Epigenetic regulation by histone methylation and histone variants

Epigenetics is the study of heritable changes in gene expression that are not mediated at the DNA sequence level. Molecular mechanisms that mediate epigenetic regulation include DNA methylation and chromatin/histone modifications. With the identification of key histone-modifying enzymes, the biological functions of many histone posttranslational modifications are now beginning to be elucidated. Histone methylation, in particular, plays critical roles in many epigenetic phenomena. In this review, we provide an overview of recent findings that shape the current paradigms regarding the roles of histone methylation and histone variants in heterochromatin assembly and the maintenance of the boundaries between heterochromatin and euchromatin. We also highlight some of the enzymes that mediate histone methylation and discuss the stability and inheritance of this modification.     

The Regulation and Function of Histone Methylation

Histones are wrapped around by genomic DNA to form nucleosomes which are the basic units of chromatin. In eukaryotes histones undergo various covalent modifications such as methylation, phosphorylation, acetylation, ubiquitination and ribosylation. Histone modifications play a fundamental role in the epigenetic regulation of gene expression in multicellular eukaryotes. Histone methylation is one of the most important modifications occurring on Lysine (K) and Arginine (R) residues of histones, dynamically regulated by histone methyltransferases and demethylases. Identifications of such histone modification enzymes and to study how they work are the most fundamental questions needs to be answered. Uncovering the regulation and functions of the various histone methylation enzymes will help us to better understand the epigenetic code. This review summarizes the regulation of histone methyltransferases activity, the recruitment of methyltransferases and the distribution patterns and function of histone methylations.     

Control of gene expression and assembly of chromosomal subdomains by chromatin regulators with antagonistic functions

Epigenetic regulation of higher-order chromatin structure controls gene expression and the assembly of chromosomal domains during cell division, differentiation, and development. The proposed “histone code” integrates a complex system of histone modifications and chromosomal proteins that establish and maintain distinctive types of chromatin, such as euchromatin, heterochromatin, and centromeric (CEN) chromatin. The reversible nature of histone acetylation, phosphorylation, and (most recently discovered) methylation are mechanisms for controlling gene expression and partitioning the genome into functional domains. Many different regions of the genome contain similar epigenetic marks (histone modifications), raising the question as to how they are independently specified and regulated. In this review, we will focus on several recent discoveries in chromatin and chromosome biology: (1) identification of long-elusive histone “de-methylating” enzymes that affect chromatin structure, and (2) assembly and maintenance of chromatin domains, specifically heterochromatin and euchromatin, through a dynamic equilibrium of modifying enzymes, histone modifications, and histone variants identified biochemically and genetically. Review related to the 15th International Chromosome Conference (ICC XV), held in September 2004, Brunel University, London, UK     

Epigenetic modifications of histones during osteoblast differentiation

In bone biology, epigenetics plays a key role in mesenchymal stem cells' (MSCs) commitment towards osteoblasts. It involves gene regulatory mechanisms governed by chromatin modulators. Predominant epigenetic mechanisms for efficient osteogenic differentiation include DNA methylation, histone modifications, and non-coding RNAs. Among these mechanisms, histone modifications critically contribute to altering chromatin configuration. Histone based epigenetic mechanisms are an essential mediator of gene expression during osteoblast differentiation as it directs the bivalency of the genome. Investigating the importance of histone modifications in osteogenesis may lead to the development of epigenetic-based remedies for genetic disorders of bone. Hence, in this review, we have highlighted the importance of epigenetic modifications such as post-translational modifications of histones, including methylation, acetylation, phosphorylation, ubiquitination, and their role in the activation or suppression of gene expression during osteoblast differentiation. Further, we have emphasized the future advancements in the field of epigenetics towards orthopaedical therapeutics.     

Tackling the epigenome in the pluripotent stem cells

Embryonic stem cells are unique in their abilities of self-renewal and to differentiate into many, if not all, cellular lineages. Transcrip- tional regulation, epigenetic modifications and chromatin structures are the key modulators in controlling such pluripotency nature of embryonic stem cell genomes, particularly in the developmental decisions and the maintenance of cell fates. Among them, epigenetic regulation of gene expression is mediated partly by covalent modifications of core histone proteins including methylation, phosphoryla- tion and acetylation. Moreover, the chromatins in stem cell genome appear as a highly organized structure containing distinct functional domains. Recent rapid progress of new technologies enables us to take a global, unbiased and comprehensive view of the epigenetic modifications and chromatin structures that contribute to gene expression regulation and cell identity during diverse developmental stages. Here, we summarized the latest advances made by high throughput approaches in profiling epigenetic modifications and chromatin con- formations, with an emphasis on genome-wide analysis of histone modifications and their implications in pluripotency nature of embry- onic stem cells.     

组蛋白甲基化研究进展

组蛋白甲基化是表观遗传修饰方式中的一种,参与异染色质形成、基因印记、X染色体失活和基因转录调控.组蛋白甲基化过程的异常参与多种肿瘤的发生.既往认为组蛋白甲基化是稳定的表观遗传标记,而组蛋白去甲基化酶的发现对这一观点提出了挑战,也为进一步深入研究组蛋白修饰提供新的途径.     

Prenatal nutrition and the risk of adult obesity: Long-term effects of nutrition on epigenetic mechanisms regulating gene expression

Solid epidemiological evidence indicates that part of the risk of obesity in adulthood could be programmed during prenatal development by the quality of maternal nutrition. Nevertheless, the molecular mechanisms involved are mostly unknown, which hinders our capacity to develop effective intervention policies. Here, we discuss the hypothesis that mechanisms underlying prenatal programming of adult risk are epigenetic and sensitive to environmental cues such as nutrition. While the information encoded in DNA is essentially stable, regulatory epigenetic mechanisms include reversible, covalent modifications of DNA and chromatin, such as methylation, acetylation etc. It is known that dietary availability of methyl donors has an impact on the patterns of gene expression by affecting DNA methylation at regulatory regions, a likely basis for reprogramming developmental plasticity. The Agouti and Axin-fused genes, as well as the embryonic growth factor IGF2/H19 locus are examples of diet-induced modulation of phenotypic traits by affecting methylation of gene-regulatory regions. Recent work has evidenced an unsuspected role for chromatin as metabolic sensor. Chromatin is susceptible to a number of post-translational modifications that modulate gene expression, among them the GlcNAcylation of histone proteins and other epigenetic regulators. Intracellular levels of the precursor molecule UDP-GlcNAc, and hence the degree of global chromatin GlcNAcylation, depend on the energetic state of the cell, making GlcNAcylation a functional link between nutrition and regulation of gene expression. Dietary interference with these regulatory mechanisms could effectively counteract the early-life programming of adult risk.