Microbiota-dependent histone butyrylation in the mammalian intestine

Abstract

Posttranslational modifications (PTMs) on histone proteins are a key source of regulation on chromatin through impacting genome organization and important cellular processes, including gene expression. These PTMs often arise from small metabolites and are thus impacted by cellular metabolism and environmental cues. One such class of metabolically regulated PTMs are histone acylations, which include histone acetylation, along with butyrylation, crotonylation, and propionylation. We asked whether histone acylations of intestinal epithelial cells (IECs) are regulated through the availability of short chain fatty acids (SCFAs), which are generated by the commensal microbiota in the intestinal lumen. We identified IECs from the cecum and distal mouse intestine as sites of high levels of histone acylations, including histone butyrylation and propionylation. We identified specific sites of butyrylation and propionylation on lysine 9 and 27 on histone H3. We demonstrate that these acylations are regulated by the microbiota, whereas histone butyrylation is additionally regulated by the metabolite tributyrin. Furthermore, we identify tributyrin-regulated gene programs that correlate with histone butyrylation and demonstrate that histone butyrylation (H3K27bu) is associated with active gene regulatory elements and levels of gene expression. Together, our observations demonstrate a physiological setting in which previously uncharacterized histone acylations are dynamically regulated and associated with gene expression.

New Histone Lysine Acylation Biomarkers and Their Roles in Epigenetic Regulation

“…Butyrate metabolism mainly occurs in the liver and intestinal epithelia, and previous studies revealed that butyrate is an abundant short chain fatty acid (SCFA) in the gastrointestinal tract (Cummings et al., 1987). Further studies identified high levels of histone Kbu in intestinal epithelial cells from the cecum and distal mouse intestine (Gates et al., 2022). More in‐depth studies report the relative changes of Kbu in different physiological states; starvation enhances histone Kbu in the liver of males, though the basal levels of Kbu is higher in female mice (Goudarzi et al., 2020).…”