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  • Review Article
  • Published:

Epigenetics of haematopoietic cell development

Nature Reviews Immunology volume 11, pages 478–488 (2011)Cite this article

Subjects

Key Points

  • Gene expression is regulated by chromatin structure, with active regions being in an open conformation and repressed genes in a closed form. This structure is determined by DNA methylation, histone modifications, nuclear localization and nucleosome positioning.

  • The immune system is generated from self-renewing haematopoietic stem cells that have a plastic chromatin structure and the potential to differentiate. Lineage commitment is associated with a more fixed chromatin structure, as genes associated with alternative lineages assume a closed conformation.

  • Lineage development takes place in distinct stages. During this process, changes in histone modification take place before alterations in gene usage and represent a primary mechanism that allows for the rapid generation of terminally differentiated cells.

  • Lineage commitment in vivo is unidirectional. This process appears to be driven by epigenetic changes (in DNA methylation, for example), which provide long-term stability to decisions made at an earlier stage.

  • Allelic choice in the immune system is controlled in a pre-programmed manner through a process that marks the two alleles separately, probably on the basis of differences in regional replication timing.

Abstract

Cells of the immune system are generated through a developmental cascade that begins in haematopoietic stem cells. During this process, gene expression patterns are programmed in a series of stages that bring about the restriction of cell potential, ultimately leading to the formation of specialized innate immune cells and mature lymphocytes that express antigen receptors. These events involve the regulation of both gene expression and DNA recombination, mainly through the control of chromatin accessibility. In this Review, we describe the epigenetic changes that mediate this complex differentiation process and try to understand the logic of the programming mechanism.

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Figure 1: Heritable epigenetic mechanisms.
Figure 2: Turning off pluripotency genes.
Figure 3: Hierarchy of differentiation in the haematopoietic system.
Figure 4: Epigenetic switches in myeloid versus lymphoid cells.
Figure 5: A model for gene priming with epigenetic marks.
Figure 6: Choreography of allelic choice in B cells.

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Acknowledgements

This work was supported by research grants from the Israel Academy of Sciences (to H.C. and Y.B.), the US National Institutes of Health (to Y.B.), the Israel Cancer Research Foundation (to H.C. and Y.B.) and the European Community 5th Framework Quality of Life Programme (to Y.B.).

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  1. Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel–Canada, Hebrew University Medical School, P.O.B. 12272, Ein Kerem, 91120, Jerusalem, Israel

    Howard Cedar & Yehudit Bergman

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  1. Howard Cedar
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Correspondence to Yehudit Bergman.

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Glossary

Epigenetic mechanisms

Mechanisms that confer heritable, but potentially reversible, states of gene activity that are imposed by the structure of chromatin or covalent modifications of DNA and histones.

Histone acetylation

A post-translational modification of histones that is associated with regions of actively transcribed chromatin.

CpG island

A DNA sequence of 0.5–2 kilobases that is rich in CpG dinucleotides. These sequences are located upstream of housekeeping genes and some tissue-specific genes. They are usually constitutively non-methylated in all animal cell types.

Induced pluripotent stem cells

Self-renewing, pluripotent stem cells that are derived by the transient introduction of transgenes encoding transcription factors such as OCT4, SOX2, KLF4 and MYC (or the gene products themselves) into adult somatic cells. Only transient expression of the transgenes is required because the reprogramming factors upregulate expression of their endogenous counterparts, which subsequently maintain pluripotency.

Polycomb repressive complex

A group of proteins that maintain gene expression states throughout development by regulating chromatin structure. In mammals, there are two core Polycomb complexes: Polycomb repressive complex 1 (PRC1) and PRC2. PRC1 catalyses the monoubiquitylation of histone H2A. Both complexes contribute to chromatin compaction. PRC2 harbours the EZH1 and EZH2 methyltransferases that catalyse the methylation of histone H3 at lysine 27. These two complexes are involved in differentiation, the maintenance of cell identity and proliferation, and stem cell plasticity.

Cohesin

A multiprotein complex that maintains the tight association of sister chromatids. Cohesin has also been implicated in the regulation of gene transcription by contributing to DNA loop formation. It stabilizes chromatin loops organized by the binding of factors such as CTCF or the Mediator complex.

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Cedar, H., Bergman, Y. Epigenetics of haematopoietic cell development. Nat Rev Immunol 11, 478–488 (2011). https://doi.org/10.1038/nri2991

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