Introduction
Mast cells are major effector cells of the immune system. They reside in virtually all vascularized tissues, especially those in direct contact with the external environment. Mast cells mediate IgE-associated type 2 immune responses, which have been implicated in anti-parasite immunity but also allergies, asthma, chronic rhinosinusitis with nasal polyps, and urticaria1–6. Allergens can crosslink allergen-specific IgE bound to the high-affinity IgE receptor (FcεRI) on the mast cell surface, resulting in their degranulation1. This causes the immediate release of preformed granule mediators such as histamine, heparin, and certain proteases, followed by de novo synthesis and release of various lipid mediators and cytokines. More recently, the Mas-related G protein-coupled receptor X2 (MRGPRX2) expressed on mast cells was shown to participate in IgE-independent mast cell activation, resulting in drug-induced pseudo-allergic reactions (e.g. against antibiotics)7–9.
Mast cell maturation, phenotype and function are determined by gene expression programs controlled by endogenous and microenvironmental factors10. These include the microbiome, which directly contributes to the development and maturation of the immune system11. Short chain fatty acids (SCFAs) including butyrate, propionate and acetate - derived from bacterial fermentation of dietary fibers - are considered key metabolites in the regulation of host physiology and pathophysiology12–14.Butyrate critically affects differentiation and function of many lymphocyte populations as well as myeloid cells such as macrophages and dendritic cells 15–23.
SCFAs, particularly butyrate, were shown to promote gut homeostasis and immunity via control of histone acetylation and subsequently gene transcription24,25. The acetylation state of a given genomic locus is controlled by two classes of antagonistic histone modifying enzymes, histone acetyl transferases (HATs) and histone deacetylases (HDACs), which add and remove target histone acetyl groups, respectively. Histone acetylation is a hallmark of active promoter regions and transcription start sites (TSSs), but also occurs at distal gene regulatory elements such as enhancers 26,27. Particularly high levels of histone acetylation are located at super-enhancers, a class of powerful enhancers that control the expression of key cell type-specific genes 28. Butyrate is a known inhibitor of all class I/II HDACs29,30 and can significantly affect gene expression, since histone acetylation is generally associated with accessible chromatin and active gene transcription31,32. HDAC inhibition is thus expected to trigger histone hyperacetylation and facilitate transcriptional activation. However, whether butyrate affects histone acetylation status and the gene regulatory function of super-enhancers remains largely unknown.
We recently reported that butyrate inhibits human mast cell activation and degranulation, which was associated with reduced expression of genes critical for FcεRI-mediated signaling - likely via epigenetic mechanisms 33. How butyrate exerts such specific effects on gene expression in mast cells while targeting a very basal component of transcriptional regulation remains incompletely understood. To address this question, we integrated transcriptome and longitudinal profiling of histone acetylation measurements to identify molecular mechanisms underlying selective gene expression changes in primary human mast cells exposed to butyrate – ultimately resulting in potent mast cell inhibition.