Acetylation and Methylation of Histones and Their Possible Role in the Regulation of Rna Synthesis

Allfrey, Vincent G.; Faulkner, Robert; Mirsky, A. E.

doi:10.1073/pnas.51.5.786

Cited by 2,186 publications

(1,558 citation statements)

References 29 publications

Supporting

Mentioning

1,492

Contrasting

Unclassified

Order By: Relevance

“…The basic repeating unit of chromatin is the nucleosome, composed of approximately 146 bp of DNA wrapped around the histone octamer composed of two copies of each of four histones, H2A, H2B and H3 and H4. It was proposed almost four decades ago that structural modification of histones by acetylation plays a role in regulation of gene expression [Allfrey et al, 1964]. There is now abundant evidence that remodeling of the chromatin proteins around which the DNA is wrapped is a fundamental epigenetic mechanism for regulating gene expression, involving the reversible post-translational modification of amino acids in the histone tails by acetylation of lysines, methylation of lysines and arginines, phosphorylation of serines, and ubiquination and sumoylation of lysines [Zhang and Reinberg, 2001;Spotswood and Turner, 2002;Fischle et al, 2003].…”

Section: Histone Deacetylases (Hdacs) and Histone Acetyltransferasesmentioning

confidence: 99%

Prospects: Histone deacetylase inhibitors

Dokmanovic

Marks

2005

J of Cellular Biochemistry

440

363

View full text Add to dashboard Cite

Histone deacetylase (HDAC), inhibitors represent a new class of targeted anti-cancer agents. Several of these compounds are in clinical trials with significant activity against a spectrum of both hematologic and solid tumors at doses that are well tolerated by the patients. The HDAC inhibitors are a structurally diverse group of molecules that can induce growth arrest, differentiation, apoptosis, and autophagocytic cell death of cancer cells. While the base sequence of DNA provides the genetic code for proteins, the expression of genes is regulated, in large part, by the structure of the chromatin proteins around which the DNA is wrapped (epigenetic gene regulation). The acetylation and deacetylation of the lysines in the tails of the core histones, among the most extensively studied aspects of chromatin structure, is controlled by the action of two families of enzymes, histone deacetylases (HDACs) and histone acetyltransferases (HATs). Protein components of transcription factor complexes and many other non-histone proteins are also substrates for HDACs and HATs. The structure and activity of these non-histone proteins may be altered by acetylation/deacetylation with consequent effects on various cell functions including gene expression, cell cycle progression, and cell death pathways. This review focuses on several key questions with respect to the mechanism of action of HDACi, including, what are the different cell phenotypes induced by HDACi, why are normal cells compared to transformed cells relatively resistant to HDACi induced cell death, why are certain tumors more responsive to HDACi than others, and what is the basis of the selectivity of HDACi in altering gene expression. The answers to these questions will have therapeutic importance since we will identify targets for enhancing the efficacy and safety of HDACi.

show abstract

Section: Histone Deacetylases (Hdacs) and Histone Acetyltransferasesmentioning

confidence: 99%

Prospects: Histone deacetylase inhibitors

Dokmanovic

Marks

2005

J of Cellular Biochemistry

440

363

View full text Add to dashboard Cite

show abstract

“…1 Besides the genetic DNA code of a cell that is replicated faithfully upon every cell division and therefore virtually identical in every cell within an individual, 2 additional 'epigenetic' information fixes differential cell development by prompting daughter cells to express a similar set of genes as their mother cell. 3 This facilitates and thus preserves the differentiation process that the mother cell and its ancestors have undergone as part of cellular diversification within an organism.…”

mentioning

confidence: 99%

Cell division curtails helper phenotype plasticity and expedites helper T‐cell differentiation

Ham

Boer

2012

Immunol Cell Biol

View full text Add to dashboard Cite

Following activation by antigen, helper T cells differentiate into one of many effector phenotypes. Formulating mechanistic mathematical models combining regulatory networks at the transcriptional, translational and epigenetic level, we study how individual helper T cells may adopt their different phenotypes. For each cytokine phenotype, for example, T helper type 1 (Th1) and type 2 (Th2) cells, we find that the intracellular molecular network allows a cell to adopt one of the three states, which we interpret as naive, active and memory states. Cell division markedly speeds up the differentiation into a particular memory state because of DNA demythelation. In a memory state, cells readily resume production of the same cytokine they produced before. Using stochastic models we show that helper T-cell plasticity (that is, the ability to switch phenotype) is low during clonal expansion. Although most memory cells rapidly secrete the original cytokine upon restimulation, some adopt another phenotype and produce different cytokines, allowing for considerable diversity in the phenotypes that are adopted during a memory response. In summary, we show that helper T-cell division expedites cell differentiation by increasing DNA demethylation. We also show that plasticity is low during the clonal expansion phase, but that helper T cells may adopt alternative phenotypes during a memory response. Keywords: epigenetic regulation; helper T-cell phenotypes; mathematical modelling; transcriptional regulation For more than a century, biologists have studied the mechanisms that enable cells to encode genetic information, and how this information is passed on to the cell's progeny. 1 Besides the genetic DNA code of a cell that is replicated faithfully upon every cell division and therefore virtually identical in every cell within an individual, 2 additional 'epigenetic' information fixes differential cell development by prompting daughter cells to express a similar set of genes as their mother cell. 3 This facilitates and thus preserves the differentiation process that the mother cell and its ancestors have undergone as part of cellular diversification within an organism.A variety of biological systems have now been studied using highthroughput technologies, which provide data that allow a better understanding of information processing within a cell. [4][5][6][7] The availability of quantitative data and the apparent complexity of cellular regulatory networks have led to a data-driven mathematical modelling approach that is usually referred to as computational or systems biology. Mathematical models have revealed nonlinearity in genetic networks that allow cells to switch between states. Examples are the Lac operon 8 and cells of the haematopoietic lineage. [9][10][11][12] Recently, epigenetic regulation mediated by histone modification has been studied using similar mathematical models. [13][14][15] At the molecular level these mathematical models describe quite different genetic and epigenetic systems. Mathematically they share im...

show abstract

“…Lysine acetylation was initially observed on histones and soon correlated with transcriptional activity [39]. Lysine acetyltransferases were only identified three decades later and it took yet another decade until the enormous prevalence of this modification across the entire proteome was appreciated.…”

Section: Lysine Acetylationmentioning

confidence: 99%

Rewiring translation – Genetic code expansion and its applications

Neumann

2012

FEBS Letters

View full text Add to dashboard Cite

a b s t r a c tWith few minor variations, the genetic code is universal to all forms of life on our planet. It is difficult to imagine that one day organisms might exist that use an entirely different code to translate the information of their genome. Recent developments in the field of synthetic biology, however, have opened the gate to their creation. The genetic code of several organisms has been expanded by the heterologous expression of evolved aminoacyl-tRNA synthetase/tRNA CUA pairs that mediate the incorporation of unnatural amino acids in response to amber codons. These UAAs introduce exciting new features into proteins, such as spectroscopic probes, UV-inducible crosslinkers, and functional groups for bioorthogonal conjugations or posttranslational modifications. Orthogonal ribosomes provide a parallel translational machinery in Escherichia coli that has lost its evolutionary constraints. Evolved variants of these ribosomes translate amber or quadruplet codons with massively enhanced efficiency. Here, I review these recent developments emphasizing their tremendous potential to facilitate biochemical and cell biological studies.

show abstract

Acetylation and Methylation of Histones and Their Possible Role in the Regulation of Rna Synthesis

Cited by 2,186 publications

References 29 publications

Prospects: Histone deacetylase inhibitors

Prospects: Histone deacetylase inhibitors

Cell division curtails helper phenotype plasticity and expedites helper T‐cell differentiation

Rewiring translation – Genetic code expansion and its applications

Contact Info

Product

Resources

About