ABSTRACT
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
Lysine acetylation has emerged as one of the most important post-translational modifications that participates in various biological and pathological processes. Histone acetyltransferase 1 (HAT1) as the first identified protein ε-amino lysine acetyltransferase is able to regulate the acetylation of histones and non-histone proteins. However‚ the acetylation substrates and sites mediated by HAT1 in liver cancer are poorly understood. In this study‚ we demonstrated that HAT1 was highly expressed in the liver cancer tissues‚ which was negatively associated with the prognosis of patients. Based on the establishment of the HAT1-knockout HepG2 cell line‚ we employed a quantitative proteomics approach to study the profiling of acetylation mediated by HAT1 in HepG2 cells. Interestingly‚ we identified a total of 858 Kac sites on 547 proteins in the HepG2 cell line‚ in which HAT1 mediated the levels of Kac of 74 sites on 68 proteins. The pathways and metabolic processes that were affected by HAT1-dependent acetylation modification were analyzed by bioinformatics. The results show that Kac regulates disease development‚ RNA biology‚ spliceosome and nucleosome assembly‚ oxidative stress‚ various signaling pathways and metabolic pathways‚ etc.. Moreover‚ we verified that the HAT1-mediated acetylation modification could promote abnormal lipid metabolism. CCK8 assays‚ clone formation and Edu assays revealed that HAT1 could remarkably enhance the cell proliferation of liver cancer in vitro. Thus‚ our finding explored the profiling of HAT1-mediated protein acetylation in HepG2 cells‚ which provides new insights into the underlying mechanism by which HAT1 mediates the development of liver cancer. Clinically‚ the HAT1-mediated acetylation sites could be used for the precise targets of drug development.
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Histone deacetylases (HDACs) are a class of epigenetic modification enzymes and closely related to chromatin structure and gene transcriptional regulation. HDAC3 belongs to class I HDACs. It is reported that HDAC3 plays a key role in heart development. Recent studies find that HDAC3 plays an important regulatory role in cardiovascular diseases. This paper reviews the class I HDAC family HDAC3, focuses on its localization, enzyme activity and the research progress of HDAC3 in congenital heart disease, coronary atherosclerotic heart disease, cardiomyopathies, heart failure, and arrhythmias. This review may provide new drug target for the clinical treatment of cardiovascular diseases.
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Parkinson's disease (PD) is an incurable neurodegenerative disease, which seriously affects the life quality of patients. Researches in recent years found that excessive production or abnormal structure of α-synuclein and forming toxic aggregates are the key factors in the pathogenesis of PD. In a variety of mechanisms, abnormal modification of α-synuclein is closely related to its aggregation state, such as phosphorylation, ubiquitination and nitration modification, but the exact effects are still uncertain. Recent studies have shown that acetylation modification of α-synuclein plays an important role in the abnormal aggregation of α-synuclein. This article reviewed the progress of acetylation modification of α-synuclein.
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Objective To explore the specific mechanism of ginsenoside Rh2(S) inducing the apoptosis of leukemia cells. Methods The effect of Rh2(S) on proliferation of leukemia cells K562 and KG1a was measured by cell counting kit-8 assay (CCK-8 assay). The growth states of cells were observed under the inverted phase microscope, and cell cycle distribution, and apoptosis were determined by flow cytometry (FCM). The expression levels of HDAC6, HSP90, Akt, GSK-3β, β-catenin, and cell cycle apoptosis related proteins were ascertained by Western blotting. Results The results of CCK-8 showed that Rh2(S) had the most obvious inhibitory effect on the proliferation of leukemia cells. Rh2(S) significantly induced apoptosis and led to cell cycle arrest at G0/G1 phase of leukemia cells by FCM. While the microscope observation showed that the number of cells was decreased and normal cell morphology changed. Rh2(S) decreased the expression of Bcl-2, Cyclin D1, HDAC6, HSP90, p-Akt, and β-catenin and increased the expression of Bax, Ac-α-tubulin, and GSK-3β by Western blotting. Conclusion Rh2(S) can effectively inhibit the proliferation and promote the apoptosis of K562 and KG1a cells, its specific mechanism may relate to inhibitting the expression of HDAC6, resulting in a decline in the expression of HSP90, so as to further inhibit the activity of Akt activation of GSK-3, and finally inhibit Wnt/β-catenin pathway.
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Objective:To investigate the relationship between cervical lesion development and histone acetylation that regulates RAR-β2 expression. Methods:Immunohistochemistry and Western blot analysis were performed to detect AcH3, RAR-β2, and involu-crin expression in normal cervical tissues as well as in tissues with cervical intraepithelial neoplasia (CIN)Ⅱ-Ⅲand squamous cell cer-vical carcinoma. The relationship among histone acetylation level, RAR-β2 expression, and cervical lesion severity were analyzed. Re-sults:AcH3, RAR-β2, and involucrin expression were reduced or absent with the progression of cervical lesions;significant differences were noted between the groups (P<0.05). Histone acetylation level and RAR-β2 expression were positively correlated (r=0.797, P<0.05). AcH3 and RAR-β2 expression, which were both associated with the cervical lesions, were negatively correlated [r=-0.547(AcH3), r=-0.585(RAR-β2), P<0.05]. Conclusion:Histone acetylation modification is associated with the regulation of RAR-β2 expression. This pro-cess is also likely to participate in the carcinogenesis of cervical carcinoma.
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The incidence of bronchial asthma in children is increasing nowadays.More and more studies have showed that epigenetics plays an important role in the pathogenesis of asthma.One of them are histone modification(acetylation and deacetylation),which is catalyzed by histone acetyltransferase (HAT) and histone deacetylase (HDAC).HAT and HDAC can mediate asthma via causing Th1/Th2 imbalance,increased airway hyperresponsiveness,regulation of various inflammatory medium and so on.This paper reviews the HAT and HDAC mediated incidence of asthma and other possible mechanisms,the latest of glucocorticoid in the treatment of children with asthma epigenetic mechanisms.