SET domain proteins in plant development

Post-translational methylation of lysine residues on histone tails is an epigenetic modification crucial for regulation of chromatin structure and gene expression in eukaryotes. The majority of the histone lysine methyltransferases (HKMTases) conferring such modifications are proteins with a conserved SET domain responsible for the enzymatic activity. The SET domain proteins in the model plant Arabidopsis thaliana can be assigned to evolutionarily conserved classes with different specificities allowing for different outcomes on chromatin structure. Here we review the present knowledge of the biochemical and biological functions of plant SET domain proteins in developmental processes. This article is part of a Special Issue entitled: Epigenetic control of cellular and developmental processes in plants.     

Dynamics of epigenetic control in plants via SET domain containing proteins: Structural and functional insights

Plants control expression of their genes in a way that involves manipulating the chromatin structural dynamics in order to adapt to environmental changes and carry out developmental processes. Histone modifications like histone methylation are significant epigenetic marks which profoundly and globally modify chromatin, potentially affecting the expression of several genes. Methylation of histones is catalyzed by histone lysine methyltransferases (HKMTs), that features an evolutionary conserved domain known as SET [Su(var)3–9, E(Z), Trithorax]. This methylation is directed at particular lysine (K) residues on H3 or H4 histone. Plant SET domain group (SDG) proteins are categorized into different classes that have been conserved through evolution, and each class have specificity that influences how the chromatin structure operates. The domains discovered in plant SET domain proteins have typically been linked to protein-protein interactions, suggesting that majority of the SDGs function in complexes. Additionally, SDG-mediated histone mark deposition also affects alternative splicing events. In present review, we discussed the diversity of SDGs in plants including their structural properties. Additionally, we have provided comprehensive summary of the functions of the SDG-domain containing proteins in plant developmental processes and response to environmental stimuli have also been highlighted.     

Complex evolutionary history and diverse domain organization of SET proteins suggest divergent regulatory interactions

? Plants and animals possess very different developmental processes, yet share conserved epigenetic regulatory mechanisms, such as histone modifications. One of the most important forms of histone modification is methylation on lysine residues of the tails, carried out by members of the SET protein family, which are widespread in eukaryotes. ? We analyzed molecular evolution by comparative genomics and phylogenetics of the SET genes from plant and animal genomes, grouping SET genes into several subfamilies and uncovering numerous gene duplications, particularly in the Suv, Ash, Trx and E(z) subfamilies. ? Domain organizations differ between different subfamilies and between plant and animal SET proteins in some subfamilies, and support the grouping of SET genes into seven main subfamilies, suggesting that SET proteins have acquired distinctive regulatory interactions during evolution. We detected evidence for independent evolution of domain organization in different lineages, including recruitment of new domains following some duplications. ? More recent duplications in both vertebrates and land plants are probably the result of whole-genome or segmental duplications. The evolution of the SET gene family shows that gene duplications caused by segmental duplications and other mechanisms have probably contributed to the complexity of epigenetic regulation, providing insights into the evolution of the regulation of chromatin structure.     

Chromatin proteomics and epigenetic regulatory circuits

Many phenotypic changes of eukaryotic cells due to changes in gene expression depend on alterations in chromatin structure. Processes involved in the alteration of chromatin are diverse and include post-translational modifications of histone proteins, incorporation of specific histone variants, methylation of DNA and ATP-dependent chromatin remodeling. Interconnected with these processes are the localization of chromatin domains within the nuclear architecture and the appearance of various classes of noncoding regulatory RNAs. Recent experiments underscore the role of these processes in influencing diverse biological functions. However, the evidence to date implies the importance of an interplay of all these chromatin-changing functions, generating an epigenetic regulatory circuit that is still not well understood.     

Chromatin proteomics and epigenetic regulatory circuits

Many phenotypic changes of eukaryotic cells due to changes in gene expression depend on alterations in chromatin structure. Processes involved in the alteration of chromatin are diverse and include post-translational modifications of histone proteins, incorporation of specific histone variants, methylation of DNA and ATP-dependent chromatin remodeling. Interconnected with these processes are the localization of chromatin domains within the nuclear architecture and the appearance of various classes of noncoding regulatory RNAs. Recent experiments underscore the role of these processes in influencing diverse biological functions. However, the evidence to date implies the importance of an interplay of all these chromatin-changing functions, generating an epigenetic regulatory circuit that is still not well understood.     

Antagonistic functions of SET-2/SET1 and HPL/HP1 proteins in C. elegans development

Cellular identity during metazoan development is maintained by epigenetic modifications of chromatin structure brought about by the activity of specific proteins which mediate histone variant incorporation, histone modifications, and nucleosome remodeling. HP1 proteins directly influence gene expression by modifying chromatin structure. We previously showed that the Caenorhabditis elegans HP1 proteins HPL-1 and HPL-2 are required for several aspects of post-embryonic development. To gain insight into how HPL proteins influence gene expression in a developmental context, we carried out a candidate RNAi screen to identify suppressors of hpl-1 and hpl-2 phenotypes. We identified SET-2, the homologue of yeast and mammalian SET1, as an antagonist of HPL-1 and HPL-2 activity in growth and somatic gonad development. Yeast Set1 and its mammalian counterparts SET1/MLL are H3 lysine 4 (H3K4) histone methyltransferases associated with gene activation as part of large multisubunit complexes. We show that the nematode counterparts of SET1/MLL complex subunits also antagonize HPL function in post-embryonic development. Genetic analysis is consistent with SET1/MLL complex subunits having both shared and unique functions in development. Furthermore, as observed in other species, we find that SET1/MLL complex homologues differentially affect global H3K4 methylation. Our results suggest that HP1 and a SET1/MLL-related complex may play antagonistic roles in the epigenetic regulation of specific developmental programs.     

Interaction of SET domains with histones and nucleic acid structures in active chromatin

Changes in the normal program of gene expression are the basis for a number of human diseases. Epigenetic control of gene expression is programmed by chromatin modifications-the inheritable "histone code"-the major component of which is histone methylation. This chromatin methylation code of gene activity is created upon cell differentiation and is further controlled by the "SET" (methyltransferase) domain proteins which maintain this histone methylation pattern and preserve it through rounds of cell division. The molecular principles of epigenetic gene maintenance are essential for proper treatment and prevention of disorders and their complications. However, the principles of epigenetic gene programming are not resolved. Here we discuss some evidence of how the SET proteins determine the required states of target genes and maintain the required levels of their activity. We suggest that, along with other recognition pathways, SET domains can directly recognize the nucleosome and nucleic acids intermediates that are specific for active chromatin regions.     

植物SET蛋白

SET蛋白是一类包含保守的SET结构域、与组蛋白甲基化密切相关的蛋白质。组蛋白修饰作为调控基因表达的重要因素,在植物体基因转录调控中发挥关键的作用。有关SET蛋白的研究为深入了解组蛋白修饰的机制提供了重要信息。植物SET蛋白具有保守的结构特征及进化机制,参与众多细胞核内的反应过程,如染色体的浓缩和分离,基因的转录,以及DNA的复制和修复等,调控植物基因的表达,影响植物体的发育。     

Histone-modifying enzymes: encrypting an enigmatic epigenetic code

Histone-modifying enzymes catalyze a diverse array of post-translational modifications of core and linker histones within chromatin. These modifications govern a multitude of genomic functions, particularly gene expression, and are believed to constitute an epigenetic code. Histone-modifying enzymes inscribe this code by catalyzing site-selective modifications, which are subsequently interpreted by effector proteins that recognize specific covalent marks. The substrate specificity of these enzymes is of fundamental biological importance because it underpins this epigenetic code. Recently, the structural basis of this specificity has been examined with regards to recently determined structures of GCN5 acetyltransferases and SET domain methyltransferases in complex with their cognate histone substrates.     

表观遗传学: 生物细胞非编码RNA调控的研究进展

表观遗传学是研究基因表达发生了可遗传的改变, 而DNA序列不发生改变的一门生物学分支, 对细胞的生长分化及肿瘤的发生发展至关重要。表观遗传学的主要机制包括DNA甲基化、组蛋白修饰及新近发现的非编码RNA。非编码RNA 是指不能翻译为蛋白的功能性RNA分子, 其中常见的具调控作用的非编码RNA包括小干涉RNA、miRNA、piRNA 以及长链非编码RNA。近年来大量研究表明非编码RNA在表观遗传学的调控中扮演了越来越重要的角色。文章综述了近年来生物细胞非编码RNA调控的表观遗传学研究进展, 以有助于理解哺乳动物细胞中非编码RNA及其调控机制和功能。     

Chromatin techniques for plant cells

A large number of recent studies have demonstrated that many important aspects of plant development are regulated by heritable changes in gene expression that do not involve changes in DNA sequence. Rather, these regulatory mechanisms involve modifications of chromatin structure that affect the accessibility of target genes to regulatory factors that can control their expression. The central component of chromatin is the nucleosome, containing the highly conserved histone proteins that are known to be subject to a wide range of post-translational modifications, which act as recognition codes for the binding of chromatin-associated factors. In addition to these histone modifications, DNA methylation can also have a dramatic influence on gene expression. To accommodate the burgeoning interest of the plant science community in the epigenetic control of plant development, a series of methods used routinely in our laboratories have been compiled that can facilitate the characterization of putative chromatin-binding factors at the biochemical, molecular and cellular levels.     

Epigenetics in cardiac development,function, and disease

Substantial new knowledge has accrued, over the past few years, concerning the epigenetic regulation of heart development and disease. Epigenetic mechanisms comprise DNA methylation, ATP-dependent chromatin remodeling, histone modifications, and non-coding RNAs. Many of these processes have been ascertained to influence the tight spatiotemporal control of gene expression during cardiac development. Nevertheless, the relative contribution of each mechanism and their potentially complex interplay remain largely unexplored. Cardiac development and disease are linked through the reactivation of fetal genes upon cardiac hypertrophy and failure. In cardiac disease, changes in gene expression are accompanied and influenced by distinct changes in histone modifications. Detailed knowledge about the epigenetic pathways of cardiac development and function is expected ultimately to lead to novel therapeutic strategies for heart disease and regenerative medicine.     

生长抑制因子(ING)抑癌基因家族的研究进展

生长抑制因子(inhibitor of growth,ING)家族成员是候选的抑癌基因.ING蛋白参与磷脂酰肌醇介导的脂类信号转导通路及激素介导的通路,能够与组蛋白乙酰转移酶、去乙酰化酶等结合参与染色质的重构,调节基因的转录,与p53协同作用,抑制细胞生长,诱导细胞凋亡和DNA损伤修复.ING家族成员通过对基因表达的表观遗传学调控将细胞周期、细胞凋亡和衰老等生物学过程有机联系起来.     

Bacterial remodelling of the host epigenome: functional role and evolution of effectors methylating host histones

The modulation of the chromatin organization of eukaryotic cells plays an important role in regulating key cellular processes including host defence mechanisms against pathogens. Thus, to successfully survive in a host cell, a sophisticated bacterial strategy is the subversion of nuclear processes of the eukaryotic cell. Indeed, the number of bacterial proteins that target host chromatin to remodel the host epigenetic machinery is expanding. Some of the identified bacterial effectors that target the chromatin machinery are ‘eukaryotic‐like’ proteins as they mimic eukaryotic histone writers in carrying the same enzymatic activities. The best‐studied examples are the SET domain proteins that methylate histones to change the chromatin landscape. In this review, we will discuss SET domain proteins identified in the Legionella, Chlamydia and Bacillus genomes that encode enzymatic activities targeting host histones. Moreover, we discuss their possible origin as having evolved from prokaryotic ancestors or having been acquired from their eukaryotic hosts during their co‐evolution. The characterization of such bacterial effectors as modifiers of the host chromatin landscape is an exciting field of research as it elucidates new bacterial strategies to not only manipulate host functions through histone modifications but it may also identify new modifications of the mammalian host cells not known before.