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There are more than 60 million alcoholic liver disease (ALD) patients in China, which has become a public health problem that cannot be ignored. Moreover, the social problem of "alcohol culture" is still hardly to solve, so that safe and effective prevention and treatment for ALD are in urgent need clinically. Previous studies on ALD have focused on the direct damaging effects of alcohol and its toxic metabolites, while recent studies have shown that the pathogenesis of ALD also include alcohol metabolic reprogramming and endogenous metabolites disorder. Although the endogenous metabolites have no direct toxicity, its long-term effect should not be ignored. These endogenous metabolites could change epigenetic modifications, cause widespread and persistent abnormal gene expression and signal pathway activation abnormally to promote metabolic reprogramming and stamp it as "metabolic memory", which manifest pathological changes and promote ALD, especially liver fibrosis/cirrhosis and liver cancer. Based on this, the article reviews the important epigenetic modifications caused by related metabolites in ALD and their associated effects. The role of traditional Chinese medicine (TCM) and its active ingredients in regulating epigenetics was also analyzed. The results suggest that regulation of epigenetics and alteration of "metabolic memory" may be a novel mechanism of TCM in the prevention and treatment of ALD.
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@#Congenital cleft lip and/or palate (CL/P) is a common malformation of maxillofacial development. At present, it is believed that the etiology of congenital cleft lip and palate mainly results from genetic factors and environmental factors. Epigenetic changes induced by environmental factors may be the key factor in the occurrence of fetal congenital malformations. As one of the important epigenetic modifications, DNA methylation has been widely and deeply studied in many fields, but as a link between the individual and the environment, its application in CL/P is limited. Existing studies have shown that DNA methylation is closely related to the occurrence of cleft lip and palate. Stimulation of folate deficiency, smoking, pollutant exposure and other environmental factors can induce changes in the state of DNA methylation, thus affecting gene expression in the development of lip and palate and leading to the occurrence of deformities.
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Clonal hematopoiesis with indeterminant potential(CHIP)is defined as the proportion of detectable clonal hematopoietic cells in peripheral blood exceeding 2% and without confirmed hematologic malignancy.CHIP could increase the risk of malignant diseases through changes in DNA damage response, transcriptional programming and epigenetic modification.The incidence of malignant tumors in the blood system is significantly higher in the CHIP patients than healthy person.In addition, CHIP represents a negative factor associated with aging.Recent studies have found that the incidences of infections, anemia, heart failure, thrombotic events, and tumors of the blood system in CHIP carriers were significantly increased.Starting with the epigenetic modifications, phenotypic changes and inflammatory mechanisms of CHIP-related gene mutations, this paper discussed the mechanisms of CHIP-related diseases and possible intervention aimed at aging.
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Epigenetic modification genes are defined as genes whose products modify the epigenome directly through DNA methylation, histone modification or chromatin remodeling.More and more studies have shown that mutations in epigenetic modification genes are an important etiology of rare diseases with abnormal cardiac development.And these diseases usually affect multiple organs including heart due to the change of epigenetic components.Moreover, children′s lives and health are often threatened by a lack of effective drugs and complex cardiovascular malformations.This article reviews advances in molecule genetics of Tatton-Brown-Rahman syndrome, Kabuki syndrome, Rubinstein-Taybi syndrome, CHARGE syndrome and Sifrim-Hitz-Weiss syndrome, and mainly elaborates the mechanism of cardiovascular malformations caused by mutations in corresponding epigenetic modification genes, providing more comprehensive reference for clinical diagnosis and management.
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Diabetes retinopathy(DR)may continue to develop even if blood sugar is well controlled, which indicates that previous hyperglycemia will lead to long-term harmful vascular dysfunction, and this phenomenon is defined as “metabolic memory” of diabetes retinopathy. Because the onset of DR is insidious, clinical symptomatic treatment is mainly used. Effective means of early diagnosis, accurate treatment and prognosis are lacking and new diagnosis and treatment ideas need to be developed urgently. In recent years, many new studies have shown that epigenetic modification is involved in the pathogenesis of DR “metabolic memory” in DNA methylation, histone post-translational modification and microRNA(microRNAs,miRNAs)regulation, which provides a direction and strategy for the exploration of DR molecular mechanism. In this review, we discussed the role of epigenetic modification in the pathogenesis of DR and analyzed the challenges and prospects of its application in the treatment of DR, with a view to provide a reference for early diagnosis and treatment of DR in the future.
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The self-renewal and differentiation of hematopoietic stem cells(HSCs)are highly regulated by epigenetic modification,in which histone acetylation can activate or silence gene transcription.Histone deacetylase inhibitors(HDACIs)can inhibit the activity of histone deacetylase in HSCs to increase histone acetylation.A variety of HDACIs,such as trichostatin A and valproic acid,are used to expand HSCs in vitro,especially cord blood HSCs,combined with cytokines in serum-free culture to obtain more long-term repopulating cells.HDACIs promote the transcription of pluripotent genes related to stem cell self-renewal and inhibit the expression of genes related to differentiation,so as to promote the expansion and inhibit differentiation of HSCs.The expansion of cord blood HSCs by small molecular HDACIs in vitro is expected to improve the quantity of cord blood HSCs.The further research will focus on high-throughput screening for the most powerful HDACIs and the highly selective HDACIs,exploring the combination of epigenetic modifiers of different pathways.
Subject(s)
Epigenesis, Genetic , Fetal Blood , Hematopoietic Stem Cells , Histone Deacetylase Inhibitors/pharmacology , Valproic Acid/pharmacologyABSTRACT
Airway epithelial barrier dysfunction has been observed in allergic asthma patients.Inhaled allergens have shown a disruptive effect on the airway epithelial barrier.Airway barrier related genetic variation and epigenetics are also involved in the airway epithelial barrier dysfunction.A lot of studies believe that airway epithelial barrier dysfunction underlie the development of asthma.The study of the relationship between allergic asthma and airway epithelial barrier function will be helpful to understand the pathogenesis of allergic asthma and provide new ideas for the treatment of allergic asthma.
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N6-methyladenosine is one of the most prevalent mRNA modification in eukaryotes. The regulation of this pervasive mark is a dynamic and reversible process. m⁶A RNA methylation is catalyzed by m⁶A writers, removed by m⁶A erasers and recognized by m⁶A readers, thereby regulating multiple RNA processes including alternative splicing, nuclear export, degradation and translation. Accumulated evidence suggests that m⁶A modification plays a crucial role in the pathogenic mechanism and malignant progression in non-small cell lung cancer (NSCLC), including cell survival, proliferation, migration, invasion, tumor metastasis and drug resistance. Moreover, the expression of m⁶A and its related proteins are dysregulated in clinical samples and circulating tumor cells (CTCs) of lung cancer patients, indicating that m⁶A modification may serve as a novel potential biomarker for the diagnosis and prognosis of lung cancer. In this review, by summarizing a great number of recent reports related to m⁶A's function and its modulators, we aim to provide a new insight on the early diagnosis and drug development in NSCLC therapy. .
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BACKGROUND: Inflammatory bowel disease is a chronic inflammatory disease associated with intestinal immune, and autophagy is a cell approach to promote immune regulation. Abnormal expression of autophagy-related genes is closely related to intestinal inflammation and immune response. However, the mechanism by which epigenetic modification regulates autophagy in inflammatory bowel disease has not been fully clarified. OBJECTIVE: To introduce the role of epigenetic modification in autophagy, and to promote a further understanding of inflammatory bowel disease. METHODS: A computer-based online research of PubMed database was performed with the key words of “inflammatory bowel disease, autophagy, autophagy-related genes, epigenetic modification, DNA methylation, histone modification, chromatin remodeling, miRNA.” The search time was from January 1998 to April 2019. Finally, 61 eligible articles were included in result analysis. RESULTS AND CONCLUSION: Epigenetic modifications such as DNA methylation, histone modification, chromatin remodeling, non-coding RNA can regulate intestinal inflammation, immune and autophagy through susceptibility genes AGL and IRGM, thereby mediating the occurrence and development of inflammatory bowel disease.
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Enhancers activate transcription in a distance-, orientation-, and position-independent manner, which makes them difficult to be identified. Self-transcribing active regulatory region sequencing (STARR-seq) measures the enhancer activity of millions of DNA fragments in parallel. Here we used STARR-seq to generate a quantitative global map of rice enhancers. Most enhancers were mapped within genes, especially at the 5' untranslated regions (5'UTR) and in coding sequences. Enhancers were also frequently mapped proximal to silent and lowly-expressed genes in transposable element (TE)-rich regions. Analysis of the epigenetic features of enhancers at their endogenous loci revealed that most enhancers do not co-localize with DNase I hypersensitive sites (DHSs) and lack the enhancer mark of histone modification H3K4me1. Clustering analysis of enhancers according to their epigenetic marks revealed that about 40% of identified enhancers carried one or more epigenetic marks. Repressive H3K27me3 was frequently enriched with positive marks, H3K4me3 and/or H3K27ac, which together label enhancers. Intergenic enhancers were also predicted based on the location of DHS regions relative to genes, which overlap poorly with STARR-seq enhancers. In summary, we quantitatively identified enhancers by functional analysis in the genome of rice, an important model plant. This work provides a valuable resource for further mechanistic studies in different biological contexts.
Subject(s)
Acetylation , Base Sequence , Deoxyribonuclease I , Metabolism , Enhancer Elements, Genetic , Epigenesis, Genetic , Genes, Plant , Genomics , Methods , Histone Code , Genetics , Histones , Metabolism , Models, Genetic , Oryza , Genetics , Promoter Regions, Genetic , Genetics , Repetitive Sequences, Nucleic Acid , Genetics , Sequence Analysis, DNA , Transcription, GeneticABSTRACT
Messenger RNA (mRNA) can be modified by more than 100 chemical modifications. Among these modifications, N6-methyladenosine (m⁶A) is one of the most prevalent modifications. During the processes of cells differentiation, embryo development or stress, m⁶A can be modified on key mRNAs and regulate the progress of cells through modulating mRNA metabolism and translation. Other mRNA modifications, including N1-methyladenosine (m¹A), 5-methylcytosine (m⁵C) and pseudouridine, together with m⁶A form the epitranscriptome of mRNA that accurately modulate the mRNA translation. Here we review the types and characteristic of mRNA epigenetic modifications, especially the recent progresses of the function of m⁶A, we also expect the main research direction of m⁶A epigenetic modification in the future.
Subject(s)
Adenosine , Genetics , Metabolism , Cell Differentiation , Genetics , Embryonic Development , Genetics , Epigenesis, Genetic , Gene Expression Regulation , RNA Processing, Post-Transcriptional , RNA, Messenger , MetabolismABSTRACT
Objective:To observe the effects of recipes for tonifying kidney and replenishing Qi, Zuoguiwan (ZG) and Yiqi Congming Tang(YQ) on memory capacity, expressions of learning and memory-related genes expression, and explore the changes in relevant epigenetic modification enzymes. Method:SD male rats with natural aging (24 months old) were used as animal models and randomly divided into aged control group, aged ZG group(12.12 g·kg-1), aged YQ group(10.18 g·kg-1), aged compound group(11.15 g·kg-1) and aged antagonist RU38486 group(5×10-3g·kg-1). Another 5 months old male SD rats were included as the young control group. Morris water maze method was used to observe the spatial learning and memory ability of the rats. The co-localizations of histone deacetylase 2 (HDAC2) and methyl CpG binding protein 2 (MeCP2) in hippocampus of rats in each group were observed by laser confocal microscope. The changes in expressions of glucocorticoid receptor (GR), synapsin1(Syn-1), HDAC2, and histone acetyltransferase 1(HAT1) proteins in hippocampus of each group were detected by Western blot, and mRNA expression of HDAC2 was detected by Real-time fluorescence quantitative polymerase Chain reaction (Real-time PCR). At the same time, the effects of ZG, YQ and compound decoction in alleviating the above-mentioned abnormal changes were observed. Result:Compared with the young control group(control group), the latency of the aged control group was significantly prolonged (PPPPPPPConclusion:ZG group, YQ group, and compound group can improve the spatial learning and memory abilities of aged rats by increasing the expression of learning-memory-associated protein GR and epigenetic modification enzyme HAT1, and reducing the expression of HDAC2 and the co-localization of HDAC2 protein and MeCP2 in the nucleus.
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N6-methyladenosine (m6A) modification is considered to be an epigenetic modification, which is similar to DNA or histone modification. Through the interaction between m6A methyltransferase and demethylase, m6A modification is involved in a variety of biological processes such as RNA splicing, protein translation and stem cell regeneration. Recently, plenty of studies have found that m6A is associated with cancer, contributes to the self-renewal of cancer stem cells, promotes the proliferation of cancer cells, and increases the resistance of radiotherapy or chemotherapy. Moreover, the inhibitors of m6A-related factors have been discovered, and some of them have been identified to inhibit cancer progression, suggesting that m6A may be a target of anticancer therapy. This article briefly reviews the function of m6A in human tumors.
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Primary liver cancer arises from chronic liver disease, and cirrhotic liver gradually develops into dysplastic nodules that eventually form malignant tumors. In recent years, molecular biotechnology development has deepened people's understanding on the pathogenesis of liver cancer. Epigenetic modifications play a significant role in DNA methylation, non-coding RNAs, chromatin remodeling, and histone modification. This review focuses on the progress of currently implicated non-coding RNAs in the molecular pathogenesis of hepatocellular carcinoma, and its potential application in improving the diagnosis and treatment.
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DNA methyltransferase 3A (DNMT3A) is one of the critical epigenetic modifiers responsible for de novo DNA methylation. DNMT3A mutations are identified in some kinds of hematological malignancies, especially in acute myeloid leukemia (AML) with high frequency, indicating poor prognosis. Recent researches have shown that abnormalities of epigenetic related genes such as DNMT3A play important roles in the development and progression of hematological malignancies, which was named as class Ⅲ mutation associated with the pathogenesis of AML. In this review, the progresses of clinical and basic researches about DNMT3A mutation in hematological malignancies were summarized.
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Epidemiological studies reveal that prenatal adverse environment could cause lower birthweight in offspring and increase the susceptibility to multiple chronic diseases (e.g. metabolic and neuropsychiatric diseases etc.) after maturity. However, the underlying mechanism remains unclarified. The hypothalamic-pituitary-adrenal (HPA) axis is a key neuroendocrine axis playing pivotal roles in systemic stress responses before and after birth. It is also an important but vulnerable fetal targeting organ. Previous studies showed that many environmental insults during pregnancy, including external environment and maternal health condition, could affect fetal development in multi-ways via maternal-placental-fetal unit, which leads to the intrauterine programming alteration of HPA axis and the in?creased susceptibility to chronic diseases in adulthood. This article reviews the latest global advances in the etiology of increased susceptibility to adult diseases induced by compromised prenatal environ?ment and the associated intrauterine programming mechanisms by incorporating our recent research findings, and proposes that the fetal over-exposure to maternal glucocorticoids (GC) could bring about the intrauterine neuroendocrine metabolic programming alteration in offspring:the core is the program?ming of GC-insulin-like growth factor 1 axis in multiple organs, and the abnormal epigenetic modification is involved in this programming.
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DNA methyltransferase 3A (DNMT3A) is one of the critical epigenetic modifiers responsible for de novo DNA methylation. DNMT3A mutations are identified in some kinds of hematological malignancies, especially in acute myeloid leukemia (AML) with high frequency, indicating poor prognosis. Recent researches have shown that abnormalities of epigenetic related genes such as DNMT3A play important roles in the development and progression of hematological malignancies, which was named as class Ⅲ mutation associated with the pathogenesis of AML. In this review, the progresses of clinical and basic researches about DNMT3A mutation in hematological malignancies were summarized.
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Radiotherapy is one of the most important methods to treat malignant tumors. Due to the presence of radiation resistance, the effect of radiotherapy is not entirely satisfactory. To alleviate radiation resistance and improve the radiotherapy effect, radiosensitizers have emerged. As a newly discovered radiosensitizer, RRx-001 has a good clinical application prospect. This paper reviewed the research progress of RRx-001 in source, safety, radiotherapy sensitizing activity and related mechanisms.
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BACKGROUND: To identify potential molecular prognostic markers in core binding factor (CBF) AML, we analyzed incidences and prognostic impacts of mutations in c-KIT, WT1, CEBPA, CBL, and a number of epigenetic genes in CBF AML. METHODS: Seventy one and 21 AML patients with t(8;21) and inv(16) were enrolled in this study, respectively. NPM1, CEBPA, c-KIT, IDH1/2, DNMT3A, EZH2, WT1, and CBL mutations were analyzed by direct sequencing. Patients were categorized with respect to c-KIT and WT1 mutation status, and both clinical features and prognoses were compared. RESULTS: The incidences of FLT3 internal tandem duplication (ITD), NPM1, CEBPA, IDH1/2, DNMT3A, EZH2, and CBL mutations were low (< or =5%) in CBF AML patients. However, c-KIT and WT1 mutations occurred frequently (10.9% and 13.8%, respectively). t(8;21) patients with c-KIT mutations showed significantly shorter overall survival (OS) and disease free survival (DFS) periods than those without mutations (P<0.001, for both); however, although the limited number of t(8;21) patients were analyzed, WT1 mutation status did not affect prognosis significantly. Relapse or death during follow-up occurred more frequently in t(8;21) patients carrying c-KIT mutations than in those without the mutation, although the difference was significant only in a specific patient subgroup with no WT1 mutations (P=0.014). CONCLUSIONS: The incidences of mutations in epigenetic genes are very low in CBF AML; however, c-KIT and WT1 mutations occur more frequently than others. The poor prognostic impact of c-KIT mutation in t(8;21) AML patients only applies in a specific patient subgroup without WT1 mutations. The prognostic impact of WT1 mutation in CBF AML is not evident and further investigation is required.
Subject(s)
Adolescent , Adult , Aged , Aged, 80 and over , Child , Female , Humans , Male , Middle Aged , Young Adult , Asian People/genetics , CCAAT-Enhancer-Binding Proteins/genetics , Core Binding Factors/genetics , Disease-Free Survival , Epigenesis, Genetic , Incidence , Leukemia, Myeloid, Acute/diagnosis , Mutation , Prognosis , Proto-Oncogene Proteins c-cbl/genetics , Proto-Oncogene Proteins c-kit/genetics , Republic of Korea/epidemiology , Survival Rate , Translocation, Genetic , WT1 Proteins/geneticsABSTRACT
OBJECTIVE: To make a review of nowadays related dissertations about epigenetic modifications (DNA methylation, histone modifications, chromatin remodeling and the non-coding microRNA interruption, etc.) mediating the abnormal expression of drug metabolic enzymes and inactive metabolism of substances in organisms. METHODS: Researches on epigenetic modifications regulating the genes expression or activity change of drug metabolism enzymes were reviewed. RESULTS AND CONCLUSION: The research in this field can provide reference for determining biomarkers in clinical diagnosis and therapies of tumors.