The many faces of histone lysine methylation

Diverse post-translational modifications of histone amino termini represent an important epigenetic mechanism for the organisation of chromatin structure and the regulation of gene activity. Within the past two years, great progress has been made in understanding the functional implications of histone methylation; in particular through the characterisation of histone methyltransferases that direct the site-specific methylation of, for example, lysine 9 and lysine 4 positions in the histone H3 amino terminus. All known histone methyltransferases of this type contain the evolutionarily conserved SET domain and appear to be able to stimulate either gene repression or gene activation. Methylation of H3 Lys9 and Lys4 has been visualised in native chromatin, indicating opposite roles in structuring repressive or accessible chromatin domains. For example, at the mating-type loci in Schizosaccharomyces pombe, at pericentric heterochromatin and at the inactive X chromosome in mammals, striking differences between these distinct marks have been observed. H3 Lys9 methylation is also important to direct additional epigenetic signals such as DNA methylation--for example, in Neurospora crassa and in Arabidopsis thaliana. Together, the available data strongly establish histone lysine methylation as a central modification for the epigenetic organisation of eukaryotic genomes.     

Histone lysine demethylases in Drosophila melanogaster

Epigenetic regulation of chromatin structure is a fundamental process for eukaryotes. Regulators include DNA methylation, microRNAs and chromatin modifications. Within the chromatin modifiers, one class of enzymes that can functionally bind and modify chromatin, through the removal of methyl marks, is the histone lysine demethylases. Here, we summarize the current findings of the 13 known histone lysine demethylases in Drosophila melanogaster, and discuss the critical role of these histone-modifying enzymes in the maintenance of genomic functions. Additionally, as histone demethylase dysregulation has been identified in cancer, we discuss the advantages for using Drosophila as a model system to study tumorigenesis.     

Histone lysine demethylases in Drosophila melanogaster

Epigenetic regulation of chromatin structure is a fundamental process for eukaryotes. Regulators include DNA methylation, microRNAs and chromatin modifications. Within the chromatin modifiers, one class of enzymes that can functionally bind and modify chromatin, through the removal of methyl marks, is the histone lysine demethylases. Here, we summarize the current findings of the 13 known histone lysine demethylases in Drosophila melanogaster, and discuss the critical role of these histone-modifying enzymes in the maintenance of genomic functions. Additionally, as histone demethylase dysregulation has been identified in cancer, we discuss the advantages for using Drosophila as a model system to study tumorigenesis.     

Histone modifying enzymes: structures, mechanisms, and specificities

Histone modifying enzymes catalyze the addition or removal of an array of covalent modifications in histone and non-histone proteins. Within the context of chromatin, these modifications regulate gene expression as well as other genomic functions and have been implicated in establishing and maintaining a heritable epigenetic code that contributes to defining cell identity and fate. Biochemical and structural characterization of histone modifying enzymes has yielded important insights into their respective catalytic mechanisms, substrate specificities, and regulation. In this review, we summarize recent advances in understanding these enzymes, highlighting studies of the histone acetyltransferases (HATs) p300 (also now known as KAT3B) and Rtt109 (KAT11) and the histone lysine demethylases (HDMs) LSD1 (KDM1) and JMJD2A (KDM4A), present overriding themes that derive from these studies, and pose remaining questions concerning their regulatory roles in mediating DNA transactions.     

Three dimensional analysis of histone methylation patterns in normal and tumor cell nuclei

Histone modifications represent an important epigenetic mechanism for the organization of higher order chromatin structure and gene regulation. Methylation of position-specific lysine residues in the histone H3 and H4 amino termini has linked with the formation of constitutive and facultative heterochromatin as well as with specifically repressed single gene loci. Using an antibody, directed against dimethylated lysine 9 of histone H3 and several other lysine methylation sites, we visualized the nuclear distribution pattern of chromatin flagged by these methylated lysines in 3D preserved nuclei of normal and malignant cell types. Optical confocal serial sections were used for a quantitative evaluation. We demonstrate distinct differences of these histone methylation patterns among nuclei of different cell types after exit of the cell cycle. Changes in the pattern formation were also observed during the cell cycle. Our data suggest an important role of methylated histones in the reestablishment of higher order chromatin arrangements during telophase/early G1. Cell type specific histone methylation patterns are possibly casually involved in the formation of cell type specific heterochromatin compartments, composed of (peri)centromeric regions and chromosomal subregions from neighboring chromosomes territories, which contain silent genes.     

组蛋白赖氨酸甲基化修饰与先天性心脏病研究进展

组蛋白修饰是表观遗传调控的一个重要组成部分, 它通过改变染色质的结构以及与其他调控蛋白相互作用, 调节真核基因的表达。组蛋白修饰异常可能导致多种疾病的发生, 同时, 组蛋白修饰的可逆性为疾病的治疗提供了新的思路。文章主要对组蛋白赖氨酸甲基化修饰与先天性心脏病发生的有关机制进行了综述, 以期能够为从事该领域研究的科研人员提供有价值的参考。     

PHD fingers in human diseases: disorders arising from misinterpreting epigenetic marks

Histone covalent modifications regulate many, if not all, DNA-templated processes, including gene expression and DNA damage response. The biological consequences of histone modifications are mediated partially by evolutionarily conserved "reader/effector" modules that bind to histone marks in a modification- and context-specific fashion and subsequently enact chromatin changes or recruit other proteins to do so. Recently, the Plant Homeodomain (PHD) finger has emerged as a class of specialized "reader" modules that, in some instances, recognize the methylation status of histone lysine residues, such as histone H3 lysine 4 (H3K4). While mutations in catalytic enzymes that mediate the addition or removal of histone modifications (i.e., "writers" and "erasers") are already known to be involved in various human diseases, mutations in the modification-specific "reader" proteins are only beginning to be recognized as contributing to human diseases. For instance, point mutations, deletions or chromosomal translocations that target PHD fingers encoded by many genes (such as recombination activating gene 2 (RAG2), Inhibitor of Growth (ING), nuclear receptor-binding SET domain-containing 1 (NSD1) and Alpha Thalassaemia and Mental Retardation Syndrome, X-linked (ATRX)) have been associated with a wide range of human pathologies including immunological disorders, cancers, and neurological diseases. In this review, we will discuss the structural features of PHD fingers as well as the diseases for which direct mutation or dysregulation of the PHD finger has been reported. We propose that misinterpretation of the epigenetic marks may serve as a general mechanism for human diseases of this category. Determining the regulatory roles of histone covalent modifications in the context of human disease will allow for a more thorough understanding of normal and pathological development, and may provide innovative therapeutic strategies wherein "chromatin readers" stand as potential drug targets.     

The histone methyltransferase SUV420H2 and Heterochromatin Proteins HP1 interact but show different dynamic behaviours

Background  

Histone lysine methylation plays a fundamental role in chromatin organization and marks distinct chromatin regions. In particular, trimethylation at lysine 9 of histone H3 (H3K9) and at lysine 20 of histone H4 (H4K20) governed by the histone methyltransferases SUV39H1/2 and SUV420H1/2 respectively, have emerged as a hallmark of pericentric heterochromatin. Controlled chromatin organization is crucial for gene expression regulation and genome stability. Therefore, it is essential to analyze mechanisms responsible for high order chromatin packing and in particular the interplay between enzymes involved in histone modifications, such as histone methyltransferases and proteins that recognize these epigenetic marks.