Transcriptional and epigenetic regulation of macrophages in atherosclerosis

Abstract

Monocytes and macrophages provide defence against pathogens and danger signals. These cells respond to stimulation in a fast and stimulus-specific manner by utilizing complex cascaded activation by lineage-determining and signal-dependent transcription factors. The complexity of the functional response is determined by interactions between triggered transcription factors and depends on the microenvironment and interdependent signalling cascades. Dysregulation of macrophage phenotypes is a major driver of various diseases such as atherosclerosis, rheumatoid arthritis and type 2 diabetes mellitus. Furthermore, exposure of monocytes, which are macrophage precursor cells, to certain stimuli can lead to a hypo-inflammatory tolerized phenotype or a hyper-inflammatory trained phenotype in a macrophage. In atherosclerosis, macrophages and monocytes are exposed to inflammatory cytokines, oxidized lipids, cholesterol crystals and other factors. All these stimuli induce not only a specific transcriptional response but also interact extensively, leading to transcriptional and epigenetic heterogeneity of macrophages in atherosclerotic plaques. Targeting the epigenetic landscape of plaque macrophages can be a powerful therapeutic tool to modulate pro-atherogenic phenotypes and reduce the rate of plaque formation. In this Review, we discuss the emerging role of transcription factors and epigenetic remodelling in macrophages in the context of atherosclerosis and inflammation, and provide a comprehensive overview of epigenetic enzymes and transcription factors that are involved in macrophage activation.

Key points

  • Atherosclerotic plaques contain a complex environment with different activation signals that result in intraplaque macrophage heterogeneity.

  • Plasticity of macrophage phenotype is modulated by an interplay between transcription factors and epigenetic enzymes.

  • Signalling pathways in inflammation have an extensive molecular crosstalk.

  • Modulating transcription factor activity is a promising therapeutic target for atherosclerosis.

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Fig. 1: Epigenetic landscape of DNA regulatory regions.
Fig. 2: Macrophage enhancer selection.
Fig. 3: Transcription factors modulate macrophage phenotypes in atherosclerosis.

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Acknowledgements

The work of M.P.J.de W. and C.K.G. is supported by The Netherlands Heart Foundation (GENIUS (CVON 2011/B019) and GENIUS2 (CVON 2017–20) to M.P.J.de W.); The Netherlands Heart Foundation and Spark-Holding BV (2015B002 to M.P.J.de W.); the European Union (ITN grant EPIMAC to M.P.J.de W.); NIH grants (DK063491, DK091183 and HL088093 to C.K.G.); and Foundation Leducq (LEAN Transatlantic Network Grant to M.P.J.de W. and C.K.G.).

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Correspondence to Menno P. J. de Winther.

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Glossary

Transcription factors

Proteins with a DNA-binding domain that guide the transcriptional machinery to or block it from regulatory elements such as promoters and enhancers, thereby facilitating the execution of tailored transcriptional programmes.

Long-range interactions

Interactions between regulatory DNA regions that occur over large linear distances, predominantly between enhancers and between enhancers and promoters. These interactions can have a regulatory role.

Promoters

Regulatory DNA regions proximal to a transcription start site. Contain consensus motifs for transcription factors and the transcriptional machinery.

Enhancers

Regulatory DNA regions distal to a transcription start site. Contain transcription factor binding sites that can regulate the transcription of target genes independently of linear distance.

Histone-modifying enzymes

(HMEs). Readers, writers or erasers of chemical histone (tail) modifications.

Lineage-determining transcription factors

(LDTFs). Transcription factors with pioneering (that is, chromatin conformation-changing) capabilities that set up the chromatin for execution of cell type-specific gene programmes.

Signal-dependent transcription factors

(SDTFs). Transcription factors that bind DNA and activate its gene programme in response to an external stimulus.

CpG islands

Genomic regions with a higher-than-average frequency of CpG sites, typically defined as a region of 500–1,500 bp in length, with CpG content >50% and an observed/expected CpG ratio of >0.6; CpG islands often occur in gene regulatory regions, and their DNA methylation status regulates genomic structures and gene transcription.

Histone marks

Chemical groups covalently bound to a specific amino acid residue on (the tail of) a histone protein. Histone marks can change the local chromatin accessibility through electrostatic effects and/or guide the transcription machinery to specific loci in the genome (Box 1).

Euchromatin

A permissive chromatin state in which the chromatin is in an open conformation accessible to the transcription machinery.

Heterochromatin

A repressive chromatin state in which the chromatin is in a closed conformation inaccessible to transcription factors.

Assay for transposase-accessible chromatin using sequencing

(ATAC-seq). Method for genome-wide identification of open chromatin regions with potential regulatory function.

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Kuznetsova, T., Prange, K.H.M., Glass, C.K. et al. Transcriptional and epigenetic regulation of macrophages in atherosclerosis. Nat Rev Cardiol (2019). https://doi.org/10.1038/s41569-019-0265-3

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