The roles of DNA, RNA and histone methylation in ageing and cancer

Abstract

Chromatin is a macromolecular complex predominantly comprising DNA, histone proteins and RNA. The methylation of chromatin components is highly conserved as it helps coordinate the regulation of gene expression, DNA repair and DNA replication. Dynamic changes in chromatin methylation are essential for cell-fate determination and development. Consequently, inherited or acquired mutations in the major factors that regulate the methylation of DNA, RNA and/or histones are commonly observed in developmental disorders, ageing and cancer. This has provided the impetus for the clinical development of epigenetic therapies aimed at resetting the methylation imbalance observed in these disorders. In this Review, we discuss the cellular functions of chromatin methylation and focus on how this fundamental biological process is corrupted in cancer. We discuss methylation-based cancer therapies and provide a perspective on the emerging data from early-phase clinical trial therapies that target regulators of DNA and histone methylation. We also highlight promising therapeutic strategies, including monitoring chromatin methylation for diagnostic purposes and combination epigenetic therapy strategies that may improve immune surveillance in cancer and increase the efficacy of conventional and targeted anticancer drugs.

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Fig. 1: Methylation of DNA, RNA and histones.
Fig. 2: Changes in DNA and histone methylation in cells from young, ageing and cancer-bearing individuals.
Fig. 3: Expression of oncometabolites and oncohistones in cancer changes DNA and histone methylation.
Fig. 4: Targeting methylation in combination with immunotherapy.
Fig. 5: New opportunities for therapeutic intervention and monitoring.

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Glossary

SET domain

An evolutionarily conserved domain initially identified in the Su(var)3-9, enhancer of zeste and trithorax proteins in the fruitfly, whose conformation determines the catalytic activity of histone methyltransferases.

X chromosome inactivation

A gene-dosage compensation process by which one of the two X chromosomes in the cells of female mammals is transcriptionally silenced through heterochromatin formation.

Gene imprinting

Heritable gene expression pattern established in the germline through epigenetic modifications to maintain parent-of-origin gene-expression status in somatic cells.

Chromodomain

A conserved structural domain of ~40–50 amino acids commonly found in proteins associated with chromatin remodelling and with proteins that bind methylated histones.

Topologically associating domains

Insulated three-dimensional chromosomal domains of submegabase size, within which DNA sequences preferentially contact each other.

Replicative lifespan

The time during which a cell can divide and produce daughter cells before becoming senescent.

Oncometabolites

Metabolic intermediates that accumulate in cancer cells, often through loss-of-function or gain-of-function mutations in genes that encode enzymes, resulting in cancer-relevant epigenetic changes.

Tumour lysis syndrome

A potentially fatal complication arising during cancer therapy from the killing (lysis) of large numbers of tumour cells and the release of their contents into the bloodstream.

Gatekeeper mutations

Mutations in the functional domain of a protein that confer resistance to a pharmacological agent while preserving the function of the protein.

Immune-checkpoint inhibitors

Drugs that target key inhibitory molecules of immune cell activation.

Viral mimicry

Reactivation of endogenous retroviruses in the genome of tumour cells, leading to activation of double-stranded RNA sensing pathways and innate immune responses.

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