The epigenetics of estrogen

Epigenetic processes have been impli- zcated in everything from cell proliferation to maternal behavior. Epigenetic alterations, including histone alterations and DNA methylation, have also been shown to play critical roles in the formation of some types of memory, and in the modulatory effects that factors, such as stress, drugs of abuse and environmental stimulation, have on the brain and memory function. Recently, we demonstrated that the ability of the sex-steroid hormone 17β-estradiol (E₂) to enhance memory formation is dependent on histone acetylation and DNA methylation, a finding that has important implications for understanding how hormones influence cognition in adulthood and aging. In this article, we provide an overview of the literature demonstrating that epigenetic processes and E₂ influence memory, describe our findings indicating that epigenetic alterations regulate E₂-induced memory enhancement, and discuss directions for future work on the epigenetics of estrogen.     

Epigenetic regulation of estrogen signaling in breast cancer

Estrogen signaling is mediated by ERα and ERβ in hormone dependent, breast cancer (BC). Over the last decade the implication of epigenetic pathways in BC tumorigenesis has emerged: cancer-related epigenetic modifications are implicated in both gene expression regulation, and chromosomal instability. In this review, the epigenetic-mediated estrogen signaling, controlling both ER level and ER-targeted gene expression in BC, are discussed: (1) ER silencing is frequently observed in BC and is often associated with epigenetic regulations while chemical epigenetic modulators restore ER expression and increase response to treatment;(2) ER-targeted gene expression is tightly regulated by co-recruitment of ER and both coactivators/corepressors including HATs, HDACs, HMTs, Dnmts and Polycomb proteins.     

表观遗传修饰在学习和记忆中的调节作用

学习和记忆行为是大脑的基本功能,它使得生物个体能够更好地适应环境的变化。揭示学习和记忆的分子生物学机制是现代神经生物学发展的目标之一。经过近40年的研究现已初步证实了突触可塑性在学习和记忆中所起的关键作用。而近年来的研究发现,表观遗传修饰对学习和记忆过程具有重要的调控作用。这一发现将有利于进一步揭示学习和记忆的复杂机制,并将为某些认知障碍性疾病的治疗提供新的思路。     

Epigenetic memory: the Lamarckian brain

Recent data support the view that epigenetic processes play a role in memory consolidation and help to transmit acquired memories even across generations in a Lamarckian manner. Drugs that target the epigenetic machinery were found to enhance memory function in rodents and ameliorate disease phenotypes in models for brain diseases such as Alzheimer's disease, Chorea Huntington, Depression or Schizophrenia. In this review, I will give an overview on the current knowledge of epigenetic processes in memory function and brain disease with a focus on Morbus Alzheimer as the most common neurodegenerative disease. I will address the question whether an epigenetic therapy could indeed be a suitable therapeutic avenue to treat brain diseases and discuss the necessary steps that should help to take neuroepigenetic research to the next level.     

The role of malate in hormone-induced enhancement of mitochondrial respiration

Shortly after the injection of glucagon, epinephrine, norepinephrine, vasopressin, or angiotensin II into fasted rats, mitochondria isolated from their livers contained elevated concentrations of malate and oxidized citrate, alpha-ketoglutarate, and, in some cases, succinate more rapidly than mitochondria from fasted, control rats. The administration of tryptophan, lactate, or ethanol and refeeding of rats fasted 24 h result in similar elevations of mitochondrial malate concentration and oxidation of added substrates. Treatments that resulted in elevated mitochondrial malate resulted also in increased uptake of added citrate, alpha-ketoglutarate, pyruvate, and, in some cases, succinate. It is postulated that the well-documented effect of gluconeogenic hormones on mitochondrial oxidation of carboxylic substrates may be mediated by malate which not only yields oxalacetate to support the tricarboxylic acid cycle but also facilitates the transport of added substrates, and which is regenerated in the tricarboxylic acid cycle.     

Epigenetic regulation of learning and memory by Drosophila EHMT/G9a

The epigenetic modification of chromatin structure and its effect on complex neuronal processes like learning and memory is an emerging field in neuroscience. However, little is known about the "writers" of the neuronal epigenome and how they lay down the basis for proper cognition. Here, we have dissected the neuronal function of the Drosophila euchromatin histone methyltransferase (EHMT), a member of a conserved protein family that methylates histone 3 at lysine 9 (H3K9). EHMT is widely expressed in the nervous system and other tissues, yet EHMT mutant flies are viable. Neurodevelopmental and behavioral analyses identified EHMT as a regulator of peripheral dendrite development, larval locomotor behavior, non-associative learning, and courtship memory. The requirement for EHMT in memory was mapped to 7B-Gal4 positive cells, which are, in adult brains, predominantly mushroom body neurons. Moreover, memory was restored by EHMT re-expression during adulthood, indicating that cognitive defects are reversible in EHMT mutants. To uncover the underlying molecular mechanisms, we generated genome-wide H3K9 dimethylation profiles by ChIP-seq. Loss of H3K9 dimethylation in EHMT mutants occurs at 5% of the euchromatic genome and is enriched at the 5' and 3' ends of distinct classes of genes that control neuronal and behavioral processes that are corrupted in EHMT mutants. Our study identifies Drosophila EHMT as a key regulator of cognition that orchestrates an epigenetic program featuring classic learning and memory genes. Our findings are relevant to the pathophysiological mechanisms underlying Kleefstra Syndrome, a severe form of intellectual disability caused by mutations in human EHMT1, and have potential therapeutic implications. Our work thus provides novel insights into the epigenetic control of cognition in health and disease.     

Gene regulation: implications of histone dispersal patterns for epigenetics

Histones are widely believed to carry regulatory information across cell generations. A recent study suggests limits to this model by measuring dispersal of ancestral histones in yeast.     

Epigenetic regulation of prostate cancer

Prostate cancer is a commonly diagnosed cancer in men and a leading cause of cancer deaths. Whilst the underlying mechanisms leading to prostate cancer are still to be determined, it is evident that both genetic and epigenetic changes contribute to the development and progression of this disease. Epigenetic changes involving DNA hypo- and hypermethylation, altered histone modifications and more recently changes in microRNA expression have been detected at a range of genes associated with prostate cancer. Furthermore, there is evidence that particular epigenetic changes are associated with different stages of the disease. Whilst early detection can lead to effective treatment, and androgen deprivation therapy has a high response rate, many tumours develop towards hormone-refractory prostate cancer, for which there is no successful treatment. Reliable markers for early detection and more effective treatment strategies are, therefore, needed. Consequently, there is a considerable interest in the potential of epigenetic changes as markers or targets for therapy in prostate cancer. Epigenetic modifiers that demethylate DNA and inhibit histone deacetylases have recently been explored to reactivate silenced gene expression in cancer. However, further understanding of the mechanisms and the effects of chromatin modulation in prostate cancer are required. In this review, we examine the current literature on epigenetic changes associated with prostate cancer and discuss the potential use of epigenetic modifiers for treatment of this disease.     

表观遗传调控健康衰老

衰老是自然界普遍存在的现象。衰老伴随着组织和器官功能的逐渐衰退,最终导致生物体死亡。衰老也是人们罹患老年性疾病如心血管疾病、神经退行性疾病、癌症、糖尿病等的主要风险因素。因此,延缓衰老对于预防和治疗衰老相关的疾病意义重大。衰老与遗传和表观遗传改变密切相关。最近,Nature杂志发表了中国科学院脑科学与智能技术卓越创新中心蔡时青研究组与中国科学院上海巴斯德研究所江陆斌研究组的合作成果。该研究发现了两个新的保守的表观调控因子妨碍健康衰老。     

Epigenetic regulation of genomic integrity

Inefficient and inaccurate repair of DNA damage is the principal cause of DNA mutations, chromosomal aberrations, and carcinogenesis. Numerous multiple-step DNA repair pathways exist whose deployment depends on the nature of the DNA lesion. Common to all eukaryotic DNA repair pathways is the need to unravel the compacted chromatin structure to facilitate access of the repair machinery to the DNA and restoration of the original chromatin state afterward. Accordingly, our cells utilize a plethora of coordinated mechanisms to locally open up the chromatin structure to reveal the underlying DNA sequence and to orchestrate the efficient and accurate repair of DNA lesions. Here we review changes to the chromatin structure that are intrinsic to the DNA damage response and the available mechanistic insight into how these chromatin changes facilitate distinct stages of the DNA damage repair pathways to maintain genomic stability.     

Epigenetic regulation of photoperiodic flowering

The cytidine analogue 5-azacytidine, which causes DNA demethylation, induced flowering in the non-vernalization-requiring plants Perilla frutescens var. crispa, Silene armeria and Pharbitis nil (synonym Ipomoea nil) under non-inductive photoperiodic conditions, suggesting that the expression of photoperiodic flowering-related genes is regulated epigenetically by DNA methylation. The flowering state induced by DNA demethylation was not heritable. Changes in the genome-wide methylation state were examined by methylation-sensitive amplified fragment length polymorphism analysis. This analysis indicated that the DNA methylation state was altered by the photoperiodic condition. DNA demethylation also induced dwarfism, and the induced dwarfism of P. frutescens was heritable.Key words: 5-azacytidine, DNA methylation, photoperiodic flowering, epigenetics, methylation-sensitive amplified fragment length polymorphism, CpG island, dwarfism     

Epigenetic regulation of cardiac fibrosis

Cardiac fibrosis is characterized by excessive extracellular matrix accumulation that ultimately destroys tissue architecture and eventually abolishes normal function. In recent years, despite the underlying mechanisms of cardiac fibrosis are still unknown, numerous studies suggest that epigenetic modifications impact on the development of cardiac fibrosis. Epigenetic modifications control cell proliferation, differentiation, migration, and so on. Epigenetic modifications contain three main processes: DNA methylation, histone modifications, and silencing by microRNAs. We here outline the recent work pertaining to epigenetic changes in cardiac fibrosis. This review focuses on the epigenetic regulation of cardiac fibrosis.