javascript:void(0)Most super-enhancers (~84%) overlapped with
non-TSS regions that were hypoacetylated (fold change > 2
and adjusted P value < 0.05) after 24 hours of butyrate
treatment (Fig. 5C,D). Pathway enrichment analyses of the 502 genes
associated with hypo-acetylated super-enhancer revealed that they are
particularly associated with regulation of cell activation, FCERI
mediated Ca+2 mobilization and mast cell mediated immunity (Fig. 5E). Of
note, ~19% of hypo-acetylated super-enhancers were linked
to transcriptionally downregulated genes (Fig. 5F), as compared to only
6-8% for hypo-acetylated typical enhancers and TSS regions. For genes
expressed prior to butyrate treatment (RPKM>1),
hypo-acetylation of super-enhancers represented the strongest predictor
of transcriptional downregulation (24%), followed by hypo-acetylation
of typical enhancers (13.0%) and TSS regions (7.7%) (Supplementary
Fig. 5A).
Genes that displayed downregulated expression and
super-enhancer hypo-acetylation (n=95, 18.9% of 502 genes) were
strongly associated with (mast cell) activation and exocytosis (Fig.
5G). By contrast, downregulated genes linked to hypo-acetylated typical
enhancer regions associated with more general immune functions
(Supplementary Fig. 5B). Together, these findings provide a plausible
epigenetic explanation for the transcriptional deregulation of many
downregulated genes, i.e., via loss of histone acetylation of their
TSSs, super-enhancers, or both (Fig. 5H ). Of note, out of the
864 downregulated genes, 112 genes were associated with super-enhancers,
a majority (85%) of which displayed hypo-acetylation after 24 hours of
butyrate.