Functional significance of histone deacetylase diversity

Nucleocytoplasmic shuttling of histone deacetylases is emerging as a major step in determining the composition, and hence the activity, of the corresponding nuclear regulatory complexes. This shuttling process is one of the distinctive characteristics of these enzymes, themselves belonging to structurally and functionally different classes. Considering the specific features of each class of deacetylases, it is possible to determine how each member can contribute to particular cellular functions.     

Regulatory interplay between deubiquitinating enzymes and cytokines

Deubiquitinating enzymes (DUBs) are cysteine protease proteins that reverse the ubiquitination by removing ubiquitins from the target protein. With over 100 DUBs identified and categorized into at least 7 families, many DUBs interact with one or more cytokines, influencing cellular processes, such as antiviral responses, inflammatory responses, apoptosis, etc. While some DUBs influence cytokine pathway or production, some DUBs are cytokine-inducible. In this article, we summarize a list of DUBs, their interaction with cytokines, target proteins and mechanisms of action.     

The interplay between microRNAs and histone deacetylases in neurological diseases

Neurological conditions, such as Alzheimer’s disease and stroke, represent a prevalent group of devastating illnesses with few treatments. Each of these diseases or conditions is in part characterized by the dysregulation of many genes, including those that code for microRNAs (miRNAs) and histone deacetylases (HDACs). Recently, a complex relationship has been uncovered linking miRNAs and HDACs and their ability to regulate one another. This provides a new avenue for potential therapeutics as the ability to reinstate a careful balance between miRNA and HDACs has lead to improved outcomes in a number of in vitro and in vivo models of neurological conditions. In this review, we will discuss recent findings on the interplay between miRNAs and HDACs and its implications for pathogenesis and treatment of neurological conditions, including amyotrophic lateral sclerosis, Alzheimer’s disease, Huntington’s disease and stroke.     

Human histone demethylase LSD1 reads the histone code

Human histone demethylase LSD1 is a flavin-dependent amine oxidase that catalyzes the specific removal of methyl groups from mono- and dimethylated Lys4 of histone H3. The N-terminal tail of H3 is subject to various covalent modifications, and a fundamental question in LSD1 biology is how these epigenetic marks affect the demethylase activity. We show that LSD1 does not have a strong preference for mono- or dimethylated Lys4 of H3. Substrate recognition is not confined to the residues neighboring Lys4, but it requires a sufficiently long peptide segment consisting of the N-terminal 20 amino acids of H3. Electrostatic interactions are an important factor in protein-substrate recognition, as indicated by the high sensitivity of Km to ionic strength. We have probed LSD1 for its ability to demethylate Lys4 in presence of a second modification on the same peptide substrate. Methylation of Lys9 does not affect enzyme catalysis. Conversely, Lys9 acetylation causes an almost 6-fold increase in the Km value, whereas phosphorylation of Ser10 totally abolishes activity. LSD1 is inhibited by a demethylated peptide with an inhibition constant of 1.8 microM, suggesting that LSD1 can bind to H3 independently of Lys4 methylation. LSD1 is a chromatin-modifying enzyme, which is able to read different epigenetic marks on the histone N-terminal tail and can serve as a docking module for the stabilization of the associated corepressor complex(es) on chromatin.     

Interplay between histone deacetylase SIR-2, linker histone H1 and histone methyltransferases in heterochromatin formation

Maintenance of intact heterochromatin structure through epigenetic mechanisms is essential for cell survival. Defects in heterochromatin formation caused by loss of chromatin-modifying enzymes lead to genomic instability and cellular senescence. The NAD+-dependent histone deacetylase SIR-2 and the H1 linker histone are intriguing chromatin elements that are connected to chromatin regulation and cell viability in the single cellular eukaryotic organism yeast. However, it remains an open question how SIR-2 and H1 mediate heterochromatin formation in simple multi-cellular organisms such as C. elegans and in even more complex organisms such as mammals. Recently we have identified SIR-2.1 and the H1 histone subtype, HIS-24 as factors involved in heterochromatin regulation at subtelomeric regions in C. elegans. In addition we show that SIR-2.1, HIS-24, and MES-2, a ortholog to Enhancer of zeste E(Z) are functionally related in heterochromatin formation contributing to fertility and embryogenesis. Here we discuss the interplay between SIR-2, H1 histone and histone methyltransferases in modulation of chromatin structure in further detail.     

组蛋白去甲基化酶PHD锌指蛋白8与神经发育

PHD锌指蛋白8(PHF8)是一种Fe2+和α-酮戊二酸依赖的组蛋白赖氨酸去甲基化酶.PHF8属于包含JmjC结构域蛋白家族,在N端还含有一个PHD(planthomeodomain)锌指结构域.人的PHF8基因突变往往破坏组蛋白去甲基化酶活性,从而引发遗传性X-连锁智力迟滞(XLMR)并伴发唇裂的发生.PHF8一方面可催化H3K9me2/1、H4K20me1和H3K27me2的去甲基化,另一方面还通过N端PHD锌指结构域与H3K4me3结合而发挥转录共激活作用.PHF8可调节rRNA和多个涉及神经发育的蛋白质编码基因如JARID1C的表达.这些研究显示,PHF8是一种重要的神经发育调节因子,从而拓宽了对组蛋白甲基化与基因表达关联的理解,同时为XLMR疾病的理解提供了新的线索.     

Structure and mechanism of lysine-specific demethylase enzymes

The discovery of histone-demethylating enzymes has revealed yet another reversible histone modification mark. In this review, we describe the structural and chemical insights that we have now derived underlying the activity of these enzymes. The recent co-crystal structures of LSD1 bound to a proparylamine-derivatized histone H3 peptide and JHDM structures bound to two different methylated histone H3 peptides illustrate the steric requirements and structural basis for substrate specificity.     

Advances and challenges in understanding histone demethylase biology

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组蛋白去甲基化酶JMJD1A

组蛋白翻译后修饰可影响特定基因的表达,从而在多个生理过程中发挥重要作用,是当前生命科学领域的研究热点之一。组蛋白去甲基化酶JMJD1A可催化一甲基化和二甲基化的H3K9(H3K9me1/2)去甲基化,通过解除组蛋白抑制效应而调节基因表达。JMJD1A拥有广泛的生物学功能,参与多种生物学过程包括核受体激活、精子生成、能量代谢、低氧调节和癌症发生等。本文就JMJD1A的特征及功能作一综述。     

A histone deacetylase regulates addiction

Epigenetic modification of chromatin has been proposed to translate environmental stimuli into persistent "cellular memories." Recent studies suggest that epigenetic pathways regulate long-term behavioral adaptation in the nervous system. In this issue of Neuron, Renthal et al. utilize genetic manipulations of HDAC5 to provide strong evidence for a role for histone acetylation in the behavioral response to cocaine.     

Alpha-mercaptoketone based histone deacetylase inhibitors

In an effort to discover novel non-hydroxamic acid histone deacetylase (HDAC) inhibitors, a novel alpha-mercaptoketone was identified in a high-throughput screen. Lead optimization of the screening hit, led to a number of potent HDAC inhibitors. In particular, alpha-mercaptoketone 19y (KD5150) exhibited nanomolar in vitro activity and inhibition of tumor growth in vivo.