Over the last two decades, cancer-related alterations in DNA methylation that regulate transcription have been reported for a variety of tumors of the gastrointestinal tract. Due to its relevance for translational res...Over the last two decades, cancer-related alterations in DNA methylation that regulate transcription have been reported for a variety of tumors of the gastrointestinal tract. Due to its relevance for translational research, great emphasis has been placed on the analysis and molecular characterization of the CpG island methylator phenotype(CIMP), defined as widespread hypermethylation of CpG islands in clinically distinct subsets of cancer patients. Here, we present an overview of previous work in this field and also explore some open questions using crossplatform data for esophageal, gastric, and colorectal adenocarcinomas from The Cancer Genome Atlas. We provide a data-driven, pan-gastrointestinal stratification of individual samples based on CIMP status and we investigate correlations with oncogenic alterations, including somatic mutations and epigenetic silencing of tumor suppressor genes. Besides known events in CIMP such as BRAF V600 E mutation, CDKN2 A silencing or MLH1 inactivation, we discuss the potential role of emerging actors such as Wnt pathway deregulation through truncating mutations in RNF43 and epigenetic silencing of WIF1. Our results highlight the existence of molecular similarities that are superimposed over a larger backbone of tissue-specific features and can be exploited to reduce heterogeneity of response in clinical trials.展开更多
Objective: To determine the relationship between nucleosome positions and formation of differential methylation of the reported region A, B, C, and D within the MLH1 CpG island. Methods: Methylation of the MLH1 prom...Objective: To determine the relationship between nucleosome positions and formation of differential methylation of the reported region A, B, C, and D within the MLH1 CpG island. Methods: Methylation of the MLH1 promoter was analyzed by combined of bisulfite restriction assay. Chromatin of RKO and MGC803 cells were extracted and digested by MNase. Mononucleosomal DNA fragment was isolated and used as templates for detection of nucleosomal distribution by a battery of quantitative PCRs covering the full MLH1 promoter region. Results: The MLH1 was methylated in RKO and unmethylated in MGC803. At the region B, where methylation of CpG sites did not correlated with transcription of this gene well, qPCR product of the M-3 (-599nt ~ -475nt) fragment was amplified in both RKO and MGC803 cells. However, at the region C and D within the core promoter, where methylation of CpG sites correlated with loss of MLH1 transcription well, the M-7 (-257nt ~ -153nt) and M-8 (-189nt ~ -71nt) fragments were amplified remarkably only in RKO cells. Conclusion: Nucleosome may be the basic unit for both CpG methylation and methylation-related regulation of gene transcription. Methylation status of CpG sites within the same nucleosome may be homogeneous; between different nucleosomes, homogeneous or heterogeneous.展开更多
AIM:To evaluate the clinical significance of CpG island methylator phenotype(CIMP) in plasma and its asso-ciation with hepatocellular carcinoma(HCC) progress.METHODS:CIMP status of 108 HCC patients wasanalyzed using a...AIM:To evaluate the clinical significance of CpG island methylator phenotype(CIMP) in plasma and its asso-ciation with hepatocellular carcinoma(HCC) progress.METHODS:CIMP status of 108 HCC patients wasanalyzed using a methylation marker panel in tumortissues and plasma with methylation-specific poly-merase chain reaction. Fifteen samples of non-neo-plastic liver tissues and 60 of plasma from healthy persons were examined simultaneously. Examinedgenes included APC,WIF-1,RUNX-3,DLC-1,SFRP-1,DKK and E-cad .RESULTS:The frequencies of high-level methylation in HCC tissue and plasma were at least 15% forthe seven genes:APC,48/108,44.44% in tissue and26/108,24.07% in plasma;WIF-1,53/108,49.07% intissue and 35/108,32.41% in plasma;RUNX-3,52/108,48.14% in tissue and 42/108,38.89% in plasma;DLC-1,38/108,35.18% in tissue and 23/108,21.30%in plasma;SFRP-1,40/108,37.04% in tissue and31/108,28.7% in plasma;DKK,39/108,36.1% in tis-sue and 25/108,23.14% in plasma;and E-cad,37/108,34.3% in tissue and 18/108,16.67% in plasma. CIMP+(≥ 3 methylated genes) was detected in 68(60.2%) tumor tissue samples and 62(57.4%) plasma samples.CIMP was not detected in non-neoplastic liver tissuesor plasma of healthy persons. CIMP status in tumortissues differed significantly in gender,hepatitis Bsurface antigen,alpha-fetoprotein,and tumor-node-metastasis stage(P < 0.05) . Similar results were obtained with plasma samples(P < 0.05) . There was nodifference in CIMP status in age,presence of hepatitis C virus antibody,cirrhosis,number of nodes,numberof tumors,tumor size,or Edmondson-Steiner stage. Aone-year follow-up found that the metastatic rate and recurrence rate in the CIMP+ group were significantly higher than in the CIMP- group as assessed with plasma samples(P < 0.05) .CONCLUSION:Plasma DNA can be a reliable samplesource for CIMP analysis. CIMP in plasma may serve asa molecular marker of late-stage and poor-prognosis HCC.展开更多
AIM:To investigate the association between the CpG island methylator phenotype(CIMP) and serum Helicobacter pylori(H.pylori) levels for clinical prediction of gastric cancer(GC) progression.METHODS:We analyzed the ser...AIM:To investigate the association between the CpG island methylator phenotype(CIMP) and serum Helicobacter pylori(H.pylori) levels for clinical prediction of gastric cancer(GC) progression.METHODS:We analyzed the serum CIMP status of 75 patients with GC using a methylation marker panel and a methylation-specific polymerase chain reaction.Serum samples from 40 healthy persons were examined at the same time.The genes examined were APC,WIF-1,RUNX-3,DLC-1,SFRP-1,DKK and E-cad.H.pylori infection in serum was assayed with an anti-H.pylori immunoglobulin G antibody test and a rapid urease test.RESULTS:The frequencies of high-level methylation in GC tissues for the seven genes were:48% for APC,57.33% for WIF-1,56% for RUNX-3,50.67% for DLC-1,52% for SFRP-1,54.67% for DKK,and 48% for E-cad.The frequencies in GC serum were 30.67% for APC,34.67% for WIF-1,37.33% for RUNX-3,29.33% for DLC-1,33.33% for SFRP-1,32% for DKK,and 26.67% for E-cad.CIMP+(defined as ≥ 3 methylated genes) was associated with 47(62.67%) GC tissue samples and 44(58.67%) GC serum samples.CIMP+ was not associated with non-neoplastic mucosal tissues or the serum of healthy persons.Of the 75 GC cases,51(68%) were H.pylori +,and 24(32%) were H.pylori-.Of the 51 H.pylori + cases,36 were CIMP+ and 15 were CIMP-.In contrast,for the 24 H.pylori-cases,11 were CIMP+,and 13 were CIMP-.The difference was significant between the H.pylori + and H.pylori-groups(χ 2 = 4.27,P < 0.05).Of the 51 H.pylori + GC patients,34 were CIMP+ and 17 were CIMP-,while among the 24 H.pylori-GC cases,10 were CIMP+ and 14 were CIMP-.The difference was significant between the H.pylori+ and H.pylori-groups(χ 2 = 4.21,P < 0.05).A 2-year follow-up showed significant difference in the rates of metastasis and recurrence between H.pylori +/CIMP+ cases and the H.pylori +/CIMP-cases or CIMP-cases associated with H.pylori assayed in serum(P < 0.05).However,there were no significant differences in survival rates between the two groups.CONCLUSION:H.pylori +/CIMP+ cases are associated with higher rates of metastasis and recurrence than H.pylori +/CIMP-cases.Serum may be useful for examining CIMP status.展开更多
AIM To identify whether Cp G island methylator phenotype(CIMP) is predictive of response to neoadjuvant chemoradiotherapy(NACRT) and outcomes in rectal cancer.METHODS Patients undergoing NACRT and surgical resection f...AIM To identify whether Cp G island methylator phenotype(CIMP) is predictive of response to neoadjuvant chemoradiotherapy(NACRT) and outcomes in rectal cancer.METHODS Patients undergoing NACRT and surgical resection for rectal cancer in a tertiary referral centre between 2002-2011 were identified. Pre-treatment tumour biopsies were analysed for CIMP status(high, intermediate or low) using methylation specific PCR. KRAS and BRAF status were also determined using pyrosequencing analysis. Clinical information was extracted from case records and cancer services databases. Response to radiotherapy was measured by tumour regression scores determined uponhistological examination of the resected specimen. The relationship between these molecular features, response to NACRT and oncological outcomes were analysed.RESULTS There were 160 patients analysed with a median followup time of 46.4 mo. Twenty-one(13%) patients demonstrated high levels of CIMP methylation(CIMP-H) and this was significantly associated with increased risk of extramural vascular invasion(EMVI) compared with CIMP-L [8/21(38%) vs 15/99(15%), P = 0.028]. CIMP status was not related to tumour regression after radiotherapy or survival, however EMVI was significantly associated with adverse survival(P < 0.001). Intermediate CIMP status was significantly associated with KRAS mutation(P = 0.01). There were 14(9%) patients with a pathological complete response(pC R) compared to 116(73%) patients having no or minimal regression after neoadjuvant chemoradiotherapy. Those patients with pC R had median survival of 106 mo compared to 65.8 mo with minimal regression, although this was not statistically significant(P = 0.26). Binary logistic regression analysis of the relationship between EMVI and other prognostic features revealed, EMVI positivity was associated with poor overall survival, advanced "T" stage and CIMP-H but not nodal status, age, sex, KRAS mutation status and presence of local or systemic recurrence.CONCLUSION We report a novel association of pre-treatment characterisation of CIMP-H with EMVI status which has prognostic implications and is not readily detectable on pre-treatment histological examination.展开更多
AIM: To investigate the functions of promoter hypermethylation of O6-methylguanine-DNA methyltransferase (MGMT) gene in colorectal tumorigenesis and progression.METHODS: The promoter hypermethylation of MGMT gene was ...AIM: To investigate the functions of promoter hypermethylation of O6-methylguanine-DNA methyltransferase (MGMT) gene in colorectal tumorigenesis and progression.METHODS: The promoter hypermethylation of MGMT gene was detected in 27 sporadic colorectal adenomas,62 sporadic colorectal carcinomas and 20 normal colorectal mucosa tissues by methylation-specific PCR. At the same time, the expression of MGMT protein was carried out in the same samples using immunohistochemistry. Mutantallele-specific amplification was used to detect K-rasG to A point mutation in codon 12.RESULTS: None of the normal colorectal mucosa tissues showed methylated bands. Promoter hypermethylation was detected in 40.7% (11 of 27) of adenomas and 43.5% (27 of 62) of carcinomas. MGMT proteins were expressed in nucleus and cytoplasm of normal colorectal mucosa tissues. Loss of MGMT expression was found in 22.2% (6 of 27) of adenomas and 45.2% (28 of 62) of carcinomas. The difference between them was significant (P = 0.041). In the 6 adenomas and 28 carcinomas losing MGMT expression, 5 and 24 cases presented methylation,respectively (P = 0.027, P<0.001). Thirteen of the 19 colorectal tumors with K-rasG to A point mutation in codon 12 had methylated MGMT(P = 0.011). The frequencies of K-rasG to A point mutation were 35.3% (12 of 34) and 12.7% (7 of 55) in tumors losing MGMT expression and with normal expression, respectively.CONCLUSION: Promoter hypermethylation and loss of expression of MGMT gene were common events in colorectal tumorigenesis, and loss of expression of MGMT occurs more frequently in carcinomas than in adenomas in sporadic patients. Hypermethylation of the CpG island of MGMT gene was associated with loss of MGMT expression and K-ras G to A point mutation in colorectal tumor. The frequency of K-ras G to A point mutation was increased in tumors losing MGMT expression. It suggests that epigenetic inactivation of MGMT plays an important role in colorectal neoplasia.展开更多
An altered pattern of epigenetic modifications, such as DNA methylation and histone modification, is critical to many common human diseases, including cancer. Recently, mitochondrial DNA (mtDNA) was reported to be a...An altered pattern of epigenetic modifications, such as DNA methylation and histone modification, is critical to many common human diseases, including cancer. Recently, mitochondrial DNA (mtDNA) was reported to be associated with tumorigenesis through epigenetic regulation of methylation patterns. One of the promising approaches to study DNA methylation and CpG islands (CGIs) is sequencing and analysis of clones derived from the physical library generated by methyl-CpG-binding domain proteins and restriction enzyme MseI. In this study, we observed that the most redundant sequences of 349 clones in a human CGI library were all generated from the human mitochondrial genome. Further analysis indicated that there was a 5,845-bp DNA transfer from mtDNA to chromosome 1, and all the clones should be the products of a 510-bp MseI fragment, which contained a putative CGI of 270 bp. The 510-bp fragment was annotated as part of cytochrome c oxidase subunit II (COXII), and phylogenetic analysis of homologous sequences containing COXII showed three DNA transfer events from mtDNA to nuclear genome, one of which underwent secondary transfer events between different chromosomes. These results may further our understanding of how the mtDNA regulates DNA methylation in the nucleus.展开更多
CpG island methylation plays important role in various biological processes. To investigate methylation landscape of all CpG islands on the human genome, we develop a model for predicting the CpG island methylation st...CpG island methylation plays important role in various biological processes. To investigate methylation landscape of all CpG islands on the human genome, we develop a model for predicting the CpG island methylation status. This model outperforms other existing methods. We apply the model on the whole human genome and predict the landscape of DNA methylation of all CpG islands. Based on the methylation profile, we find that about 31% of CpG islands are methylation-prone and CpG islands located in promoter regions are seldom methylated. There is no significant difference in the CpG island methylation level between R and G bands among the chromosomes. The occupancy of RNA polymerase II is significantly higher in methylation-resistant promoter CpG islands, indicating that genes with such promoter CpG islands tend to be more active.展开更多
As an important epigenetic modification,DNA methylation is involved in many biological processes such as animal cell differentiation,embryonic development,genomic imprinting and sex chromosome inactivation.As DNA meth...As an important epigenetic modification,DNA methylation is involved in many biological processes such as animal cell differentiation,embryonic development,genomic imprinting and sex chromosome inactivation.As DNA methylation sequencing becomes more sophisticated,it becomes possible to use it to solve more zoological problems.This paper reviews the characteristics of DNA methylation,with emphasis on the research and application of DNA methylation in poultry.展开更多
基金funded by the Intramural program of the National Human Genome Research Institute,the National Institutes of Health
文摘Over the last two decades, cancer-related alterations in DNA methylation that regulate transcription have been reported for a variety of tumors of the gastrointestinal tract. Due to its relevance for translational research, great emphasis has been placed on the analysis and molecular characterization of the CpG island methylator phenotype(CIMP), defined as widespread hypermethylation of CpG islands in clinically distinct subsets of cancer patients. Here, we present an overview of previous work in this field and also explore some open questions using crossplatform data for esophageal, gastric, and colorectal adenocarcinomas from The Cancer Genome Atlas. We provide a data-driven, pan-gastrointestinal stratification of individual samples based on CIMP status and we investigate correlations with oncogenic alterations, including somatic mutations and epigenetic silencing of tumor suppressor genes. Besides known events in CIMP such as BRAF V600 E mutation, CDKN2 A silencing or MLH1 inactivation, we discuss the potential role of emerging actors such as Wnt pathway deregulation through truncating mutations in RNF43 and epigenetic silencing of WIF1. Our results highlight the existence of molecular similarities that are superimposed over a larger backbone of tissue-specific features and can be exploited to reduce heterogeneity of response in clinical trials.
基金supported by the National Natural Science Foundation of China(No.30571056)the National"973"Basic Research Program of China(No.2005CB522403).
文摘Objective: To determine the relationship between nucleosome positions and formation of differential methylation of the reported region A, B, C, and D within the MLH1 CpG island. Methods: Methylation of the MLH1 promoter was analyzed by combined of bisulfite restriction assay. Chromatin of RKO and MGC803 cells were extracted and digested by MNase. Mononucleosomal DNA fragment was isolated and used as templates for detection of nucleosomal distribution by a battery of quantitative PCRs covering the full MLH1 promoter region. Results: The MLH1 was methylated in RKO and unmethylated in MGC803. At the region B, where methylation of CpG sites did not correlated with transcription of this gene well, qPCR product of the M-3 (-599nt ~ -475nt) fragment was amplified in both RKO and MGC803 cells. However, at the region C and D within the core promoter, where methylation of CpG sites correlated with loss of MLH1 transcription well, the M-7 (-257nt ~ -153nt) and M-8 (-189nt ~ -71nt) fragments were amplified remarkably only in RKO cells. Conclusion: Nucleosome may be the basic unit for both CpG methylation and methylation-related regulation of gene transcription. Methylation status of CpG sites within the same nucleosome may be homogeneous; between different nucleosomes, homogeneous or heterogeneous.
基金Supported by The Department of Health of Jiangsu Province,China,No.H200957
文摘AIM:To evaluate the clinical significance of CpG island methylator phenotype(CIMP) in plasma and its asso-ciation with hepatocellular carcinoma(HCC) progress.METHODS:CIMP status of 108 HCC patients wasanalyzed using a methylation marker panel in tumortissues and plasma with methylation-specific poly-merase chain reaction. Fifteen samples of non-neo-plastic liver tissues and 60 of plasma from healthy persons were examined simultaneously. Examinedgenes included APC,WIF-1,RUNX-3,DLC-1,SFRP-1,DKK and E-cad .RESULTS:The frequencies of high-level methylation in HCC tissue and plasma were at least 15% forthe seven genes:APC,48/108,44.44% in tissue and26/108,24.07% in plasma;WIF-1,53/108,49.07% intissue and 35/108,32.41% in plasma;RUNX-3,52/108,48.14% in tissue and 42/108,38.89% in plasma;DLC-1,38/108,35.18% in tissue and 23/108,21.30%in plasma;SFRP-1,40/108,37.04% in tissue and31/108,28.7% in plasma;DKK,39/108,36.1% in tis-sue and 25/108,23.14% in plasma;and E-cad,37/108,34.3% in tissue and 18/108,16.67% in plasma. CIMP+(≥ 3 methylated genes) was detected in 68(60.2%) tumor tissue samples and 62(57.4%) plasma samples.CIMP was not detected in non-neoplastic liver tissuesor plasma of healthy persons. CIMP status in tumortissues differed significantly in gender,hepatitis Bsurface antigen,alpha-fetoprotein,and tumor-node-metastasis stage(P < 0.05) . Similar results were obtained with plasma samples(P < 0.05) . There was nodifference in CIMP status in age,presence of hepatitis C virus antibody,cirrhosis,number of nodes,numberof tumors,tumor size,or Edmondson-Steiner stage. Aone-year follow-up found that the metastatic rate and recurrence rate in the CIMP+ group were significantly higher than in the CIMP- group as assessed with plasma samples(P < 0.05) .CONCLUSION:Plasma DNA can be a reliable samplesource for CIMP analysis. CIMP in plasma may serve asa molecular marker of late-stage and poor-prognosis HCC.
基金Supported by Department of Health of Jiangsu Province o China,No.H200957
文摘AIM:To investigate the association between the CpG island methylator phenotype(CIMP) and serum Helicobacter pylori(H.pylori) levels for clinical prediction of gastric cancer(GC) progression.METHODS:We analyzed the serum CIMP status of 75 patients with GC using a methylation marker panel and a methylation-specific polymerase chain reaction.Serum samples from 40 healthy persons were examined at the same time.The genes examined were APC,WIF-1,RUNX-3,DLC-1,SFRP-1,DKK and E-cad.H.pylori infection in serum was assayed with an anti-H.pylori immunoglobulin G antibody test and a rapid urease test.RESULTS:The frequencies of high-level methylation in GC tissues for the seven genes were:48% for APC,57.33% for WIF-1,56% for RUNX-3,50.67% for DLC-1,52% for SFRP-1,54.67% for DKK,and 48% for E-cad.The frequencies in GC serum were 30.67% for APC,34.67% for WIF-1,37.33% for RUNX-3,29.33% for DLC-1,33.33% for SFRP-1,32% for DKK,and 26.67% for E-cad.CIMP+(defined as ≥ 3 methylated genes) was associated with 47(62.67%) GC tissue samples and 44(58.67%) GC serum samples.CIMP+ was not associated with non-neoplastic mucosal tissues or the serum of healthy persons.Of the 75 GC cases,51(68%) were H.pylori +,and 24(32%) were H.pylori-.Of the 51 H.pylori + cases,36 were CIMP+ and 15 were CIMP-.In contrast,for the 24 H.pylori-cases,11 were CIMP+,and 13 were CIMP-.The difference was significant between the H.pylori + and H.pylori-groups(χ 2 = 4.27,P < 0.05).Of the 51 H.pylori + GC patients,34 were CIMP+ and 17 were CIMP-,while among the 24 H.pylori-GC cases,10 were CIMP+ and 14 were CIMP-.The difference was significant between the H.pylori+ and H.pylori-groups(χ 2 = 4.21,P < 0.05).A 2-year follow-up showed significant difference in the rates of metastasis and recurrence between H.pylori +/CIMP+ cases and the H.pylori +/CIMP-cases or CIMP-cases associated with H.pylori assayed in serum(P < 0.05).However,there were no significant differences in survival rates between the two groups.CONCLUSION:H.pylori +/CIMP+ cases are associated with higher rates of metastasis and recurrence than H.pylori +/CIMP-cases.Serum may be useful for examining CIMP status.
文摘AIM To identify whether Cp G island methylator phenotype(CIMP) is predictive of response to neoadjuvant chemoradiotherapy(NACRT) and outcomes in rectal cancer.METHODS Patients undergoing NACRT and surgical resection for rectal cancer in a tertiary referral centre between 2002-2011 were identified. Pre-treatment tumour biopsies were analysed for CIMP status(high, intermediate or low) using methylation specific PCR. KRAS and BRAF status were also determined using pyrosequencing analysis. Clinical information was extracted from case records and cancer services databases. Response to radiotherapy was measured by tumour regression scores determined uponhistological examination of the resected specimen. The relationship between these molecular features, response to NACRT and oncological outcomes were analysed.RESULTS There were 160 patients analysed with a median followup time of 46.4 mo. Twenty-one(13%) patients demonstrated high levels of CIMP methylation(CIMP-H) and this was significantly associated with increased risk of extramural vascular invasion(EMVI) compared with CIMP-L [8/21(38%) vs 15/99(15%), P = 0.028]. CIMP status was not related to tumour regression after radiotherapy or survival, however EMVI was significantly associated with adverse survival(P < 0.001). Intermediate CIMP status was significantly associated with KRAS mutation(P = 0.01). There were 14(9%) patients with a pathological complete response(pC R) compared to 116(73%) patients having no or minimal regression after neoadjuvant chemoradiotherapy. Those patients with pC R had median survival of 106 mo compared to 65.8 mo with minimal regression, although this was not statistically significant(P = 0.26). Binary logistic regression analysis of the relationship between EMVI and other prognostic features revealed, EMVI positivity was associated with poor overall survival, advanced "T" stage and CIMP-H but not nodal status, age, sex, KRAS mutation status and presence of local or systemic recurrence.CONCLUSION We report a novel association of pre-treatment characterisation of CIMP-H with EMVI status which has prognostic implications and is not readily detectable on pre-treatment histological examination.
基金Supported by the Key Technologies R&D Program of Hubei Province, No. 2002AA301C84
文摘AIM: To investigate the functions of promoter hypermethylation of O6-methylguanine-DNA methyltransferase (MGMT) gene in colorectal tumorigenesis and progression.METHODS: The promoter hypermethylation of MGMT gene was detected in 27 sporadic colorectal adenomas,62 sporadic colorectal carcinomas and 20 normal colorectal mucosa tissues by methylation-specific PCR. At the same time, the expression of MGMT protein was carried out in the same samples using immunohistochemistry. Mutantallele-specific amplification was used to detect K-rasG to A point mutation in codon 12.RESULTS: None of the normal colorectal mucosa tissues showed methylated bands. Promoter hypermethylation was detected in 40.7% (11 of 27) of adenomas and 43.5% (27 of 62) of carcinomas. MGMT proteins were expressed in nucleus and cytoplasm of normal colorectal mucosa tissues. Loss of MGMT expression was found in 22.2% (6 of 27) of adenomas and 45.2% (28 of 62) of carcinomas. The difference between them was significant (P = 0.041). In the 6 adenomas and 28 carcinomas losing MGMT expression, 5 and 24 cases presented methylation,respectively (P = 0.027, P<0.001). Thirteen of the 19 colorectal tumors with K-rasG to A point mutation in codon 12 had methylated MGMT(P = 0.011). The frequencies of K-rasG to A point mutation were 35.3% (12 of 34) and 12.7% (7 of 55) in tumors losing MGMT expression and with normal expression, respectively.CONCLUSION: Promoter hypermethylation and loss of expression of MGMT gene were common events in colorectal tumorigenesis, and loss of expression of MGMT occurs more frequently in carcinomas than in adenomas in sporadic patients. Hypermethylation of the CpG island of MGMT gene was associated with loss of MGMT expression and K-ras G to A point mutation in colorectal tumor. The frequency of K-ras G to A point mutation was increased in tumors losing MGMT expression. It suggests that epigenetic inactivation of MGMT plays an important role in colorectal neoplasia.
文摘An altered pattern of epigenetic modifications, such as DNA methylation and histone modification, is critical to many common human diseases, including cancer. Recently, mitochondrial DNA (mtDNA) was reported to be associated with tumorigenesis through epigenetic regulation of methylation patterns. One of the promising approaches to study DNA methylation and CpG islands (CGIs) is sequencing and analysis of clones derived from the physical library generated by methyl-CpG-binding domain proteins and restriction enzyme MseI. In this study, we observed that the most redundant sequences of 349 clones in a human CGI library were all generated from the human mitochondrial genome. Further analysis indicated that there was a 5,845-bp DNA transfer from mtDNA to chromosome 1, and all the clones should be the products of a 510-bp MseI fragment, which contained a putative CGI of 270 bp. The 510-bp fragment was annotated as part of cytochrome c oxidase subunit II (COXII), and phylogenetic analysis of homologous sequences containing COXII showed three DNA transfer events from mtDNA to nuclear genome, one of which underwent secondary transfer events between different chromosomes. These results may further our understanding of how the mtDNA regulates DNA methylation in the nucleus.
基金supported by the National Natural Science Foundation of China (30625012 and 60721003)National Basic Research Program of China (2004CB518605)
文摘CpG island methylation plays important role in various biological processes. To investigate methylation landscape of all CpG islands on the human genome, we develop a model for predicting the CpG island methylation status. This model outperforms other existing methods. We apply the model on the whole human genome and predict the landscape of DNA methylation of all CpG islands. Based on the methylation profile, we find that about 31% of CpG islands are methylation-prone and CpG islands located in promoter regions are seldom methylated. There is no significant difference in the CpG island methylation level between R and G bands among the chromosomes. The occupancy of RNA polymerase II is significantly higher in methylation-resistant promoter CpG islands, indicating that genes with such promoter CpG islands tend to be more active.
基金supported by the Project of the Seed Industry Revitalization of Department of Agriculture and Rural Affairs of Guangdong Province(2022-XPY-05-001)the Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program(2019BT02N630).
文摘As an important epigenetic modification,DNA methylation is involved in many biological processes such as animal cell differentiation,embryonic development,genomic imprinting and sex chromosome inactivation.As DNA methylation sequencing becomes more sophisticated,it becomes possible to use it to solve more zoological problems.This paper reviews the characteristics of DNA methylation,with emphasis on the research and application of DNA methylation in poultry.