Chapter 31 : Epigenetic Regulation of Myeloid Cells

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Epigenetics in the context of cell differentiation and activation refers to mechanisms that regulate and potentially stabilize gene expression in response to developmental and environmental cues. Epigenetic regulation is mediated by posttranslational modification of DNA or chromatin and by noncoding RNAs. In myeloid cells, the predominant focus of research on epigenetic mechanisms has been chromatin-mediated regulation of macrophages, which will be the focus of this review ( ). Differentiation of macrophages from myeloid precursors is regulated by developmental signals and pioneer transcription factors that impart an “epigenetic landscape” that helps determine macrophage phenotype and how cells respond to environmental challenges. Macrophages protect the host from pathogenic microorganisms and other environmental insults, providing a rapid response as an initial line of defense. Accordingly, recognition of pathogen-associated molecular patterns through germ line-encoded receptors initiates and subsequently amplifies the adaptive immune response through cytokine production and antigen presentation. Importantly, macrophage phenotype is plastic, and macrophages carry out their distinct roles while maintaining the ability to adapt to local or systemic environmental changes ( ).

Citation: Ivashkiv L, Park S. 2017. Epigenetic Regulation of Myeloid Cells, p 571-590. In Gordon S (ed), Myeloid Cells in Health and Disease. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MCHD-0010-2015
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Figure 1

Epigenetic features of promoters and enhancers of inflammatory genes under basal and acute activated conditions. During macrophage differentiation, PU.1 binds to promoters and enhancers and facilitates the opening of chromatin and an increase in H3K4me3 at promoters and H3K4me1 at enhancers. The negative histone marks/corepressors also are distributed at both promoters and enhancers. There is often low or nonproductive basal transcription. Inflammatory stimulation of macrophages leads to release and loss of corepressors and negative histone marks, increased histone acetylation, additional nucleosome remodeling by BRG1, and recruitment of signaling transcription factors such as NF-κB. The subsequent recruitment of histone acetyltransferases (HATs) results in histone acetylation, which is subsequently bound by Brd4/P-TEFb complex. This results in successive rounds of Pol II elongation and active transcription. Enhancers of active genes are characterized by occupancy by HATs, H3K27ac, and low levels of transcription of eRNA. Interaction between enhancers and promoters involves structural connections that include the Mediator complex and cohesions to promote formation of the preinitiation complex, to initiate transcription. Substantial data support that many interactions between enhancers and promoters (“looping”) are constitutive, although it is possible that such interactions may be enhanced by stimulation. NFR, nucleosome free region.

Citation: Ivashkiv L, Park S. 2017. Epigenetic Regulation of Myeloid Cells, p 571-590. In Gordon S (ed), Myeloid Cells in Health and Disease. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MCHD-0010-2015
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Figure 2

Epigenetic regulators of macrophage polarization. A color spectrum illustrates different polarized macrophage populations, showing the linear scale of two macrophage designations, M1 and M2. Histone modifiers implicated in M1 and M2 macrophage polarization are indicated. TF, transcription factor.

Citation: Ivashkiv L, Park S. 2017. Epigenetic Regulation of Myeloid Cells, p 571-590. In Gordon S (ed), Myeloid Cells in Health and Disease. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MCHD-0010-2015
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Figure 3

Epigenetic regulation of endotoxin tolerance and trained immunity in macrophages. A proposed model of endotoxin tolerance and trained immunity is depicted in the graph. The red line indicates tolerized genes that remain refractory to a second stimulus, and the blue line represents trained genes that show enhanced expression in response to subsequent stimulation. Innate immune responses during and after first stimuli can lead to epigenetic reprogramming, which translates into decreased or increased immune response to subsequent stimulation.

Citation: Ivashkiv L, Park S. 2017. Epigenetic Regulation of Myeloid Cells, p 571-590. In Gordon S (ed), Myeloid Cells in Health and Disease. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MCHD-0010-2015
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