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Covalent modifications of both DNA and histones act in concert to define the landscape of our epigenome. In this review, we explore the interconnections between histone and DNA modifications by focusing on a conserved chromatin-binding regulatory domain, the ATRX-DNMT3-DNMT3L (ADD) domain. New studies show that the ADD domain is capable of sensing, and therefore integrating, the status of multiple histone modifications. This in turn dictates the in vivo localization or allosteric regulation of the full-length ADD-containing protein and its ability to function in downstream chromatin remodeling events. Strategies to re-engineer the ADD "reader pocket" in the de novo DNA methyltransferase DNMT3A such that it redirects this "writer" to new genomic loci proved useful in understanding important biological downstream consequences of mis-targeting of DNA methylation via altered reading of histone marks. Combined with genome-editing tools, this approach stands as a poof-of-principle and will be broadly applicable to the elucidation of epigenetic networks that have been altered by "reader" mutations, either artificially or as naturally occurs in some human diseases.
ACS Chem Biol 2016 Mar 18
PMID:Reading between the Lines: "ADD"-ing Histone and DNA Methylation Marks toward a New Epigenetic "Sum". 2954 64

Protein arginine methyltransferases (PRMTs) play a crucial role in a variety of biological processes. Overexpression of PRMTs has been implicated in various human diseases including cancer. Consequently, selective small-molecule inhibitors of PRMTs have been pursued by both academia and the pharmaceutical industry as chemical tools for testing biological and therapeutic hypotheses. PRMTs are divided into three categories: type I PRMTs which catalyze mono- and asymmetric dimethylation of arginine residues, type II PRMTs which catalyze mono- and symmetric dimethylation of arginine residues, and type III PRMT which catalyzes only monomethylation of arginine residues. Here, we report the discovery of a potent, selective, and cell-active inhibitor of human type I PRMTs, MS023, and characterization of this inhibitor in a battery of biochemical, biophysical, and cellular assays. MS023 displayed high potency for type I PRMTs including PRMT1, -3, -4, -6, and -8 but was completely inactive against type II and type III PRMTs, protein lysine methyltransferases and DNA methyltransferases. A crystal structure of PRMT6 in complex with MS023 revealed that MS023 binds the substrate binding site. MS023 potently decreased cellular levels of histone arginine asymmetric dimethylation. It also reduced global levels of arginine asymmetric dimethylation and concurrently increased levels of arginine monomethylation and symmetric dimethylation in cells. We also developed MS094, a close analog of MS023, which was inactive in biochemical and cellular assays, as a negative control for chemical biology studies. MS023 and MS094 are useful chemical tools for investigating the role of type I PRMTs in health and disease.
ACS Chem Biol 2016 Mar 18
PMID:A Potent, Selective, and Cell-Active Inhibitor of Human Type I Protein Arginine Methyltransferases. 2659 75

Histones are subject to frequent combinatorial post-translational modifications (PTMs), forming a complex chemical "language" that is interpreted by PTM-specific histone-interacting protein modules (reader domains). These specific interactions are thought to instruct gene expression and downstream biological functions. While the majority of studies have focused on individual modifications, our current understanding of the combinatorial PTM patterns on histones is starting to emerge, benefiting from the convergence of multiple technologies. Here, we review the key technical advances and progress on discovery and characterization of combinatorial histone PTM patterns. We focus on the interactions between reader domains and combinatorial PTMs, which is essential for understanding the mechanism and biological meaning of establishing and interpreting information embedded in histone PTM patterns.
ACS Chem Biol 2016 Mar 18
PMID:Reading the Combinatorial Histone Language. 2667 28

The post-translational modification of arginine residues represents a key mechanism for the epigenetic control of gene expression. Aberrant levels of histone arginine modifications have been linked to the development of several diseases including cancer. In recent years, great progress has been made in understanding the physiological role of individual arginine modifications and their effects on chromatin function. The present review aims to summarize the structural and functional aspects of histone arginine modifying enzymes and their impact on gene transcription. We will discuss the potential for targeting these proteins with small molecules in a variety of disease states.
ACS Chem Biol 2016 Mar 18
PMID:Protein Arginine Methylation and Citrullination in Epigenetic Regulation. 2668 81

Methyllysine post-translational modifications (PTMs) of histones create binding sites for evolutionarily conserved reader domains that link nuclear host proteins and chromatin-modifying complexes to specific genomic regions. In the context of these events, adjacent histone PTMs are capable of altering the binding activity of readers toward their target marks. This provides a mechanism of "combinatorial readout" of PTMs that can enhance, decrease, or eliminate the association of readers with chromatin. In this Perspective, we focus on recent studies describing the impact of dynamic phospho-serine/threonine/tyrosine marks on the interaction of methyllysine readers with histones, summarize mechanistic aspects of the phospho/methyl readout, and highlight the significance of crosstalk between these PTMs. We also demonstrate that in addition to inhibiting binding and serving as a true switch, promoting dissociation of the methyllysine readers from chromatin, the phospho/methyl combination can act together in a cooperative manner--thus adding a new layer of regulatory information that can be encoded in these dual histone PTMs.
ACS Chem Biol 2016 Mar 18
PMID:Regulation of Methyllysine Readers through Phosphorylation. 2672 24

A network of reader proteins and enzymes precisely controls gene transcription through the dynamic addition, removal, and recognition of post-translational modifications (PTMs) of histone tails. Histone PTMs work in concert with this network to regulate gene transcription through the histone code, and the dysregulation of PTM maintenance is linked to a large number of diseases, including many types of cancer. A wealth of research aims to elucidate the functions of this code, but our understanding of the effects of PTMs, specifically the methylation of lysine (Lys) and arginine (Arg), is lacking. The development of new tools to study PTMs relies on a sophisticated understanding of the mechanisms that drive protein and small molecule recognition in water. In this review, we outline the physical organic concepts that drive the molecular recognition of Lys and Arg methylation by reader proteins and draw comparisons to the binding mechanisms of small molecule receptors for methylated Lys and Arg that have been developed recently.
ACS Chem Biol 2016 Mar 18
PMID:Molecular Recognition of Lys and Arg Methylation. 2675 15

Lysine acetylation serves as an epigenetic marker for myriad cellular processes, such as signaling, differentiation, DNA repair, angiogenesis, and the like. Sirtuin 1 (SIRT1) and sirtuin 2 (SIRT2) are NAD(+)-dependent histone deacetylases that operate as post-translational regulators for the deacetylation of acetyllysine. Here, we discuss the ability for SIRT1 and SIRT2 to deacetylate monoacetylated histone H3 on two separate architectures-the peptide and the nucleosome. In addition, we analyze the site-specificity of SIRT1 and SIRT2 on 10 different monoacetylated histone H3 nucleosomes. By utilizing a rapid screening array, SIRT1 and SIRT2 were found to demonstrate heightened enzymatic activity when incubated with nucleosomal substrates over their peptide counterparts. These two enzymes displayed little site-specificity among the acetyl-nucleosomes screened, contrary to previous expectations, as well. The implication of the overall nonspecificity of SIRT1 and SIRT2 on the nucleosome suggests that these sirtuin enzymes have an adaptive nature, harnessing an ability to respond to various cellular situations, rather than an enzyme specifically designed for a particular task or function.
ACS Chem Biol 2016 Mar 18
PMID:Sirtuins 1 and 2 Are Universal Histone Deacetylases. 2682 May 17

Chromatin is the universal template of genetic information in all eukaryotic organisms. Chemical modifications of the DNA-packaging histone proteins and the DNA bases are crucial signaling events in directing the use and readout of eukaryotic genomes. The enzymes that install and remove these chromatin modifications as well as the proteins that bind these marks govern information that goes beyond the sequence of DNA. Therefore, these so-called epigenetic regulators are intensively studied and represent promising drug targets in modern medicine. We summarize and discuss recent advances in the field of chemical biology that have provided chromatin research with sophisticated tools for investigating the composition, activity, and target sites of chromatin modifying enzymes and reader proteins.
ACS Chem Biol 2016 Mar 18
PMID:Probing Chromatin-modifying Enzymes with Chemical Tools. 2684 2

Monocyclic aromatic amines are widespread environmental contaminants with multiple sources such as combustion products, pharmaceuticals, and pesticides. Their phenolic metabolites are converted intracellularly to electrophilic quinone imines upon autoxidation and can embed in the cellular matrix through a transimination reaction that leaves a redox-active residue as a substituent of lysine side-chain amino groups. To demonstrate the occurrence of this process within the cellular nucleus, Chinese hamster ovary AA8 cells were treated with the para-phenol of 3,5-dimethylamine, after which the histone proteins were isolated, derivatized, and subjected to tryptic digestion. The resulting peptides were analyzed by tandem mass spectrometry to determine which lysines were modified. Nine residues in histones H2A, H2B, and H4 were identified; these were located in histone tails, close to where DNA makes contact with the nuclear core particle, elsewhere on the protein surface, and deep within the core. Kinetics of disappearance of the modified lysines in cultured cells was determined using isotope-dilution mass spectrometry. AA8 cells were also transfected with the genetically encoded hydrogen peroxide biosensor HyPer in constructs that lead to expression of HyPer in different cellular compartments. Challenging the resulting cells with the dimethylaminophenol resulted in sustained fluorescence emission in each of the compartments, demonstrating ongoing production of H2O2. The kinetics of modified lysine loss determined by mass spectrometry was consistent with persistence of HyPer fluorescence emission. We conclude that the para-phenol of 3,5-dimethylamine can become stably integrated into the histone proteins, which are minimally repaired, if at all, and function as a persistent source of intracellular H2O2.
ACS Chem Biol 2016 05 20
PMID:Hydroxyphenylation of Histone Lysines: Post-translational Modification by Quinone Imines. 2686 76

Epigenetic regulation is a key factor in cellular homeostasis. Post-translational modifications (PTMs) are a central focus of this regulation as they function as signaling markers within the cell. Lysine acetylation is a dynamic, reversible PTM that has garnered recent attention due to alterations in various types of cancer. Acetylation levels are regulated by two opposing enzyme families: lysine acetyltransferases (KATs) and histone deacetylases (HDACs). HDACs are key players in epigenetic regulation and have a role in the silencing of tumor suppressor genes. The dynamic equilibrium of acetylation makes HDACs attractive targets for drug therapy. However, substrate selectivity and biological function of HDAC isozymes is poorly understood. This review outlines the current understanding of the roles and specific epigenetic interactions of the metal-dependent HDACs in addition to their roles in cancer.
ACS Chem Biol 2016 Mar 18
PMID:Metal-dependent Deacetylases: Cancer and Epigenetic Regulators. 2690 66


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