The genetic information of human cells is stored in the context of chromatin, which is subjected to DNA methylation and various histone modifications. Such a ‘language’ of chromatin modification constitutes a fundamental means of gene and (epi)genome regulation, underlying a myriad of cellular and developmental processes. In recent years, mounting evidence has demonstrated that miswriting, misreading or mis-erasing of the modification language embedded in chromatin represents a common, sometimes early and pivotal, event across a wide range of human cancers, contributing to oncogenesis through the induction of epigenetic, transcriptomic and phenotypic alterations. It is increasingly clear that cancer-related metabolic perturbations and oncohistone mutations also directly impact chromatin modification, thereby promoting cancerous transformation. Phase separation-based deregulation of chromatin modulators and chromatin structure is also emerging to be an important underpinning of tumorigenesis. Understanding the various molecular pathways that underscore a misregulated chromatin language in cancer, together with discovery and development of more effective drugs to target these chromatin-related vulnerabilities, will enhance treatment of human malignancies.
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This work was supported by NIH grants (R01-CA215284 and R01-CA218600 to G.G.W.). This research was also supported by a NIH grant (P01CA196539 to C.D.A.) and funds of St. Jude Children’s Research Hospital and The Rockefeller University (to C.D.A). G.G.W. is an American Cancer Society Research Scholar and a Leukemia and Lymphoma Society Scholar. The authors apologize to colleagues whose works are not cited in this Review owing to space limitations.
The authors declare no competing interests.
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- Polycomb repressive complex 2
(PRC2). Complex consisting of core subunits EZH2 or EZH1, EED, SUZ12 and RbAp46 or RbAp48, which catalyses the methylation of histone H3K27.
- SWI/SNF chromatin remodelling complex
Comprising approximately 15 subunits, uses the energy from ATP hydrolysis to mobilize nucleosomes.
- Germinal centre (GC) B cells
B cells residing in the GC sites of secondary lymphoid organs such as spleen and lymph nodes where B cells proliferate, differentiate and mutate the antibody-encoding genes (through somatic hypermutation) to generate antibodies of higher affinity during the immune response.
A chemical process of transferring an acyl group to the substrate. It includes but is not limited to acetylation.
Chromatin regions that comprise multiple enhancers and are enriched in transcription factors and mediators.
- De novo DNA methylation
DNA methylation occurring at previously unmethylated sites.
- Acidic patch
A negatively charged region in nucleosome, formed by six residues from H2A and H2B.
- CpG islands
Genomic regions (typically 300–3,000 bp) that are highly enriched for CpG dinucleotides and usually lack DNA methylation.
- Maintenance DNA methylation
DNA methylation that is maintained based on the existing template DNA methylation.
- Clonal haematopoiesis
A phenomenon of the expansion of a clonal blood cell population with the same genetic mutation.
Describes mutation that causes a partial loss of gene function (such as reduced enzymatic activity).
- Intrinsically disordered regions
Flexible linkers or loops within a protein that form no secondary structure and often mediate phase separation.
- π-π-π stacking
The noncovalent interaction between aromatic rings.
A metabolite that is significantly elevated in quantity in tumours.
Oxidoreductase enzyme that incorporates both atoms of O2 into the substrate.
Three-stranded nucleic acid structures formed by one DNA–RNA duplex and one associated non-template single-strand DNA.
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Zhao, S., Allis, C.D. & Wang, G.G. The language of chromatin modification in human cancers. Nat Rev Cancer 21, 413–430 (2021). https://doi.org/10.1038/s41568-021-00357-x
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