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Chromatin dependencies in cancer and inflammation

Key Points

  • Cell signalling pathways converge on chromatin, where they induce transcriptional programmes. The inducible programmes are regulated by shared chromatin factors.

  • Targeted inhibition of numerous chromatin factors preferentially suppresses the expression of inducible genes, such as those induced by inflammatory or oncogenic stimuli. Housekeeping genes are not affected by these treatments, as their kinetics of activation and chromatin environment, including the abundance, composition and dependency on some chromatin regulators, are different.

  • Targeting chromatin dependencies unique to the promoter–enhancer structure and composition of inducible genes is an effective, although possibly transient, therapy for cancer and for immunopathologies driven by overt inflammation.

  • The combination of immunotherapy and epigenetic therapy should be carefully tested to evaluate its efficacy. In particular, inhibitors of inducible gene expression programmes might have concurrent effects on cancer cells, immune cells and tumour microenvironment cells.

Abstract

Multiple cell-signalling pathways converge on chromatin to induce gene expression programmes. The inducible transcriptional programmes that are established as a result of inflammatory or oncogenic signals are controlled by shared chromatin regulators. Therapeutic targeting of such chromatin dependencies has proved effective for controlling tumorigenesis and for preventing immunopathologies that are driven by overt inflammation. In this Review, we discuss how chromatin dependencies are established to regulate the expression of key oncogenes and inflammation-promoting genes and how a better mechanistic understanding of such chromatin dependencies can be leveraged to improve the magnitude, timing, duration and selectivity of cell responses with the aim of minimizing unwanted cellular and systemic effects. Recently, exciting progress has been made in cancer immunotherapy and in the development of drugs that target chromatin regulators. We discuss recent advances in clinical trials and the challenge of combining immune-cell-based therapies and epigenetic therapies to improve human health.

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Figure 1: Chromatin regulators involved in transcription induction.
Figure 2: Inducible gene programmes.
Figure 3: Defining features of gene classes.
Figure 4: Chromatin remodelling and susceptibility to inhibitors.

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Acknowledgements

The authors acknowledge that several primary manuscripts could not be duly cited owing to space limitations. The authors thank J. Venables for critical reading and editing of the manuscript. B. Amati, L.. S. Weinberger, S. Campaner, A. Sabo and J. Ho for constructive suggestions and discussions. I.M. thanks D. Charney. The work was partially supported by a seed fund from the Icahn School of Medicine (I.M.), by grant NRF2016-CRP001-103 CRP award (E.G.) and by the RNA Biology Center at the Cancer Science Institute (CSI) of Singapore, National University of Singapore, from funding by the Singapore Ministry of Education's Tier 3 grants, grant number MOE2014-T3-1-006 (D.H.P.L.).

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Contributions

Researching data for the article: I.M., E.G., B.D.G. and D.H.P.L.; substantial contributions to the discussion of content: I.M. and E.G.; writing: I.M. and E.G.; reviewing and/or editing the manuscript before submission: I.M. and E.G.

Corresponding authors

Correspondence to Ivan Marazzi or Ernesto Guccione.

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The authors declare no competing financial interests.

Supplementary information

Supplementary information S1 (box)

Cross-comparative analysis of promoter chromatin states with inflammation and oncogenic gene expression signatures. (PDF 5519 kb)

Supplementary information S2 (figure)

Analysis of CpG content or RNA polymerase II (Pol II) occupancy at genes belonging to the categories described in supplementary information S1 (box). (PDF 368 kb)

Supplementary information S3 (box)

Methods used in preparing Figure 3 (PDF 127 kb)

PowerPoint slides

Glossary

Tonic signals

Basal, constitutive and slow-acting signals (in contrast to stimulus-induced and fast-acting signals).

Chemical probes

Small-molecule inhibitors that are potent, selective and cell permeable. They are used in the early stages of drug discovery to study the function of a drug target in a complex biological system.

Bromodomain and extra-terminal domain

(BET). A protein domain of transcription cofactors that allows for interaction with acetylated lysine, mainly on histone tails, to coordinate RNA polymerase II pause–release.

Inducible gene

A gene that is expressed under specific conditions and under the control of a signalling cascade, the expression of which is tightly regulated.

Immunotherapy

The therapeutic use of small molecules, antibodies or cell-based therapies that either stimulate or suppress the immune system or introduce immune system components.

R-Loops

RNA–DNA hybrid structures that can regulate several phases of the transcription process, such as RNA polymerase II processivity and termination.

Super enhancers

Large enhancers with binding sites for multiple transcription factors.

Pioneer transcription factor

A transcription factor that is able to bind compact chromatin and recruit chromatin remodellers, thereby facilitating the subsequent binding of other factors.

YEATS domain

A domain characterized by an immunoglobulin-like fold, which is able to bind specifically to acetylated lysine residues.

Housekeeping genes

Genes that are constitutively expressed in most or all cells of an organism, under a wide range of physiological and pathological conditions. They are essential to maintain cell homeostasis.

DNA G-quadruplexes

Intramolecular and intermolecular four-stranded non-B-DNA structures formed by folding of single-stranded guanine-rich DNA.

Epigenetic therapy

Therapy consisting of small molecules or techniques that target epigenetic regulators of histone post-translational modifications and DNA modifications.

Immune checkpoints

Inhibitory molecules that are essential for modulating the amplitude and duration of immune responses.

Pattern-recognition receptors

Innate immune system receptors present in immune and non-immune cells that recognize pathogen-derived material and induce a protective cellular response.

Stem cell-like memory T cells

T cells at an early and long-lasting stage in the process to becoming memory T cells, between the stages of naive memory T cells and central memory T cells.

Central memory T cells

A long-lived population of memory T cells, which are highly proliferative and produce interleukin-2. They can differentiate into shorter-lived effector memory T cells following antigen stimulation.

Effector memory T cells

A population of mature T cells with low proliferation index and increased levels of interferon-γ and interleukin-4 secretion.

Adoptive T cell therapy

A therapy in which T cells are harvested from a patient and expanded in vitro to enhance their ability to recognize a specific antigen and/or to selectively kill cancer cells. These T cells are then reintroduced into the patient as cell-based therapy.

T cell receptor-redirected therapy

A therapy in which T cells are engineered with an exogenous T cell receptor to redirect antigen specificity.

Chimeric antigen receptor-redirected therapy

A therapy in which T cells are engineered with a chimeric antigen receptor to confer new antigen specificity.

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Marazzi, I., Greenbaum, B., Low, D. et al. Chromatin dependencies in cancer and inflammation. Nat Rev Mol Cell Biol 19, 245–261 (2018). https://doi.org/10.1038/nrm.2017.113

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