Mass-Cytometry-Based Quantification of Global Histone Post-Translational Modifications at Single-Cell Resolution Across Peripheral Immune Cells in IBD

Background and Aims Current understanding of histone post-translational modifications [histone modifications] across immune cell types in patients with inflammatory bowel disease [IBD] during remission and flare is limited. The present study aimed to quantify histone modifications at a single-cell resolution in IBD patients during remission and flare and how they differ compared to healthy controls. Methods We performed a case-control study of 94 subjects [83 IBD patients and 11 healthy controls]. IBD patients had either ulcerative colitis [n = 38] or Crohn's disease [n = 45] in clinical remission or flare. We used epigenetic profiling by time-of-flight [EpiTOF] to investigate changes in histone modifications within peripheral blood mononuclear cells from IBD patients. Results We discovered substantial heterogeneity in histone modifications across multiple immune cell types in IBD patients. They had a higher proportion of less differentiated CD34(+) haematopoietic progenitors, and a subset of CD56(bright) natural killer [NK] cells and gamma delta T cells characterized by distinct histone modifications associated with gene transcription. The subset of CD56(bright) NK cells had increases in several histone acetylations. An epigenetically defined subset of NK cells was associated with higher levels of C-reactive protein in peripheral blood. CD34(+) monocytes from IBD patients had significantly decreased cleaved H3T22, suggesting they were epigenetically primed for macrophage differentiation. Conclusion We describe the first systems-level quantification of histone modifications across immune cells from IBD patients at a single-cell resolution, revealing the increased epigenetic heterogeneity that is not possible with traditional ChIP-seq profiling. Our data open new directions in investigating the association between histone modifications and IBD pathology using other epigenomic tools.