Epigenetic memory: A macrophage perspective

- Chromosomes are the sites of very intricate molecular transactions that ultimately dictate transcription unit activity.
- Epigenetic information stored in macrophage chromosomes affects the response to subsequent microbe encounters.
- Cis-regulatory DNA sites represent an as yet underdeveloped molecular biology resource for medicine.

The molecular basis of cellular memory is a fascinating topic that progressed with great strides during the last few decades. In the case of cells of the immune system, cellular memory likely extends beyond cell fate determination mechanisms, since immunity can tailor its responses to a potentially hostile environment that is a priori variable if not unpredictable. One particularly versatile innate immune system cell type is the macrophage. These phagocytes occur in all organs and tissues as resident cells or as differentiation products of recruited circulating blood monocytes. They come in many flavours determined by the tissue of residence and by external factors such as microbes. Recently, macrophage epigenome profiling has revealed thousands of chromosomal loci that are differentially active in macrophages, revealing chromosome elements that drive macrophage gene expression. The most dynamic epigenomic mark is nucleosomal histone acetylation. This mark is found at gene promoters and enhancers and correlates very well with gene expression changes. A second mark is H3K4me3, which sharply decorates the promoters of most protein coding genes that are (potentially) expressed. H3K4me3 at promoters is surrounded by its precursor H3K4me1. However, most often H3K4me1 occurs without H3K4me3 at enhancers where it appears together with histone acetylation, but can persist long after acetylation decreased. Hence, the biochemical signal H3K4me1 embodies appears to be a key to the plasticity of macrophage gene expression potential.