Quantitative Proteomics Reveals a Role for Epigenetic Reprogramming During Human Monocyte Differentiation

Abstract

The differentiation of monocytes into macrophages and dendritic cells involves mechanisms for activation of the innate immune system in response to inflammatory stimuli, such as pathogen infection and environmental cues. Epigenetic reprogramming is thought to play an important role during monocyte differentiation. Complementary to cell surface markers, the characterization of monocytic cell lineages by mass spectrometry based protein/histone expression profiling opens a new avenue for studying immune cell differentiation. Here, we report the application of mass spectrometry and bioinformatics to identify changes in human monocytes during their differentiation into macrophages and dendritic cells. Our data show that linker histone H1 proteins are significantly down-regulated during monocyte differentiation. Although highly enriched H3K9-methyl/S10-phos/K14-acetyl tri-modification forms of histone H3 were identified in monocytes and macrophages, they were dramatically reduced in dendritic cells. In contrast, histone H4 K16 acetylation was found to be markedly higher in dendritic cells than in monocytes and macrophages. We also found that global hyperacetylation generated by the nonspecific histone deacetylase HDAC inhibitor Apicidin induces monocyte differentiation. Together, our data suggest that specific regulation of inter-and intra-histone modifications including H3 K9 methylation, H3 S10 phosphorylation, H3 K14 acetylation, and H4 K16 acetylation must occur in concert with chromatin remodeling by linker histones for cell cycle progression and differentiation of human myeloid cells into macrophages and dendritic cells. Molecular & Cellular

Modulations of DNA Contacts by Linker Histones and Post-translational Modifications Determine the Mobility and Modifiability of Nucleosomal H3 Tails

“…In support of a causal relationship between linker histone occupancy and H3 modifications, overexpression of linker histones caused a global reduction of core histone acetylation (Gunjan et al, 2001). Besides, a recent proteomic study revealed that downregulated expression of linker histones is correlated with generally elevated H3 modifications (Nicholas et al, 2014).…”

Heat-killed Mycobacterium tuberculosis prime-boost vaccination induces myeloid-derived suppressor cells with spleen dendritic cell–killing capability

“…It is unclear whether epigenetic modifications induced by M. tuberculosis are restricted to myeloid precursors or whether they can also occur in differentiated monocytes. Again, in vitro evidence suggests that the late developmental switch from differentiated human CD14 + monocytes into either macrophages or DCs is directed by epigenetic changes (40). We found previously that in GM-CSF differentiated BM-MD-SC cultures, transcriptional and translational changes occur that are prerequisite for their development into M-MDSCs (21).…”

Specific low-frequency electromagnetic fields induce expression of active KDM6B associated with functional changes in U937 cells

“…Hence, thanks to this biological setup, it is possible to study molecular changes linked to differentiation both as result of chemical stimulation and as result of physical stimulation by PEMF. Furthermore, because primary tissue macrophages cannot be readily expanded ex vivo, differentiation of monocytes from primary leukemia cell lines into macrophage-like cells has been frequently used as a mimic model for understanding the process of innate and adaptive immune responses to inflammatory stimuli [57,58].…”