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.