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  • Review Article
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Epigenetic protein families: a new frontier for drug discovery

Nature Reviews Drug Discovery volume 11, pages 384–400 (2012)Cite this article

Subjects

Key Points

  • Epigenetic regulation of gene expression relies on covalent, reversible and sequence-specific modifications of histone proteins that package DNA. Deregulation of this control mechanism can lead to multiple diseases.

  • Acetylation and methylation of lysine and arginine residues are the most abundant modifications of the known histone marks. Histone acetyl marks are written by histone acetyltranferases, read by bromodomain-containing proteins and erased by histone deacetylases.

  • Histone methyl marks are written by protein methyltransferases and read by proteins containing chromodomains, Tudor domains, malignant brain tumour domains, PWWP domains and plant homeodomain (PHD) fingers. Histone methyl marks are erased by lysine demethylases.

  • Domains that write, read or erase histone marks are often grouped within a single gene, and these proteins are often combined within multiprotein complexes that mediate crosstalk between specific marks.

  • When they are mutated, aberrantly expressed or driven by aberrant upstream signals, writers, readers and erasers of histone marks can affect the expression patterns of genes that lead to — or even drive — and maintain disease states. Direct associations have been observed in cancer, neuropsychiatric disorders, inflammation and metabolic diseases.

  • Several histone deacetylase inhibitors have reached the clinic and two are approved in oncology. Small-molecule antagonists of bromodomain-containing proteins have demonstrated efficacy in animal models of cancer and inflammation. The chemical tractability of histone acetyltransferases, however, remains unclear.

  • Potent protein methyltransferase inhibitors have been reported, and one compound was active against tumour xenografts in mice. Lysine demethylase inhibitors and antagonists of methyl-lysine readers are at an earlier development stage.

Abstract

Epigenetic regulation of gene expression is a dynamic and reversible process that establishes normal cellular phenotypes but also contributes to human diseases. At the molecular level, epigenetic regulation involves hierarchical covalent modification of DNA and the proteins that package DNA, such as histones. Here, we review the key protein families that mediate epigenetic signalling through the acetylation and methylation of histones, including histone deacetylases, protein methyltransferases, lysine demethylases, bromodomain-containing proteins and proteins that bind to methylated histones. These protein families are emerging as druggable classes of enzymes and druggable classes of protein–protein interaction domains. In this article, we discuss the known links with disease, basic molecular mechanisms of action and recent progress in the pharmacological modulation of each class of proteins.

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Figure 1: Covalent modification of histones and DNA are key mechanisms involved in epigenetic regulation of gene expression.
Figure 2: Phylogenetic trees of epigenetic protein families.
Figure 3: Drugging acetyl mark-mediated signalling.
Figure 5: Drugging methyl mark-mediated signalling.
Figure 4: Structural mechanism of representative inhibitors.

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Acknowledgements

We are grateful to P. Brennan for his contribution on demethylase inhibitors, and S. Knapp for his comments on the manuscript. The Structural Genomics Consortium is a registered charity (charity number 1097737) that receives funds from the Canadian Institutes of Health Research, Eli Lilly, Genome Canada (through the Ontario Genomics Institute), GlaxoSmithKline, the Ontario Ministry for Research and Innovation, the Novartis Research Foundation, Pfizer and the Wellcome Trust.

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Authors and Affiliations

  1. Structural Genomics Consortium, University of Toronto, 101 College Street, Toronto, M5G 1L7, Ontario, Canada

    Cheryl H. Arrowsmith & Matthieu Schapira

  2. Ontario Cancer Institute, University of Toronto, 101 College Street, Toronto, M5G 1L7, Ontario, Canada

    Cheryl H. Arrowsmith

  3. Department of Medical Biophysics, University of Toronto, 101 College Street, Toronto, M5G 1L7, Ontario, Canada

    Cheryl H. Arrowsmith

  4. Nuffield Department of Clinical Medicine, Structural Genomics Consortium, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, OX3 7LD, Oxford, UK

    Chas Bountra

  5. Worldwide Medicinal Chemistry, Pfizer, Ramsgate Road, Sandwich, CT13 9NJ, Kent, UK

    Paul V. Fish

  6. Epinova DPU, Immuno-Inflammation Centre of Excellence for Drug Discovery, GlaxoSmithKline, Gunnels Wood Road, SG1 2NY, Stevenage, UK

    Kevin Lee

  7. Department of Pharmacology & Toxicology, University of Toronto, 101 College Street, Toronto, M5G 1L7, Ontario, Canada

    Matthieu Schapira

  8. Pfizer Biotherapeutics, 200 Cambridge Park Drive, Cambridge, 02140, Massachusetts, USA

    Kevin Lee

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Correspondence to Cheryl H. Arrowsmith.

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K.L. was an employee of GlaxoSmithKline and is now an employee of Pfizer. All other authors declare no competing financial interests.

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FURTHER INFORMATION

ClinicalTrials.gov website

EnVivo Pharmaceuticals website — Pipeline & Programs

Pfam protein family database

RCSB Protein Data Bank website

RepliGen website (RG2833: Potential to Alter the Course of Friedreich's Ataxia)

Siena Biotech website — Development Pipeline

SMART (Simple Modular Architecture Research Tool) database

Structural Genomics Consortium (Annotated Phylogenetic Trees)

Structural Genomics Consortium (Chemical Probes)

Structural Genomics Consortium (Epigenetics: Chemical Probes for Drug Discovery)

Structural Genomics Consortium (Histone Tails)

Glossary

Chromatin

The fibres in which DNA and genes are packaged in the nucleus of a cell. Chromatin consists of the DNA double helix wrapped around a complex of histone proteins — together called the nucleosome.

Epigenetics

Heritable changes in gene expression or phenotype that are stable between cell divisions, and sometimes between generations, but do not involve changes in the underlying DNA sequence of the organism.

Differentiation

The process by whicha stem cell, or other precursor cell, commits towards a more specialized cell type with a specific function, and represents an exit from self-renewal. Differentiation is controlled by cell signalling pathways and maintained through epigenetic mechanisms.

Post-translational modification

A chemical modification of proteins that acts as a signal to other proteins that recognize the modification. In the context of epigenetic signalling, post-translational modifications are often called 'marks'.

Epigenome

The combination of histone and DNA post-translational modifications and related interacting proteins that together package the genome and help define the transcriptional programme in a given cell.

Heterochromatin

A tightly packed form of DNA associated with transcriptionally silent or repressed genes. It is highly correlated with di- and trimethlyated H3K9 (Lys9 of histone 3) marks.

Euchromatin

A more loosely packed form of DNA that is associated with transcriptionally active genes.

Bromodomain

An evolutionarily conserved, ∼110-amino-acid motif composed of four left-handed, antiparallel α-helices.

Stem cell

An unspecialized precursor cell withthe capacity to self-renew (continuously produce unaltered progeny) and to differentiate into more mature specialized cell types.

Haploinsufficiency

A disease mechanism in which one of two copies of a gene is mutated, resulting in insufficient activity of the gene products (typically a protein) to bring about a functional, wild-type condition.

Brachydactyly mental retardation syndrome

A disorder that presents with a range of features, including intellectual disabilities, developmental delays, behavioural abnormalities, sleep disturbance, craniofacial and skeletal abnormalities, and autism spectrum disorder.

Presenilins

A family of related multipass transmembrane proteins that function as part of the γ-secretase intramembrane protease complex. They were first identified in screens for mutations causing early-onset forms of familial Alzheimer's disease.

Amyotrophic lateral sclerosis

A progressive neurological disease that is associated with the degeneration of central and spinal motor neurons. This neuron loss causes muscles to weaken and waste away, leading to paralysis.

Jumonji domain

A conserved domain originally identified in the Jumonji family of transcription factors, now known to be histone demethylases. The Jumonji C domain comprises the catalytic domain of the 2-oxoglutarate-dependent lysine demethylases.

Hyperglycaemic memory

A phenomenon in which the deleterious end-organ effects resulting from exposure to high glucose levels persist for several years after usual glycaemic control is restored.

Malignant brain tumour domains

Conserved sequence motifs found in certain developmental proteins. These domains bind to mono- or dimethylated lysine-containing peptides and, when deleted in fruitflies, lead to brain tumours.

Allosteric stimulation

The regulation of an enzyme or protein by binding an effector molecule at a site other than the protein's active site, thereby causing a conformational change in the protein.

P300/CBP-associated factor

A trancriptional co-activator protein containing a bromodomain and a histone acetyltransferase domain.

π electron interactions

A non-covalent interaction between the π-electron cloud of aromatic rings and the cationic charge of, for example, methylated lysine.

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Arrowsmith, C., Bountra, C., Fish, P. et al. Epigenetic protein families: a new frontier for drug discovery. Nat Rev Drug Discov 11, 384–400 (2012). https://doi.org/10.1038/nrd3674

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