Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Targets in epigenetics: inhibiting the methyl writers of the histone code.

ABSTRACT: Growing evidence suggests that protein lysine methyltransferases (PKMTs) and protein arginine methyltransferases (PRMTs) are associated with the development of various human diseases, including cancer, inflammation, and psychiatric disorders. Given the significant role of these proteins in human disease, efforts to discover selective small-molecule inhibitors of these enzymes are quickly gaining momentum. In this review, we focus on the recent progress in the discovery of selective PKMT and PRMT inhibitors. A future perspective on developing methyltransferase inhibitors is also offered.

SUBMITTER: Yost JM

PROVIDER: S-EPMC3178896 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Targets in epigenetics: inhibiting the methyl writers of the histone code.

Yost Julianne M JM Korboukh Ilia I Liu Feng F Gao Cen C Jin Jian J

Current chemical genomics 20110822 Suppl 1

Growing evidence suggests that protein lysine methyltransferases (PKMTs) and protein arginine methyltransferases (PRMTs) are associated with the development of various human diseases, including cancer, inflammation, and psychiatric disorders. Given the significant role of these proteins in human disease, efforts to discover selective small-molecule inhibitors of these enzymes are quickly gaining momentum. In this review, we focus on the recent progress in the discovery of selective PKMT and PRMT ...[more]

PMID: 21966347

Similar Datasets

Epigenetics gets sweeter: O-GlcNAc joins the "histone code".

Project description:O-GlcNAcylation has now been added to the growing list of histone modifications making up the multifaceted "histone-code" (Sakabe et al., 2010). The sites of O-GlcNAc-histone modification hint at a role in chromatin remodeling, thus adding to mounting evidence that O-GlcNAc cycling sits atop a robust regulatory network maintaining higher-order chromatin structure and epigenetic memory.

| S-EPMC3010756 | biostudies-literature

Dynamics of histone lysine methylation: structures of methyl writers and erasers.

Project description:In Eukarya, the packaging of DNA into chromatin provides a barrier that allows for regulation of access to the genome. Chromatin is refractory to processes acting on DNA. ATP-dependent chromatin remodeling machines and histone-modifying complexes can overcome this barrier (or strengthen it in silencing processes). Both components of chromatin (DNA and histones) are subject to postsynthetic covalent modifications, including methylation of lysines (the focus of this chapter). These lysine marks are generated by a host of histone lysine methyltransferases (writers) and can be removed by histone lysine demethylases (erasers). Importantly, epigenetic modifications impact chromatin structure directly or can be read by effector regulatory modules. Here, we summarize current knowledge on structural and functional properties of various histone lysine methyltransfereases and demethylases, with emphasis on their importance as druggable targets.

| S-EPMC3048032 | biostudies-literature

Epigenetics: intrauterine growth retardation (IUGR) modifies the histone code along the rat hepatic IGF-1 gene.

Project description:Intrauterine growth restriction (IUGR) decreases serum insulin growth factor-1 (IGF-1) levels. IGF-1 is an epigenetically regulated gene that has two promoters, alternative exon 5 splicing, and multiple termination sites. The regulation of gene expression involves the whole gene, as evidenced by the aforementioned IGF-1 paradigm. We hypothesized that IUGR in the rat would affect hepatic IGF-1 expression and alter the epigenetic characteristics of the IGF-1 gene along its length. IUGR was induced through a bilateral uterine artery ligation of the pregnant rat, a well-characterized model of IUGR. Pups from anesthesia and sham-operated dams were used as controls. Real-time RT-PCR and ELISA was used to measure expression at day of life (DOL) 0 and 21. Bisulfite sequencing and chromatin immunoprecipitation (ChIP) quantified IGF-1 epigenetic characteristics. A nontranscribed intergenic control was used for ChIP studies. IUGR decreased hepatic and serum IGF-1. Concurrently, IUGR modified epigenetic characteristics, particularly the histone code, along the length of the hepatic IGF-1 gene. Many changes persisted postnatally, and the postnatal effect of IUGR on the histone code was gender-specific. We conclude that IUGR modifies epigenetic characteristics of the rat hepatic IGF-1 gene along the length of the whole gene.

| S-EPMC2717764 | biostudies-literature

Epigenetics and beyond: targeting writers of protein lysine methylation to treat disease.

Project description:Protein lysine methylation is a crucial post-translational modification that regulates the functions of both histone and non-histone proteins. Deregulation of the enzymes or 'writers' of protein lysine methylation, lysine methyltransferases (KMTs), is implicated in the cause of many diseases, including cancer, mental health disorders and developmental disorders. Over the past decade, significant advances have been made in developing drugs to target KMTs that are involved in histone methylation and epigenetic regulation. The first of these inhibitors, tazemetostat, was recently approved for the treatment of epithelioid sarcoma and follicular lymphoma, and several more are in clinical and preclinical evaluation. Beyond chromatin, the many KMTs that regulate protein synthesis and other fundamental biological processes are emerging as promising new targets for drug development to treat diverse diseases.

| S-EPMC8035164 | biostudies-literature

Writers and readers of histone acetylation: structure, mechanism, and inhibition.

Project description:Histone acetylation marks are written by histone acetyltransferases (HATs) and read by bromodomains (BrDs), and less commonly by other protein modules. These proteins regulate many transcription-mediated biological processes, and their aberrant activities are correlated with several human diseases. Consequently, small molecule HAT and BrD inhibitors with therapeutic potential have been developed. Structural and biochemical studies of HATs and BrDs have revealed that HATs fall into distinct subfamilies containing a structurally related core for cofactor binding, but divergent flanking regions for substrate-specific binding, catalysis, and autoregulation. BrDs adopt a conserved left-handed four-helix bundle to recognize acetyllysine; divergent loop residues contribute to substrate-specific acetyllysine recognition.

| S-EPMC4067988 | biostudies-literature

The Histone Code of Senescence.

Project description:Senescence is the end point of a complex cellular response that proceeds through a set of highly regulated steps. Initially, the permanent cell-cycle arrest that characterizes senescence is a pro-survival response to irreparable DNA damage. The maintenance of this prolonged condition requires the adaptation of the cells to an unfavorable, demanding and stressful microenvironment. This adaptation is orchestrated through a deep epigenetic resetting. A first wave of epigenetic changes builds a dam on irreparable DNA damage and sustains the pro-survival response and the cell-cycle arrest. Later on, a second wave of epigenetic modifications allows the genomic reorganization to sustain the transcription of pro-inflammatory genes. The balanced epigenetic dynamism of senescent cells influences physiological processes, such as differentiation, embryogenesis and aging, while its alteration leads to cancer, neurodegeneration and premature aging. Here we provide an overview of the most relevant histone modifications, which characterize senescence, aging and the activation of a prolonged DNA damage response.

| S-EPMC7072776 | biostudies-literature

Oncohistones: Hijacking the histone code.

Project description:Chromatin dysfunction has been implicated in a growing number of cancers especially in children and young adults. In addition to chromatin modifying and remodeling enzymes, mutations in histone genes are linked to human cancers. Since the first reports of hotspot missense mutations affecting key residues at histone H3 tail, studies have revealed how these so-called "oncohistones" dominantly (H3K27M and H3K36M) or locally (H3.3G34R/W) inhibit corresponding histone methyltransferases and misregulate epigenome and transcriptome to promote tumorigenesis. More recently, widespread mutations in all four core histones are identified in diverse cancer types. Furthermore, an "oncohistone-like" protein EZHIP has been implicated in driving childhood ependymomas through a mechanism highly reminiscent of H3K27M mutation. We will review recent progresses on understanding the biochemical, molecular and biological mechanisms underlying the canonical and novel histone mutations. Importantly, these mechanistic insights have identified therapeutic opportunities for oncohistone-driven tumors.

| S-EPMC9802661 | biostudies-literature

Epigenetics and therapeutic targets mediating neuroprotection.

Project description:The rapidly evolving science of epigenetics is transforming our understanding of the nervous system in health and disease and holds great promise for the development of novel diagnostic and therapeutic approaches targeting neurological diseases. Increasing evidence suggests that epigenetic factors and mechanisms serve as important mediators of the pathogenic processes that lead to irrevocable neural injury and of countervailing homeostatic and regenerative responses. Epigenetics is, therefore, of considerable translational significance to the field of neuroprotection. In this brief review, we provide an overview of epigenetic mechanisms and highlight the emerging roles played by epigenetic processes in neural cell dysfunction and death and in resultant neuroprotective responses. This article is part of a Special Issue entitled SI: Neuroprotection.

| S-EPMC4681633 | biostudies-literature

Functional coupling between writers, erasers and readers of histone and DNA methylation.

Project description:DNA and histone lysine methylation are dynamic chemical modifications that play a crucial role in the establishment of gene expression patterns during development. Both types of genomic methylation patterns are enzymatically regulated by the opposing activities of enzymes that introduce and remove these marks, known as methylation 'writers' and 'erasers', respectively. The appropriate localization and activity of these enzymes on chromatin is, in part, regulated by chromatin 'readers', protein modules that recognize histone and DNA modifications. Such reading modules are either encoded within the same polypeptide as the catalytic domains of writers and erasers, or present in protein partners that associate with them. Here, we review recent structural, biochemical and biological studies that demonstrate that there are multiple mechanisms by which reader domains can regulate the writers and erasers of histone and DNA methylation.

| S-EPMC4688207 | biostudies-literature

Targeting the histone orthography of cancer: drugs for writers, erasers and readers.

Project description:Gene expression is dynamically controlled by epigenetics through post-translational modifications of histones, chromatin-associated proteins and DNA itself. All these elements are required for the maintenance of chromatin structure and cell identity in the context of a normal cellular phenotype. Disruption of epigenetic regulation is a common event in human cancer. Here, we review the key protein families that control epigenetic signalling through writing, erasing or reading specific post-translational modifications. By exploiting the leading role of epigenetics in tumour development and the reversibility of epigenetic modifications, promising novel epigenetic-based therapies are being developed. In this article, we highlight the emerging low MW inhibitors targeting each class of chromatin-associated protein, their current use in preclinical and clinical trials and the likelihood of their being approved in the near future.

| S-EPMC4439870 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data