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  • Review Article
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Epigenetic control of myeloid cell differentiation, identity and function

Nature Reviews Immunology volume 15, pages 7–17 (2015)Cite this article

Subjects

Key Points

  • The interplay between transcription factors and epigenetic regulators is crucial for regulating gene-expression programmes during haematopoiesis. Epigenetic regulation — including post-translational modification of histones and DNA methylation — is also linked with upstream signalling pathways and external signals that shape the identity and function of immune cells.

  • Distinctive DNA methylation changes characterize the differentiation of myeloid cells and lymphoid cells from their progenitors. DNA demethylation is more predominant during myeloid differentiation than during lymphoid differentiation.

  • The methylcytosine hydroxylase TET2, which oxidizes 5-methylcytosine, has a major role in the acquisition of myeloid cell identity. This has been demonstrated using transdifferentiation models and is highlighted by the association of TET2 mutations with myeloid malignancies.

  • Epigenetic control has a key role in defining macrophage polarization, connecting external stimuli with the establishment of specific transcriptional programmes.

  • Epigenetic modifications have a key role in the generation of memory-type behaviour in innate immune cells. Following an initial stimulus, the persistence of the trimethylated histone H3K4 at latent enhancers ensures the increased expression of pro-inflammatory genes after restimulation.

Abstract

Myeloid cells are crucial effectors of the innate immune response and important regulators of adaptive immunity. The differentiation and activation of myeloid cells requires the timely regulation of gene expression; this depends on the interplay of a variety of elements, including transcription factors and epigenetic mechanisms. Epigenetic control involves histone modifications and DNA methylation, and is coupled to lineage-specifying transcription factors, upstream signalling pathways and external factors released in the bone marrow, blood and tissue environments. In this Review, we highlight key epigenetic events controlling myeloid cell biology, focusing on those related to myeloid cell differentiation, the acquisition of myeloid identity and innate immune memory.

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Figure 1: DNA methylation events in the early stages of haematopoiesis.
Figure 2: Transcription factors and epigenetic regulators of haematopoietic cell differentiation.
Figure 3: Epigenetic regulation of memory-like activity in monocytes and macrophages.

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Acknowledgements

This work was supported by grant SAF2011-29635 from the Spanish Ministry of Science and Innovation, grant CIVP16A1834 from the Fundación Ramón Areces and grant Precisesads 115565–3 of the Innovative Medicines Initiative (IMI) Programme.

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Authors and Affiliations

  1. Chromatin and Disease Group, Cancer Epigenetics and Biology Programme (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), 08908L'Hospitalet de Llobregat, Barcelona, Spain

    Damiana Álvarez-Errico, Roser Vento-Tormo & Esteban Ballestar

  2. Stem Cell and Macrophage Biology, Centre d'Immunologie de Marseille-Luminy, Campus de Luminy, Case 906, Marseille Cedex 09, 13288, France

    Michael Sieweke

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PowerPoint slides

Glossary

Histones

A family of basic proteins found in the nuclei of eukaryotic cells that package and organize DNA into repetitive structural units named nucleosomes.

Shores

Regions that are located within 2 kb of CpG islands and are usually methylation hotspots.

Shelves

Regions that flank CpG island shores and are located 2–4 kb from CpG islands.

Open sea

CpG sites that are located outside of the CpG island context.

Imprinted genes

Genes for which the expression status is determined by the parent that contributed them.

Methyl-CpG binding proteins

A family of proteins characterized by the presence of the methyl-CpG binding domain, several of which are integral components of or are involved in the recruitment of different histone deacetylase complexes and chromatin remodelling factors of different nuclear complexes that have a role in gene expression.

Yamanaka factors

A set of transcription factors that are highly expressed in embryonic stem cells. Their overexpression induces pluripotency in somatic cells.

'M1' or 'classical' activation

Lipopolysaccharide- or interferon-γ-mediated stimulation of macrophages leading to a pro-inflammatory phenotype.

'M2' or 'alternative' activation

Interleukin-4-dependent stimulation of macrophages that leads to an anti-inflammatory phenotype.

Enhancer RNAs

(eRNAs). A class of relatively short non-coding RNA molecules (50–2000 nucleotides in length) that are transcribed from the DNA sequence of enhancer regions.

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Álvarez-Errico, D., Vento-Tormo, R., Sieweke, M. et al. Epigenetic control of myeloid cell differentiation, identity and function. Nat Rev Immunol 15, 7–17 (2015). https://doi.org/10.1038/nri3777

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