Global DNA hypomethylation at CpG islands coupled with local hypermethylation is a hallmark for breast cancer, yet the mechanism underlying this change remains elusive. In this study, we showed that DNMT1, which encod...Global DNA hypomethylation at CpG islands coupled with local hypermethylation is a hallmark for breast cancer, yet the mechanism underlying this change remains elusive. In this study, we showed that DNMT1, which encodes a methylation maintenance enzyme, is a transcriptional target of BRCA1. BRCA1 binds to the promoter of the DNMT1 gene through a potential OCT1 site and the binding is required for maintaining a transcriptional active configuration of the promoter in both mouse and human cells. We further demonstrated that impaired function of BRCA1 leads to global DNA hypomethylation, loss of genomic imprinting, and an open chromatin configuration in several types of tissues examined in a BRCA1 mutant mouse model at premaligant stages. BRCA1 deficiency is also associated with significantly increased expression levels of several protooncogenes, including c-Fos, Ha-Ras, and c-Myc, with a higher expression in tumors, while premalignant mammary epithelial cells displayed an intermediate state between tumors and controls. In human clinical samples, reduced expression of BRCA1 correlates with decreased levels of DNMT1, and reduced methylation of CpG islands. Thus, BRCA1 prevents global DNA hypomethylation through positively regulating DNMT1 expression, and this provides one of mechanisms for BRCAl-associated breast cancer formation.展开更多
DNA methylation is an important epigenetic regulatory mechanism that influences genomic stability, gene activation, X-chromosome inactivation and other factors. A change in DNA methylation is usually associated with a...DNA methylation is an important epigenetic regulatory mechanism that influences genomic stability, gene activation, X-chromosome inactivation and other factors. A change in DNA methylation is usually associated with aging and cellular senescence. DNA methyltransferase 1(DNMT1) is the most abundant DNA methyltransferase, and it plays an important role in maintaining the established methylation pattern during DNA replication in vertebrates. Although the effect of aging on DNA methylation has been well studied in vertebrates, little research has been conducted in invertebrates, especially in marine bivalves. In this study, we examined global DNA methylation levels in four groups of adult Zhikong scallop Chlamys farreri at different ages. The results showed that both the age and tissue type had a strong effect on the DNA methylation. In addition, a significant decrease in DNA methylation with aging(1–4 years) can be detected in mantle, kidney and hepatopancreas. We further measured the change in DNMT1 transcript abundance using quantitative reverse transcription PCR(q RT-PCR), which revealed that DNMT1 transcription significantly decreased with aging in mantle and hepatopancreas and strongly correlated with DNA methylation(R = 0.72). Our data provided greater insight into the aging-related decline of DNA methylation, which could aid in gaining a better understanding of the relationship between DNA methylation and the aging process in bivalve mollusks.展开更多
目的通过检测免疫性血小板减少症(ITP)患儿外周血淋巴细胞中DNA甲基转移酶1(Dnmt1)、DNA甲基转移酶3a(Dnmt3a)m RNA的表达,探讨DNA甲基化与儿童ITP发病机制之间的联系。方法采用RT-PCR方法检测36例新诊断ITP患儿与26例健康体检儿童外周...目的通过检测免疫性血小板减少症(ITP)患儿外周血淋巴细胞中DNA甲基转移酶1(Dnmt1)、DNA甲基转移酶3a(Dnmt3a)m RNA的表达,探讨DNA甲基化与儿童ITP发病机制之间的联系。方法采用RT-PCR方法检测36例新诊断ITP患儿与26例健康体检儿童外周血淋巴细胞中Dnmt1、Dnmt3a m RNA的表达水平;并进行分析比较。结果新诊断ITP患儿外周血淋巴细胞中Dnmt1的m RNA表达为(3.02±0.49),较对照组(4.58±0.52)明显降低,差异有统计学意义(t=11.95,P<0.01);ITP患儿Dnmt3a m RNA的表达为(1.49±0.44),较对照组(2.41±0.32)明显降低,差异有统计学意义(t=9.12,P<0.01)。结论新诊断ITP患儿可能存在DNA低甲基化,这种DNA低甲基化与儿童ITP发病机制关系密切。展开更多
文摘Global DNA hypomethylation at CpG islands coupled with local hypermethylation is a hallmark for breast cancer, yet the mechanism underlying this change remains elusive. In this study, we showed that DNMT1, which encodes a methylation maintenance enzyme, is a transcriptional target of BRCA1. BRCA1 binds to the promoter of the DNMT1 gene through a potential OCT1 site and the binding is required for maintaining a transcriptional active configuration of the promoter in both mouse and human cells. We further demonstrated that impaired function of BRCA1 leads to global DNA hypomethylation, loss of genomic imprinting, and an open chromatin configuration in several types of tissues examined in a BRCA1 mutant mouse model at premaligant stages. BRCA1 deficiency is also associated with significantly increased expression levels of several protooncogenes, including c-Fos, Ha-Ras, and c-Myc, with a higher expression in tumors, while premalignant mammary epithelial cells displayed an intermediate state between tumors and controls. In human clinical samples, reduced expression of BRCA1 correlates with decreased levels of DNMT1, and reduced methylation of CpG islands. Thus, BRCA1 prevents global DNA hypomethylation through positively regulating DNMT1 expression, and this provides one of mechanisms for BRCAl-associated breast cancer formation.
基金supported by the National Natural Science Foundation of China(31130054)the National High Technology Research and Development Program of China(2012AA10A401)Doctoral Fund of Ministry of Education of China(20120132130002)
文摘DNA methylation is an important epigenetic regulatory mechanism that influences genomic stability, gene activation, X-chromosome inactivation and other factors. A change in DNA methylation is usually associated with aging and cellular senescence. DNA methyltransferase 1(DNMT1) is the most abundant DNA methyltransferase, and it plays an important role in maintaining the established methylation pattern during DNA replication in vertebrates. Although the effect of aging on DNA methylation has been well studied in vertebrates, little research has been conducted in invertebrates, especially in marine bivalves. In this study, we examined global DNA methylation levels in four groups of adult Zhikong scallop Chlamys farreri at different ages. The results showed that both the age and tissue type had a strong effect on the DNA methylation. In addition, a significant decrease in DNA methylation with aging(1–4 years) can be detected in mantle, kidney and hepatopancreas. We further measured the change in DNMT1 transcript abundance using quantitative reverse transcription PCR(q RT-PCR), which revealed that DNMT1 transcription significantly decreased with aging in mantle and hepatopancreas and strongly correlated with DNA methylation(R = 0.72). Our data provided greater insight into the aging-related decline of DNA methylation, which could aid in gaining a better understanding of the relationship between DNA methylation and the aging process in bivalve mollusks.
文摘目的通过检测免疫性血小板减少症(ITP)患儿外周血淋巴细胞中DNA甲基转移酶1(Dnmt1)、DNA甲基转移酶3a(Dnmt3a)m RNA的表达,探讨DNA甲基化与儿童ITP发病机制之间的联系。方法采用RT-PCR方法检测36例新诊断ITP患儿与26例健康体检儿童外周血淋巴细胞中Dnmt1、Dnmt3a m RNA的表达水平;并进行分析比较。结果新诊断ITP患儿外周血淋巴细胞中Dnmt1的m RNA表达为(3.02±0.49),较对照组(4.58±0.52)明显降低,差异有统计学意义(t=11.95,P<0.01);ITP患儿Dnmt3a m RNA的表达为(1.49±0.44),较对照组(2.41±0.32)明显降低,差异有统计学意义(t=9.12,P<0.01)。结论新诊断ITP患儿可能存在DNA低甲基化,这种DNA低甲基化与儿童ITP发病机制关系密切。
