背景:E1A结合蛋白300(E1A Binding Protein 300,EP300)作为一种多功能组蛋白乙酰转移酶,广泛参与基因表达调控、细胞生长及分化等生物学过程,并与多种炎症及免疫相关疾病相关,但它在过敏性鼻炎发病中的具体功能尚不明确。目的:探究过敏...背景:E1A结合蛋白300(E1A Binding Protein 300,EP300)作为一种多功能组蛋白乙酰转移酶,广泛参与基因表达调控、细胞生长及分化等生物学过程,并与多种炎症及免疫相关疾病相关,但它在过敏性鼻炎发病中的具体功能尚不明确。目的:探究过敏性鼻炎相关基因表达变化,分析其与程序性细胞死亡的关联,寻找潜在生物标志物和治疗靶点。方法:①从GSE51392、GSE43523和GSE206149数据集中收集过敏性鼻炎患者和对照组的基因表达数据,筛选差异表达基因并进行WGCNA分析。②于2022年3月至2024年5月从新疆医科大学第五附属医院收集10例进行翼管神经切断术治疗的过敏性鼻炎患者和10例健康对照者,采集患者术前术后血液和鼻腔黏膜组织样本。③构建大鼠过敏性鼻炎模型并敲降EP300,并将大鼠分为对照组、模型组、模型+shEP300-NC组、模型+shEP300组。通过ELISA、苏木精-伊红染色、RT-qPCR和Western blot技术分别检测血清炎症因子水平、鼻黏膜组织病理变化及相关基因和蛋白表达。结果与结论:①过敏性鼻炎和对照之间鉴定出43个交集基因;WGCNA发现Green模块与过敏性鼻炎相关性强,通过与程序性细胞死亡相关基因和共同差异表达基因进行交集分析得到关键基因EP300。②与术前相比,过敏性鼻炎患者术后血清白细胞介素4、白细胞介素5、白细胞介素13水平及鼻黏膜组织EP300、LC3B、Beclin1、cleaved-Caspase的表达显著降低,鼻黏膜组织p62、Bcl2的表达显著升高。③与对照组比较,模型组大鼠血清白细胞介素4、白细胞介素5、白细胞介素13水平及鼻黏膜组织EP300、LC3B、Beclin1、cleaved-Caspase的表达显著升高,鼻黏膜组织p62、Bcl2的表达显著降低;与模型组比较,模型+shEP300组大鼠上述指标均呈现相反变化。④结论:EP300可通过调控炎症、自噬与凋亡参与过敏性鼻炎的发生发展过程。展开更多
目的:探讨乳酸对三阴性乳腺癌(triple-negative breast cancer,TNBC)细胞恶性行为的影响,并揭示胰岛素样生长因子2 mRNA结合蛋白3(insulin-like growth factor 2 m RNA binding protein 3,IGF2BP3)通过m6A依赖性方式调控EP300,进而介导...目的:探讨乳酸对三阴性乳腺癌(triple-negative breast cancer,TNBC)细胞恶性行为的影响,并揭示胰岛素样生长因子2 mRNA结合蛋白3(insulin-like growth factor 2 m RNA binding protein 3,IGF2BP3)通过m6A依赖性方式调控EP300,进而介导代谢重编程的表观遗传学机制。方法:通过外源性添加乳酸钠处理TNBC细胞,采用CCK-8、集落形成、划痕愈合和Transwell实验检测细胞增殖与迁移能力;利用shRNA慢病毒载体构建IGF2BP3稳定敲低细胞模型,结合Western blot分析组蛋白乳酸化修饰水平;进一步通过RIP-seq、MeRIP-seq筛选IGF2BP3的m6A靶基因,并利用qRT-PCR和Western blot验证关键分子表达。结果:乳酸钠处理显著增强了TNBC细胞的增殖和迁移能力,且泛乳酸化水平随乳酸浓度梯度升高而增加。IGF2BP3敲低可降低组蛋白乳酸化修饰水平。通过整合RIP-seq和MeRIP-seq数据,鉴定出699个其转录本同时被IGF2BP3特异性结合且携带m6A修饰的候选基因,这些基因显著富集于表观遗传调控和代谢相关通路。EP300转录本上IGF2BP3的结合区域与m6A修饰位点高度重合,且EP300的表达水平在IGF2BP3敲低后明显下调。结论:外源性乳酸通过泛乳酸化修饰促进TNBC的恶性进展。IGF2BP3通过m6A依赖性机制调控EP300的表达,进而介导组蛋白乳酸化修饰与代谢重编程的协同作用,最终驱动TNBC的肿瘤进展。上述发现为靶向代谢-表观遗传交互调控的新型治疗策略提供了理论依据。展开更多
The genetic adaptation of Tibetans to high altitude hypoxia likely involves a group of genes in the hypoxic pathway, as suggested by earlier studies. To test the adaptive role of the previously reported candidate gene...The genetic adaptation of Tibetans to high altitude hypoxia likely involves a group of genes in the hypoxic pathway, as suggested by earlier studies. To test the adaptive role of the previously reported candidate gene EP300 （histone acetyltransferase p300）, we conducted resequencing of a 108.9 kb gene region of EP300 in 80 unrelated Tibetans. The allele-frequency and haplotype-based neutrality tests detected signals of positive Darwinian selection on EP300 in Tibetans, with a group of variants showing allelic divergence between Tibetans and lowland reference populations, including Han Chinese, Europeans, and Africans. Functional prediction suggested the involvement of multiple EP300 variants in gene expression regulation. More importantly, genetic association tests in 226 Tibetans indicated significant correlation of the adaptive EP300 variants with blood nitric oxide （NO） concentration. Collectively, we propose that EP300 harbors adaptive variants in Tibetans, which might contribute to high-altitude adaptation through regulating NO production.展开更多
Objective: The results of a previous study showed that a clear dysregulation was evident in the global gene expression of the BCL11A-suppressed B-lymphoma cells. In this study, the bone morphogenetic protein receptor,...Objective: The results of a previous study showed that a clear dysregulation was evident in the global gene expression of the BCL11A-suppressed B-lymphoma cells. In this study, the bone morphogenetic protein receptor, type II(BMPR2), E1 A binding protein p300(EP300), transforming growth factor-β2(TGFβ2), and tumor necrosis factor, and alpha-induced protein 3(TNFAIP3) gene expression patterns in B-cell malignancies were studied. Methods: The relative expression levels of BMPR2, EP300, TGFβ2, and TNFAIP3 mRNA in B-lymphoma cell lines, myeloid cell lines, as well as in cells from healthy volunteers, were determined by real-time quantitative reverse transcriptpolymerase chain reaction(qRT-PCR) with SYBR Green Dye. Glyceraldehyde-3-phosphate dehydrogenase(GAPDH) was used as reference. Results: The expression level of TGFβ2 mRNA in B-lymphoma cell lines was significantly higher than those in the cells from the healthy control(P<0.05). However, the expression level of TNFAIP3 mRNA in B-malignant cells was significantly lower than that of the healthy control(P<0.05). The expression levels of BMPR2 and EP300 mRNA showed no significant difference between B-malignant cell lines and the healthy group(P>0.05). In B-lymphoma cell lines, correlation analyses revealed that the expression of BMPR2 and TNFAIP3(r=0.882, P=0.04) had significant positive relation. The expression levels of BMPR2, EP300, and TNFAIP3 mRNA in cell lines from myeloid leukemia were significantly lower than those in the cells from the healthy control(P<0.05). The expression levels of TGFβ2 mRNA showed no significant difference between myeloid leukemia cell lines and the healthy control or B-malignant cell lines(P>0.05). The expression levels of BMPR2, EP300, and TNFAIP3 mRNA in B-lymphoma cells were significantly higher than those of the myeloid leukemia cells(P<0.05).Conclusion: Different expression patterns of BMPR2, EP300, TGFβ2, and TNFAIP3 genes in B-lymphoma cells exist.展开更多
<strong>Background</strong><span style="font-family:Verdana;"><strong>:</strong></span><b><span style="font-family:""> </span></b>&l...<strong>Background</strong><span style="font-family:Verdana;"><strong>:</strong></span><b><span style="font-family:""> </span></b><span style="font-family:""><span style="font-family:Verdana;">Malignant granular cell tumor (GCT) is extremely rare. Malignant GCT with EP300 gene mutation in the bladder has not been reported in the literature. </span><b><span style="font-family:Verdana;">Case Presentation</span></b></span><b><span style="font-family:Verdana;">:</span></b><span style="font-family:""><span style="font-family:Verdana;"> We report a special case of 45-year-old female with malignant GCT of the bladder. Pathological examination showed that the mass was 11 × 11 × 4.5 cm in size, involved in the bladder’s posterior wall. Under the microscope, the tumor cells were arranged in the shape of a nest or cord to infiltrate the bladder’s wall. The tumor cells were pleomorphic, red-stained granular within the cytoplasm, with increased nuclear/cyto</span><span style="font-family:Verdana;">plasmic ratio, vacuolar nuclei, and obvious nucleoli. The tumor cells were</span> <span style="font-family:Verdana;">showed obvious nuclear atypia, and the mitosis was more than 5/50HPF. </span><span style="font-family:Verdana;">Coagulative necrosis was widely showed within the tumor. Immunohistochemi</span><span><span style="font-family:Verdana;">stry (IHC) showed that S-100, NSE, CD68, CR, </span><i><span style="font-family:Verdana;">α</span></i><span style="font-family:Verdana;">-AT, and TFE-3 were</span></span><span style="font-family:Verdana;"> strongly </span><span style="font-family:Verdana;">positive, and the Ki-67 proliferation index was around 15%. The</span><span style="font-family:Verdana;"> next-genera</span><span style="font-family:Verdana;">tion high throughput sequencing indicated that EP300 gene was missense</span><span style="font-family:Verdana;"> mutated (c.457A > G) with 33% mutation abundance, and genes of DPYD (c.1627A > G), ERCC1 (c.354T > C), NQO1 (c.559C > T), TPMT (c.719A > G) and XRCC1 (c.1196A > G) were polymorphic mutated. The patient died after three months of the second surgical treatment. </span><b><span style="font-family:Verdana;">Conclusions</span></b></span><b><span style="font-family:Verdana;">:</span></b><b><span style="font-family:""> </span></b><span style="font-family:Verdana;">We report for the first time a primary bladder malignant GCM accompanied by mutations in special driving genes such as EP300. We also conducted a comprehensive literature review and an in-depth discussion.</span>展开更多
文摘背景:E1A结合蛋白300(E1A Binding Protein 300,EP300)作为一种多功能组蛋白乙酰转移酶,广泛参与基因表达调控、细胞生长及分化等生物学过程,并与多种炎症及免疫相关疾病相关,但它在过敏性鼻炎发病中的具体功能尚不明确。目的:探究过敏性鼻炎相关基因表达变化,分析其与程序性细胞死亡的关联,寻找潜在生物标志物和治疗靶点。方法:①从GSE51392、GSE43523和GSE206149数据集中收集过敏性鼻炎患者和对照组的基因表达数据,筛选差异表达基因并进行WGCNA分析。②于2022年3月至2024年5月从新疆医科大学第五附属医院收集10例进行翼管神经切断术治疗的过敏性鼻炎患者和10例健康对照者,采集患者术前术后血液和鼻腔黏膜组织样本。③构建大鼠过敏性鼻炎模型并敲降EP300,并将大鼠分为对照组、模型组、模型+shEP300-NC组、模型+shEP300组。通过ELISA、苏木精-伊红染色、RT-qPCR和Western blot技术分别检测血清炎症因子水平、鼻黏膜组织病理变化及相关基因和蛋白表达。结果与结论:①过敏性鼻炎和对照之间鉴定出43个交集基因;WGCNA发现Green模块与过敏性鼻炎相关性强,通过与程序性细胞死亡相关基因和共同差异表达基因进行交集分析得到关键基因EP300。②与术前相比,过敏性鼻炎患者术后血清白细胞介素4、白细胞介素5、白细胞介素13水平及鼻黏膜组织EP300、LC3B、Beclin1、cleaved-Caspase的表达显著降低,鼻黏膜组织p62、Bcl2的表达显著升高。③与对照组比较,模型组大鼠血清白细胞介素4、白细胞介素5、白细胞介素13水平及鼻黏膜组织EP300、LC3B、Beclin1、cleaved-Caspase的表达显著升高,鼻黏膜组织p62、Bcl2的表达显著降低;与模型组比较,模型+shEP300组大鼠上述指标均呈现相反变化。④结论:EP300可通过调控炎症、自噬与凋亡参与过敏性鼻炎的发生发展过程。
文摘目的:探讨乳酸对三阴性乳腺癌(triple-negative breast cancer,TNBC)细胞恶性行为的影响,并揭示胰岛素样生长因子2 mRNA结合蛋白3(insulin-like growth factor 2 m RNA binding protein 3,IGF2BP3)通过m6A依赖性方式调控EP300,进而介导代谢重编程的表观遗传学机制。方法:通过外源性添加乳酸钠处理TNBC细胞,采用CCK-8、集落形成、划痕愈合和Transwell实验检测细胞增殖与迁移能力;利用shRNA慢病毒载体构建IGF2BP3稳定敲低细胞模型,结合Western blot分析组蛋白乳酸化修饰水平;进一步通过RIP-seq、MeRIP-seq筛选IGF2BP3的m6A靶基因,并利用qRT-PCR和Western blot验证关键分子表达。结果:乳酸钠处理显著增强了TNBC细胞的增殖和迁移能力,且泛乳酸化水平随乳酸浓度梯度升高而增加。IGF2BP3敲低可降低组蛋白乳酸化修饰水平。通过整合RIP-seq和MeRIP-seq数据,鉴定出699个其转录本同时被IGF2BP3特异性结合且携带m6A修饰的候选基因,这些基因显著富集于表观遗传调控和代谢相关通路。EP300转录本上IGF2BP3的结合区域与m6A修饰位点高度重合,且EP300的表达水平在IGF2BP3敲低后明显下调。结论:外源性乳酸通过泛乳酸化修饰促进TNBC的恶性进展。IGF2BP3通过m6A依赖性机制调控EP300的表达,进而介导组蛋白乳酸化修饰与代谢重编程的协同作用,最终驱动TNBC的肿瘤进展。上述发现为靶向代谢-表观遗传交互调控的新型治疗策略提供了理论依据。
基金supported by grants from the Strategic Priority Research Program of the Chinese Academy of Sciences(XDB13010000)the National Natural Science Foundation of China(91631306 to BS,31671329 to XQ,31460287 to Ou,31501013 to HZ,and 31360032 to CC)+2 种基金the National 973 program(2012CB518202 to TW)the State Key Laboratory of Genetic Resources and Evolution(GREKF15-05,GREKF16-04)the Zhufeng Scholar Program of Tibetan University
文摘The genetic adaptation of Tibetans to high altitude hypoxia likely involves a group of genes in the hypoxic pathway, as suggested by earlier studies. To test the adaptive role of the previously reported candidate gene EP300 （histone acetyltransferase p300）, we conducted resequencing of a 108.9 kb gene region of EP300 in 80 unrelated Tibetans. The allele-frequency and haplotype-based neutrality tests detected signals of positive Darwinian selection on EP300 in Tibetans, with a group of variants showing allelic divergence between Tibetans and lowland reference populations, including Han Chinese, Europeans, and Africans. Functional prediction suggested the involvement of multiple EP300 variants in gene expression regulation. More importantly, genetic association tests in 226 Tibetans indicated significant correlation of the adaptive EP300 variants with blood nitric oxide （NO） concentration. Collectively, we propose that EP300 harbors adaptive variants in Tibetans, which might contribute to high-altitude adaptation through regulating NO production.
基金supported by the Guangdong Province Key Foundation of Science and Technology Program (Grant No.2009B0507000029)the Guangdong Province Science and Technology Program (Grant No.2012B031800474)a grant from the Overseas Chinese Affairs Office of the State Council Key Discipline Construction Fund (Grant No.51205002)
文摘Objective: The results of a previous study showed that a clear dysregulation was evident in the global gene expression of the BCL11A-suppressed B-lymphoma cells. In this study, the bone morphogenetic protein receptor, type II(BMPR2), E1 A binding protein p300(EP300), transforming growth factor-β2(TGFβ2), and tumor necrosis factor, and alpha-induced protein 3(TNFAIP3) gene expression patterns in B-cell malignancies were studied. Methods: The relative expression levels of BMPR2, EP300, TGFβ2, and TNFAIP3 mRNA in B-lymphoma cell lines, myeloid cell lines, as well as in cells from healthy volunteers, were determined by real-time quantitative reverse transcriptpolymerase chain reaction(qRT-PCR) with SYBR Green Dye. Glyceraldehyde-3-phosphate dehydrogenase(GAPDH) was used as reference. Results: The expression level of TGFβ2 mRNA in B-lymphoma cell lines was significantly higher than those in the cells from the healthy control(P<0.05). However, the expression level of TNFAIP3 mRNA in B-malignant cells was significantly lower than that of the healthy control(P<0.05). The expression levels of BMPR2 and EP300 mRNA showed no significant difference between B-malignant cell lines and the healthy group(P>0.05). In B-lymphoma cell lines, correlation analyses revealed that the expression of BMPR2 and TNFAIP3(r=0.882, P=0.04) had significant positive relation. The expression levels of BMPR2, EP300, and TNFAIP3 mRNA in cell lines from myeloid leukemia were significantly lower than those in the cells from the healthy control(P<0.05). The expression levels of TGFβ2 mRNA showed no significant difference between myeloid leukemia cell lines and the healthy control or B-malignant cell lines(P>0.05). The expression levels of BMPR2, EP300, and TNFAIP3 mRNA in B-lymphoma cells were significantly higher than those of the myeloid leukemia cells(P<0.05).Conclusion: Different expression patterns of BMPR2, EP300, TGFβ2, and TNFAIP3 genes in B-lymphoma cells exist.
文摘<strong>Background</strong><span style="font-family:Verdana;"><strong>:</strong></span><b><span style="font-family:""> </span></b><span style="font-family:""><span style="font-family:Verdana;">Malignant granular cell tumor (GCT) is extremely rare. Malignant GCT with EP300 gene mutation in the bladder has not been reported in the literature. </span><b><span style="font-family:Verdana;">Case Presentation</span></b></span><b><span style="font-family:Verdana;">:</span></b><span style="font-family:""><span style="font-family:Verdana;"> We report a special case of 45-year-old female with malignant GCT of the bladder. Pathological examination showed that the mass was 11 × 11 × 4.5 cm in size, involved in the bladder’s posterior wall. Under the microscope, the tumor cells were arranged in the shape of a nest or cord to infiltrate the bladder’s wall. The tumor cells were pleomorphic, red-stained granular within the cytoplasm, with increased nuclear/cyto</span><span style="font-family:Verdana;">plasmic ratio, vacuolar nuclei, and obvious nucleoli. The tumor cells were</span> <span style="font-family:Verdana;">showed obvious nuclear atypia, and the mitosis was more than 5/50HPF. </span><span style="font-family:Verdana;">Coagulative necrosis was widely showed within the tumor. Immunohistochemi</span><span><span style="font-family:Verdana;">stry (IHC) showed that S-100, NSE, CD68, CR, </span><i><span style="font-family:Verdana;">α</span></i><span style="font-family:Verdana;">-AT, and TFE-3 were</span></span><span style="font-family:Verdana;"> strongly </span><span style="font-family:Verdana;">positive, and the Ki-67 proliferation index was around 15%. The</span><span style="font-family:Verdana;"> next-genera</span><span style="font-family:Verdana;">tion high throughput sequencing indicated that EP300 gene was missense</span><span style="font-family:Verdana;"> mutated (c.457A > G) with 33% mutation abundance, and genes of DPYD (c.1627A > G), ERCC1 (c.354T > C), NQO1 (c.559C > T), TPMT (c.719A > G) and XRCC1 (c.1196A > G) were polymorphic mutated. The patient died after three months of the second surgical treatment. </span><b><span style="font-family:Verdana;">Conclusions</span></b></span><b><span style="font-family:Verdana;">:</span></b><b><span style="font-family:""> </span></b><span style="font-family:Verdana;">We report for the first time a primary bladder malignant GCM accompanied by mutations in special driving genes such as EP300. We also conducted a comprehensive literature review and an in-depth discussion.</span>
