Alcohol exposure during development: Impact on the epigenome

Fetal alcohol spectrum disorders represent a wide range of symptoms associated with in utero alcohol exposure. Animal models of FASD have been useful in determining the specific neurological consequences of developmental alcohol exposure, but the mechanisms of those consequences are unclear. Long-lasting changes to the epigenome are proposed as a mechanism of alcohol-induced teratogenesis in the hippocampus. The current study utilized a three-trimester rodent model of FASD to examine changes to some of the enzymatic regulators of the epigenome in adolescence. Combined pre- and post-natal alcohol exposureresulted in a significant increase in DNA methyltransferase activity (DNMT), without affecting histone deacetylase activity (HDAC). Developmental alcohol exposure also caused a change in gene expression of regulators of the epigenome, in particular, DNMT1, DNMT3a, and methyl CpG binding protein 2 (MeCP2). The modifications of the activity and expression of epigenetic regulators in the hippocampus of rodents perinatally exposed to alcohol suggest that alcohol's impact on the epigenome and its regulators may be one of the underlying mechanisms of alcohol teratogenesis.     

Acute leukemia associated with valproic acid treatment: A novel mechanism for leukemogenesis?

Valproic acid has been previously associated with hematologic toxicity, including a reversible myelodysplasia-like syndrome without chromosomal abnormalities. We now report three cases of acute leukemia with features of secondary leukemia associated with valproic acid therapy: two cases of acute myelogenous leukemia with multilineage dysplasia, one with trisomy 8 and one with monosomy 7, and one case of secondary acute lymphoblastic leukemia with del (7) (q22q34), del (9) (q21.11q22), del (11) (q12q23). One patient had a previous myelodysplastic syndrome while on valproic acid. Valproic acid has been previously shown to be a histone deacetylase inhibitor. Inhibition of histone deacetylase causes a relaxation of chromatin structure and thus increases susceptibility to DNA damage and sensitizes cells to radiation. We propose that valproic acid therapy may lead to secondary leukemia by increasing DNA damage through chronic inhibition of histone deacetylase.     

曲古抑菌素A对乙型肝炎病毒HBx蛋白与组蛋白去乙酰化酶1相互作用的影响

目的 探讨曲古抑菌素A对乙型肝炎病毒HBx蛋白与组蛋白去乙酰化酶1(HDAC1)相互作用的影响. 方法 常规分子克隆技术构建HBx蛋白及HDAC1表达载体,Western blot分别验证蛋白质表达;谷胱甘肽转移酶沉降试验及免疫共沉淀技术分别于体内外验证HBx蛋白与HDAC1存在的相互作用. 结果成功构建了HBx蛋白及HDAC1表达载体,体内外实验均证实HBx蛋白与HDACI间存在相互作用,但HDACI抑制剂曲古抑菌素A不影响两者间相互作用.结论 HBx蛋白以曲古抑菌素A非依赖方式与HDAC1存在相互作用.     

香烟提取物通过减少HDAC2表达诱导小鼠C2C12成肌细胞衰老

目的:探讨香烟提取物(CSE)能否引起小鼠C2C12成肌细胞衰老,并研究成肌细胞衰老与组蛋白去乙酰化酶2(HDAC2)的关系。方法:培养C2C12细胞株,分化为成熟成肌细胞,观察CSE干预对成肌细胞衰老和HDAC2表达的影响,采用real-time PCR和Western blot方法分别检测HDAC2 mRNA和蛋白的表达;β-半乳糖苷酶染色检测衰老细胞的百分率。结果:MTT法测定最佳CSE浓度与干预时间分别为60 m L/L和24 h。CSE干预后β-半乳糖苷酶染色阳性细胞数增加,同时伴有HDAC2 mRNA和蛋白表达的减少。四溴苯三唑(TBB)在促进HDAC2 mRNA和蛋白表达的同时,β-半乳糖苷酶染色阳性细胞数减少;用HDAC2的特异性阻滞剂丙戊酸抑制HDAC2 mRNA和蛋白的表达时,β-半乳糖苷酶染色阳性细胞数增加。结论:香烟提取物可通过减少小鼠C2C12成肌细胞HDAC2的表达促进细胞老化。     

Epigenetic Role of Histone 3 Lysine Methyltransferase and Demethylase in Regulating Apoptosis Predicting the Recurrence of Atypical Meningioma

Alteration of apoptosis is related with progression and recurrence of atypical meningiomas (AMs). However, no comprehensive study has been conducted regarding histone modification regulating apoptosis in AMs. This study aimed to determine the prognostic values of certain apoptosis-associated factors, and examine the role of histone modification on apoptosis in AMs. The medical records of 67 patients with AMs, as diagnosed during recent 13 yr, were reviewed retrospectively. Immunohistochemical staining was performed on archived paraffin-embedded tissues for pro-apoptotic factors (CASP3, IGFBP, TRAIL-R1, BAX, and XAF1), anti-apoptotic factors (survivin, ERK, RAF1, MDM2, and BCL2), and the histone modifying enzymes (MLL2, RIZ, EZH1, NSD2, KDM5c, JMJD2a, UTX, and JMJD5). Twenty-six (38.8%) patients recurred during the follow-up period (mean duration 47.7 months). In terms of time-to-recurrence (TTR), overexpression of CASP3, TRAIL-R1, and BAX had a longer TTR than low expression, and overexpression of survivin, MDM2, and BCL2 had a shorter TTR than low expression (P<0.05). Additionally, overexpression of MLL2, UTX, and JMJ5 had shorter TTRs than low expression, and overexpression of KDM5c had a longer TTR than low expression. However, in the multi-variate analysis of predicting factors for recurrence, low expression of CASP3 (P<0.001), and BAX (P<0.001), and overexpression of survivin (P=0.007), and MDM2 (P=0.037) were associated with recurrence independently, but any enzymes modifying histone were not associated with recurrence. Conclusively, this study suggests certain apoptosis-associated factors should be associated with recurrence of AMs, which may be regulated epigenetically by histone modifying enzymes.

Graphical Abstract

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Epigenetic dimension of oxygen radical injury in spermatogonial epithelial cells

The present work reports a direct role of mitochondrial oxidative stress induced aberrant chromatin regulation, as a central phenomenon, to perturbed genomic integrity in the testicular milieu. Oxygen-radical injury following N-succinimidyl N-methylcarbamate treatment in mouse spermatogonial epithelial (GC-1 spg) cells induced functional derailment of mitochondrial machinery. Mitophagy resulted in marked inhibition of mitochondrial respiration and reduced mtDNA copy number. Impaired cell cycle progression along with altered H3K9me1, H4K20me3, H3, AcH3 and uH2A histone modifications were observed in the treated cells. Dense heterochromatin foci and aberrant expression of HP1α in nuclei of treated cells implied onset of senescence associated secretory phenotype mediated through nuclear accumulation of NF-κB. Neoplastic nature of daughter clones, emerged from senescent mother phenotypes was confirmed by cytogenetic instability, aberrant let-7a and let-7b miRNA expression and anchorage independent growth. Together, our results provide the first insights of redox-dependent epigenomic imbalance in spermatogonia, a previously unknown molecular paradigm.     

Synergistic interaction of the histone deacetylase inhibitor SAHA with the proteasome inhibitor bortezomib in mantle cell lymphoma

Objectives:  Mantle cell lymphoma (MCL) is an incurable B cell lymphoma, and novel treatment strategies are urgently needed. We evaluated the effects of combined treatment with the proteasome inhibitor bortezomib and the histone deacetylase inhibitor (HDACi) suberoylanilide hydroxamic acid (SAHA) on MCL. Bortezomib acts by targeting the proteasome, and – among other mechanisms – results in a reduced nuclear factor-kappa B (NF-κB) activity. HDACi promote histone acetylation, and also interfere with NF-κB signaling.
Methods:  Human MCL cell lines (JeKo-1, Granta-519 and Hbl-2) were exposed to bortezomib and/or SAHA. Cell viability and apoptosis were quantified by the MTT and annexin-V assay, respectively. Reactive oxygen species (ROS) were analyzed using the fluorophore H₂DCFDA. In addition, activated caspases, proteasome- and NF-κB activity were quantified.
Results:  Combined incubation with bortezomib and SAHA resulted in synergistic cytotoxic effects, as indicated by combination index values <1 using the median effect method of Chou and Talalay. The combination of both inhibitors led to a strong increase in apoptosis as compared to single agents and was accompanied by enhanced ROS generation, while each agent alone only modestly induced ROS. The free radical scavenger N -acetyl- l -cysteine blocked the ROS generation and reduced the apoptosis significantly. In addition, coexposure of bortezomib and SAHA led to increased caspase-3, -8 and -9 activity, marked reduction of proteasome activity and decrease of NF-κB activity.
Conclusions:  This is the first report giving evidence that SAHA and bortezomib synergistically induce apoptosis in MCL cells. These data build the framework for clinical trials using combined proteasome and histone deacetylase inhibition in the treatment of MCL.