Stable transmission of reversible modifications: maintenance of epigenetic information through the cell cycle

Even though every cell in a multicellular organism contains the same genes, the differing spatiotemporal expression of these genes determines the eventual phenotype of a cell. This means that each cell type contains a specific epigenetic program that needs to be replicated through cell divisions, along with the genome, in order to maintain cell identity. The stable inheritance of these programs throughout the cell cycle relies on several epigenetic mechanisms. In this review, DNA methylation and histone methylation by specific histone lysine methyltransferases (KMT) and the Polycomb/Trithorax proteins are considered as the primary mediators of epigenetic inheritance. In addition, non-coding RNAs and nuclear organization are implicated in the stable transfer of epigenetic information. Although most epigenetic modifications are reversible in nature, they can be stably maintained by self-recruitment of modifying protein complexes or maintenance of these complexes or structures through the cell cycle.     

Histone methylation and ubiquitination with their cross-talk and roles in gene expression and stability

Methylation of lysine residues of histones is associated with functionally distinct regions of chromatin, and, therefore, is an important epigenetic mark. Over the past few years, several enzymes that catalyze this covalent modification on different lysine residues of histones have been discovered. Intriguingly, histone lysine methylation has also been shown to be cross-regulated by histone ubiquitination or the enzymes that catalyze this modification. These covalent modifications and their cross-talks play important roles in regulation of gene expression, heterochromatin formation, genome stability, and cancer. Thus, there has been a very rapid progress within past several years towards elucidating the molecular basis of histone lysine methylation and ubiquitination, and their aberrations in human diseases. Here, we discuss these covalent modifications with their cross-regulation and roles in controlling gene expression and stability. Received 24 September 2008; received after revision 21 November 2008; accepted 28 November 2008     

Influence of bacteria on epigenetic gene control

Cellular information is inherited by daughter cells through epigenetic routes in addition to genetic routes. Epigenetics, which is primarily mediated by inheritable DNA methylation and histone post-translational modifications, involves changes in the chromatin structure important for regulating gene expression. It is widely known that epigenetic control of gene expression plays an essential role in cell differentiation processes in vertebrates. Furthermore, because epigenetic changes can occur reversibly depending on environmental factors in differentiated cells, they have recently attracted considerable attention as targets for disease prevention and treatment. These environmental factors include diet, exposure to bacteria or viruses, and air pollution, of which this review focuses on the influence of bacteria on epigenetic gene control in a host. Host-bacterial interactions not only occur upon pathogenic bacterial infection but also continuously exist between commensal bacteria and the host. These bacterial stimuli play an essential role in various biological responses involving external stimuli and in maintaining physiological homeostasis by altering epigenetic markers and machinery.     

Memory

In this review we address the idea that conservation of epigenetic mechanisms for information storage represents a unifying model in biology, with epigenetic mechanisms being utilized for cellular memory at levels from behavioral memory to development to cellular differentiation. Epigenetic mechanisms typically involve alterations in chromatin structure, which in turn regulate gene expression. An emerging idea is that the regulation of chromatin structure through histone acetylation and DNA methylation may mediate long-lasting behavioral change in the context of learning and memory. We find this idea fascinating because similar mechanisms are used for triggering and storing long-term 'memory' at the cellular level, for example when cells differentiate. An additional intriguing aspect of the hypothesis of a role for epigenetic mechanisms in information storage is that lifelong behavioral memory storage may involve lasting changes in the physical, three-dimensional structure of DNA itself.     

Epigenetic mechanisms in mammals

DNA and histone methylation are linked and subjected to mitotic inheritance in mammals. Yet how methylation is propagated and maintained between successive cell divisions is not fully understood. A series of enzyme families that can add methylation marks to cytosine nucleobases, and lysine and arginine amino acid residues has been discovered. Apart from methyltransferases, there are also histone modification enzymes and accessory proteins, which can facilitate and/or target epigenetic marks. Several lysine and arginine demethylases have been discovered recently, and the presence of an active DNA demethylase is speculated in mammalian cells. A mammalian methyl DNA binding protein MBD2 and de novo DNA methyltransferase DNMT3A and DNMT3B are shown experimentally to possess DNA demethylase activity. Thus, complex mammalian epigenetic mechanisms appear to be dynamic yet reversible along with a well-choreographed set of events that take place during mammalian development.     

Critical effects of epigenetic regulation in pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is characterized by persistent pulmonary vasoconstriction and pulmonary vascular remodeling. The pathogenic mechanisms of PAH remain to be fully clarified and measures of effective prevention are lacking. Recent studies; however, have indicated that epigenetic processes may exert pivotal influences on PAH pathogenesis. In this review, we summarize the latest research findings regarding epigenetic regulation in PAH, focusing on the roles of non-coding RNAs, histone modifications, ATP-dependent chromatin remodeling and DNA methylation, and discuss the potential of epigenetic-based therapies for PAH.     

Crosstalk between metabolism and epigenetic modifications in autoimmune diseases: a comprehensive overview

Little information is available regarding mechanistic links between epigenetic modifications and autoimmune diseases. It seems plausible to surmise that aberrant gene expression and energy metabolism would disrupt immune tolerance, which could ultimately result in autoimmune responses. Metaboloepigenetics is an emerging paradigm that defines the interrelationships between metabolism and epigenetics. Epigenetic modifications, such as the methylation/demethylation of DNA and histone proteins and histone acetylation/deacetylation can be dynamically produced and eliminated by a group of enzymes that consume several metabolites derived from various physiological pathways. Recent insights into cellular metabolism have demonstrated that environmental stimuli such as dietary exposure and nutritional status act through the variation in concentration of metabolites to affect epigenetic regulation and breakdown biochemical homeostasis. Metabolites, including S-adenosylmethionine, acetyl-CoA, nicotinamide adenine dinucleotide, α-ketoglutarate, and ATP serve as cofactors for chromatin-modifying enzymes, such as methyltransferases, deacetylases and kinases, which are responsible for chromatin remodelling. The concentration of crucial nutrients, such as glucose, glutamine, and oxygen, spatially and temporally modulate epigenetic modifications to regulate gene expression and the reaction to stressful microenvironments in disease pathology. In this review, we focus on the interaction between metabolic intermediates and epigenetic modifications, integrating environmental signals with programmes through modification of the epigenome–metabolome to speculate as to how this may influence autoimmune diseases.     

Macro domains as metabolite sensors on chromatin

How metabolism and epigenetics are molecularly linked and regulate each other is poorly understood. In this review, we will discuss the role of direct metabolite-binding to chromatin components and modifiers as a possible regulatory mechanism. We will focus on globular macro domains, which are evolutionarily highly conserved protein folds that can recognize NAD⁺-derived metabolites. Macro domains are found in histone variants, histone modifiers, and a chromatin remodeler among other proteins. Here we summarize the macro domain-containing chromatin proteins and the enzymes that generate relevant metabolites. Focusing on the histone variant macroH2A, we further discuss possible implications of metabolite binding for chromatin function.     

Propagation of histone marks and epigenetic memory during normal and interrupted DNA replication

Although all nucleated cells within a multicellular organism contain a complete copy of the genome, cell identity relies on the expression of a specific subset of genes. Therefore, when cells divide they must not only copy their genome to their daughters, but also ensure that the pattern of gene expression present before division is restored. While the carrier of this epigenetic memory has been a topic of much research and debate, post-translational modifications of histone proteins have emerged in the vanguard of candidates. In this paper we examine the mechanisms by which histone post-translational modifications are propagated through DNA replication and cell division, and we critically examine the evidence that they can also act as vectors of epigenetic memory. Finally, we consider ways in which epigenetic memory might be disrupted by interfering with the mechanisms of DNA replication.