移酶1 (DNMT1),负责通过影响其启动子甲基化来调节PCDH10的表达。结果:我们发现PCDH10在胃癌细胞和组织中表达下调,PCDH10低表达与胃癌患者淋巴结转移和预后不良相关。此外,PCDH10过表达抑制胃癌细胞的增殖和转移。在机制上,dnmt1介导的启动子超甲基化导致PCDH10在GC组织和细胞中的表达降低。进一步分析发现,RNF180可以直接与DNMT1结合,并通过泛素化参与DNMT1的降解。此外,RNF180与PCDH10表达呈正相关,DNMT1与PCDH10表达呈负相关,具有重要的预后意义。结论:我们的数据显示,RNF180过表达通过泛素依赖的DNMT1降解上调PCDH10的表达,从而抑制胃癌细胞的增殖,表明RNF180/DNMT1/PCDH10轴可能是胃癌治疗的潜在靶点。
{"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}
引用次数: 1
The impact of epigenetic landscape on ovarian cells in infertile older women undergoing IVF procedures. 表观遗传景观对接受体外受精手术的不孕老年妇女卵巢细胞的影响。
IF 5.7 2区 医学 Q1 Medicine Pub Date : 2023-05-04 DOI: 10.1186/s13148-023-01490-0
Giulia Sgueglia, Salvatore Longobardi, Domenico Valerio, Maria Rosaria Campitiello, Nicola Colacurci, Cinzia Di Pietro, Rosalia Battaglia, Thomas D'Hooghe, Lucia Altucci, Carmela Dell'Aversana

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.

生育率的持续下降和生育年龄的延长是工业化国家临床怀孕率低的主要原因。表观遗传机制对接受体外受精(IVF)方案的妇女胚胎发育的影响。在这里,我们描述了可能影响女性生殖并可能影响试管婴儿成功的主要表观遗传修饰。
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引用次数: 0
Epigenetic priming improves salvage chemotherapy in diffuse large B-cell lymphoma via endogenous retrovirus-induced cGAS-STING activation. 表观遗传启动通过内源性逆转录病毒诱导的cGAS-STING激活改善弥漫性大b细胞淋巴瘤的补救性化疗。
IF 5.7 2区 医学 Q1 Medicine Pub Date : 2023-05-03 DOI: 10.1186/s13148-023-01493-x
Jun Liu, Suji Min, Dongchan Kim, Jihyun Park, Eunchae Park, Youngil Koh, Dong-Yeop Shin, Tae Kon Kim, Ja Min Byun, Sung-Soo Yoon, Junshik Hong

Background: 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.

Results: 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.

Conclusions: 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.

背景:尽管大多数弥漫性大b细胞淋巴瘤(DLBCL)患者在一线含利妥昔单抗免疫化疗后完全缓解,但高达40%的患者复发并需要补救性治疗。在这些患者中,由于疗效不足或毒性不耐受,相当大比例的患者对挽救性治疗仍然难治。一种低甲基化药物5-氮杂胞苷在淋巴瘤细胞系和新诊断的DLBCL患者化疗前启动时显示出化疗增敏作用。然而,其改善DLBCL救助性化疗结果的潜力尚未被研究。结果:在这项研究中,我们证明了5-氮杂胞苷在铂基救助方案中作为化学增敏剂的机制。这种化学增敏效应与内源性逆转录病毒(ERV)通过cGAS-STING轴诱导的病毒模仿反应有关。我们发现缺乏cGAS会损害5-氮杂胞苷的化学增敏作用。此外,联合维生素C和5-阿扎胞苷协同激活STING可能是单独5-阿扎胞苷引起的启动不足的潜在补救措施。结论:综上所述,5-氮杂胞苷的化疗增敏作用可以克服目前含铂补救性化疗在DLBCL中的局限性,cGAS-STING的状态有可能预测5-氮杂胞苷启动的疗效。
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引用次数: 1
Epigenetic reactivation of tumor suppressor genes with CRISPRa technologies as precision therapy for hepatocellular carcinoma. 利用CRISPRa技术实现肿瘤抑制基因的表观遗传再激活作为肝癌的精准治疗。
IF 5.7 2区 医学 Q1 Medicine Pub Date : 2023-04-29 DOI: 10.1186/s13148-023-01482-0
Agustin Sgro, Joseph Cursons, Charlene Waryah, Eleanor A Woodward, Momeneh Foroutan, Ruqian Lyu, George C T Yeoh, Peter J Leedman, Pilar Blancafort

Background: 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.

Results: 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.

Conclusions: 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.

背景:肿瘤抑制基因(TSGs)的表观遗传沉默是肝细胞癌(HCC)发生的一个关键特征。肝脏靶向递送crispr激活(CRISPRa)系统使得利用染色质可塑性成为可能,通过重编程转录失调。结果:利用肝癌基因组图谱数据,我们确定了12个假定的tsg,它们在启动子DNA甲基化和转录物丰度之间存在负相关,遗传改变有限。所有HCC样本都含有至少一个沉默的TSG,这表明结合一组特定的基因组靶点可以最大限度地提高疗效,并有可能改善HCC患者的个性化治疗策略。与缺乏基因座选择性的表观遗传修饰药物不同,CRISPRa系统能够有效和精确地重新激活至少4种针对代表性HCC细胞系的tsg。Hep3B细胞中的HHIP、MT1M、PZP和TTC36协同再激活可抑制HCC发病机制的多个方面,如细胞活力、增殖和迁移。结论:通过结合多个效应域,我们证明了表观遗传效应和grna的CRISPRa工具箱在侵袭性HCC患者特异性治疗中的实用性。
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引用次数: 1
Characterization of molecular subtypes based on chromatin regulators and identification of the role of NPAS2 in lung adenocarcinoma. 基于染色质调控因子的分子亚型特征和NPAS2在肺腺癌中的作用鉴定。
IF 5.7 2区 医学 Q1 Medicine Pub Date : 2023-04-29 DOI: 10.1186/s13148-023-01486-w
Yongbiao Huang, Lingyan Xiao, Motuma Yigezu Daba, Duo Xu, Yuan Wang, Long Li, Qian Li, Bo Liu, Wan Qin, Huixian Zhang, Xianglin Yuan

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

背景:染色质调节因子(CRs)是一种重要的表观遗传修饰因子,在各种肿瘤的进展过程中发挥着重要作用,但其在肺腺癌(LUAD)中的作用尚未得到全面研究。方法:采用差异表达和单因素Cox回归分析,确定预后cr。基于预后cr,采用共识聚类对LUAD亚型进行分类。采用lasso -多变量Cox回归方法构建预后标记并开发染色质调控因子相关基因指数(CRGI)。通过Kaplan-Meier方法在多个数据集中评估CRGI区分生存的能力。评价CRGI与肿瘤微环境(TME)的关系。此外,临床变量和CRGI被纳入创建一个nomogram。预后基因NPAS2在LUAD中的作用通过临床样本验证和一系列体外和体内实验得以阐明。结果:基于46个预后cr,通过共识聚类将LUAD分为两种亚型,其生存期和TME有显著差异。研究人员开发了一个由6个cr (MOCS、PBK、CBX3、A1CF、NPAS2和CTCFL)组成的预后特征,并在多个独立数据集中证明了它是一个有效的生存预测指标。预后特征也被证明是TME和对免疫治疗和化疗敏感性的指标。nomogram是一种简单的预测生存率的方法。临床样本显示,NPAS2在LUAD组织中高表达,体外和体内实验表明,抑制NPAS2可阻碍LUAD细胞的恶性进展。结论:我们的研究全面揭示了CRs在LUAD中的功能,开发了一种预测生存和治疗反应的分类器,并首次提示NPAS2促进LUAD进展。
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Clinical Epigenetics
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