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In neuronal system, epigenetic modifications are essential for neuronal development, the fate determination of neural stem cells and neuronal function. The dysfunction of epigenetic regulation is closely related to occurrence and development of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease. Abnormally elevated DNA methylation inhibits the expression of some DNA repair-related genes and affects the progression of Huntington's disease. In the brain of Alzheimer's disease patients, the levels of H3K27ac and H3K9ac histone modifications increased. In addition, the alteration of RNA methylation in animal models of Alzheimer's disease and Parkinson's disease showed discrepancy trends. Therefore, epigenetic modifications may serve as potential therapeutic targets for neurodegenerative diseases. Here, we summarize the recent progress of the roles of epigenetic modifications in neurodegenerative diseases.
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Animals , Humans , DNA Methylation , Epigenesis, Genetic , Neurodegenerative Diseases/genetics , Parkinson Disease/genetics , Protein Processing, Post-TranslationalABSTRACT
Over 17 and 160 types of chemical modifications have been identified in DNA and RNA, respectively. The interest in understanding the various biological functions of DNA and RNA modifications has lead to the cutting-edged fields of epigenomics and epitranscriptomics. Developing chemical and biological tools to detect specific modifications in the genome or transcriptome has greatly facilitated their study. Here, we review the recent technological advances in this rapidly evolving field. We focus on high-throughput detection methods and biological findings for these modifications, and discuss questions to be addressed as well. We also summarize third-generation sequencing methods, which enable long-read and single-molecule sequencing of DNA and RNA modification.
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Animals , Humans , DNA/metabolism , DNA Methylation , Epigenesis, Genetic , Epigenomics , RNA/metabolism , TranscriptomeABSTRACT
Background: DNA methylation plays an important role in the development of gastric cancer, but it needs the modification with DNA methyltransferases (DNMTs). Aims: To investigate the expression and clinical significance of DNMTs in the occurrence and development of gastric cancer. Methods: A total of 80 cases of gastric cancer tissues and corresponding adjacent normal tissues were collected. Immunohistochemistry was used to detect the expressions of DNMT1, DNMT3a, DNMT3b, and their correlations with clinicopathological features of gastric cancer were analyzed. mRNA and protein expressions of DNMT1, DNMT3a, DNMT3b in 4 gastric cancer cell lines and human gastric epithelial cell line were determined by qRT-PCR and Western blotting, respectively. Results: Compared with adjacent normal tissue, the positive expression rate of DNMT1 was significantly increased in gastric cancer (68.8% vs. 10.0%, P<0.01). The positive expression of DNMT1 in gastric cancer tissue was significantly higher than that of DNMT3a and DNMT3b (68.8% vs. 38.8%, 40.0%, P<0.05), while the positive expression of DNMT1 in adjacent tissue was significantly lower than that of DNMT3a and DNMT3b (10.0% vs. 60.0%, 52.5%, P<0.05). The positive expression of DNMT1 was correlated with depth of invasion, lymph node metastasis and TNM stage in patients with gastric cancer (P<0.05), while the positive expression of DNMT3a, DNMT3b were not correlated with clinicopathological features of gastric cancer. The expression of DNMT1 in gastric cancer cells was significantly higher than that in normal gastric epithelial cells, while the expressions of DNMT3a and DNMT3b were significantly decreased. Moreover, the expression of DNMT1 was related to the degree of differentiation of gastric cancer cells (P<0.05). Conclusions: DNMT1 maybe play an important role in the occurrence and development of gastric cancer.
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Objective To investigate the relationship between the expression of 06-methyl guanine DNA methyltransferase (MGMT),X-ray repair cross complementation gene 1 (XRCC1) and the incidence of glioma.Methods From February 2015 to September 2017,53 glioma patients (glioma group) in our hospital were enrolled in the study.50 patients with hypertensive intracerebral hemorrhage were selected as control A group,and 106 healthy volunteers as control B group.Immunohistochemical staining was used to detect the expression of MGMT and XRCC1 in brain tissue of glioma group and control A group,and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) were used to detect the polymorphism of MGMT and XRCC1 gene in glioma group and control B group.Results The positive expression rates of MGMT and XRCC1 in the tissues of brain glioma were 47.17％ and 39.62％,respectively,which were significantly higher than those in the control A group (P ＜ 0.05).There was no significant difference in the positive expression rate of MGMT and XRCC1 in patients with grade Ⅰ,,Ⅲ and Ⅳ (P ＞ 0.05);There was no correlation between the expression of MGMT and XRCC1 in glioma tissues (rs =0.162,P ＞ 0.05);The proportion of XRCC1 genotype AG + GG in brain glioma group was 58.49％,which was significantly higher than that of control B group (P ＜ 0.05);The proportion of MGMT genotype LP + PP in brain glioma group was 28.30％,which was significantly higher than that of control B group (P ＜ 0.05).Conclusions MGMT and XRCC1 are increased significantly in glioma brain tissues,but not correlatedwith pathological grades;The polymorphism of MGMT and XRCC1 genes may be related to the susceptibilityof gliomas.
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Objective To investigate the expression of DNA methyltransferase 2 (DNMT2) and 3a (DNMT3a) in the epidermis of patients with psoriasis vulgaris.Methods Between March 2009 and December 2010,46 patients with psoriasis vulgaris were enrolled from the Department of Dermatology,Hospital for Skin Diseases,Chinese Academy of Medical Sciences and Peking Union Medical College,and the Department of Dermatology of Yixing People's Hospital,and 28 healthy controls were enrolled from the Department of Dermatologic Surgery,Hospital for Skin Diseases,Chinese Academy of Medical Sciences and Peking Union Medical College.Real-time quantitative PCR was performed to determine the mRNA expression of DNMT2 and DNMT3a in the epidermis of the lesional and nonlesional skin of patients with psoriasis vulgaris,as well as in the epidermis of normal skin of the healthy controls.Results The mRNA expression of DNMT2 (expressed as 2-△△Ct) in the lesional skin,non-lesional skin of the patients and normal skin of the healthy controls was 0.62 ± 0.02,0.36-± 0.05 and 0.15 ± 0.11,respectively.The mRNA expression of DNMT2 was significantly higher in the lesional skin than in the non-lesional skin of the patients (t =6.23,P ＜ 0.01),and higher in the non-lesional skin of the patients than in the normal skin of the healthy controls (t =7.33,P ＜ 0.01).Additionally,the mRNA expression of DNMT3a was significantly higher in the lesional skin (0.85 ± 0.03) than in the non-lesional skin (0.43 ± 0.04) of the patients (t =5.66,P ＜ 0.01),and higher in the non-lesiona] skin of the patients than in the normal skin of healthy controls (0.18 ± 0.09,t =8.62,P ＜ 0.01).Conclusion Both DNMT2 and DNMT3a mRNA were abnormally expressed in the epidermis of patients with psoriasis vulgaris.
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Recent studies have shown that the pathophysiology of hepatocellular carcinoma (HCC) involves epigenetic alterations in DNA methylation, histone modifications, and microRNAs. In this review, we describe the general characteristics of epigenetic machinery in HCC as well as the current advances in epigenetic therapy for HCC. It is pointed out that epigenetic therapy has good prospects in the treatment of HCC, but there is still a long way before clinical application.
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Objective To observe the expressions of DNA methyltransferases (DNMTs) 1,3a and 3b in retinoblastoma (RB).Methods Sixty-two RB samples and six normal retinas were studied,including 17 poorly differentiated and 45 well differentiated samples; 16 invasive and 46 non-invasive samples.The expressions of DNMT1,3a,and 3b,and Ki-67 were detected using immunohistochemical analysis.Brown staining of nuclei was considered to represent the positive stain for DNMT1,3a and 3b,and ki-67,blue staining as negative.The level of high expression of nuclear staining was,positive cells in DNMT1≥65 ％,in DNMT3a≥60％ and in DNMT3b≥40％.The correlations of DNMT1,3a and 3b expression in RB samples,and MIB-1 labeling index were analyzed.Results Viewed under the light microscope,negative expressions of DNMT1,3a and 3b were demonstrated in normal retinas,however,positive expression was observed in RB samples,with 100％ in DNMT1,98％ in DNMT3a and 92％ in DNMT3b.Comparing well differentiated RB samples with poorly differentiated samples,significant differences were found in high expression of DNMT1 (x2 =12.57,P＜0.05) and DNMT3a (x2 =10.54,P＜0.05) ; also in the positive cells of DNMT1 (U=179,P＜0.05) and DNMT3a (U=198,P＜0.05).No significant difference was found comparing high expression (x2=1.5,P＞0.05) and positive cells (U=307,P＞0.05) of DNMT3b.When comparing invasive tumor tissues with non-invasive tumors,significant differences were shown between high expression (x2 =4.72,P＜0.05) and positive cells comparing DNMT1 (U=236,P＜0.05).No significant difference was shown in high expression (x2=3.53,0.84; P＞0.05) in DNMT3a and DNMT3b,or in comparison with positive cells (U=338,257; P＞0.05).The expression of DNMTs was positively correlated with the MIB-1 labeling index in RB tissues (R2=0.554,0.376,0.219; P＜0.05).Conclusion There are high expressions of DNMT1,3a,and 3b in RB.
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Objective To explore the association between DNA methyltrsansferase 3a (DNMT3a) expression and interleukin-4 (IL-4),interferon-gamma (IFN-γ) in mononuclear cells of colonic laminapropriamucosae in ulcerative colitis (UC) patients.Methods From November 2009 to March 2010,sixty colonic mucosa biopsy specimens through colon scopy were collected,specimens of active UC or normal controls were 30 in each group.The expression of DNMT3a,IL-4,and IFN-γ was detected with immunohistochemical method (SABC) in mononuclear cells of colonic laminapropriamucosae,and their relation with different degrees of colonic inflammatory response was analyzed.Results The positive expression rate of DNMT3a,IL-4,IFN-γ in mononuclear cells of colonic laminapropriamucosae in active UC group was significant higher than that in control group and there were statistically significant differences (x2 =16.596,P=0.000;x2 =42.857,P=0.000;x2 =6.667,P=0.024;).The expression of them was higher in sever inflammatory response than that in mild inflammatory response,and its expression intensity increased as inflammatory activity became more severe.There was positive correlation between IL-4,IFN-γ and DNMT3 expression in UC group (r=0.46,P=0.01 ;r=0.559,P=0.001).Conclusions The expression of DNMT3a,IL-4 and IFN-γ is associated with the degree of colonic inflammatory response.DNA methylation maybe involved in Th1/Th2 immune balance regulation in UC pathogenesis.
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Objective To study the effects of histone deacertylase inhibitor (TSA) on promoter methylation and expression of E-cadherin gene in a hepatocellular carcinoma cell line SMMC7721. Methods Hepatocellular carcinoma cell line SMMC-7721 was treated with TSA (300 nm/L), MTT method was used to investigate the growth inhibition ratio, TUNNL was conducted to measure the apoptosis ratio, methylation-specific PCR (MSP) was employed to detect changes in the CpG island methylation of E-cad promoter region, Western blot technique was used to detect the expression of E-cad gene and DNMT3b before and after TSA treatment, respectively. Results TSA decreases the SMMC-7721 cell viability and induces apoptosis, the growth inhibition ratio was 21.85% compared with control group. The apoptosis ratio of control group was (4.69±0.56)% ,the apoptosis ratio of TSA treatment group was (14.94±0.91)%. The apoptosis ratio of TSA treatment group was significantly higher than that of control group(P = 0.000). Before treated with TSA, the CpG island of E-cad promoter region was methylated, and the expression of E-cad was negative. TSA treatment induces demethylation of the CpG island in E-cad promoter region, causes the re-expression of E-cad. TSA reduces the expression of DNMT3b. Conclusions TSA decreases the SMMC-7721 cell viability and induces apoptosis, reverses the methylation status of E-cad promoter region, and resumes E-cad gene expression. TSA may induce demethylation through down-regulating the expression of DNMT3b.
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Various cell types in higher multicellular organisms are genetically homogenous, but are functionally and morphologically heterogeneous due to the differential expression of genes during development, which appears to be controlled by epigenetic mechanisms. However, the exact molecular mechanisms that govern the tissue-specific gene expression are poorly understood. Here, we show that dynamic changes in histone modifications and DNA methylation in the upstream coding region of a gene containing the transcription initiation site determine the tissue-specific gene expression pattern. The tissue-specific expression of the transgene correlated with DNA demethylation at specific CpG sites as well as significant changes in histone modifications from a low ratio of methylated H3- lysine 4 or acetylated H3-lysine 9, 14 to acetylated H4 to higher ratios. Based on the programmed status of transgene silenced in cloned mammalian ear-derived fibroblasts, the transgene could be reprogrammed by change of histone modification and DNA methylation by inhibiting both histone deacetylase and DNA methylation, resulting in high expression of the transgene. These findings indicate that dynamic change of histone modification and DNA methylation is potentially important in the establishment and maintenance of tissue-specific gene expression.