Abstract
Both HDAC1 and HDAC2 are class I deacetylases acting as erasers of lysine-acetyl marks on histones and non-histone proteins. Several histone deacetylase inhibitors, either endogenous to the cell, such as the ketogenic β-hydroxybutyrate metabolite, or exogenous, such as butyrate, a microbial-derived metabolite, regulate HDAC activity. Different combinations of intestinal epithelial cell (IEC)-specific Hdac1 and/or Hdac2 deletion differentially alter mucosal homeostasis in mice. Thus, HDAC1 and HDAC2 could act as sensors and transmitters of environmental signals to the mucosa. In this study, enteroid culture models deleted for Hdac1 or Hdac2 were established to determine IEC-specific function as assessed by global transcriptomic and proteomic approaches. Results show that Hdac1 or Hdac2 deficiency altered differentiation of Paneth and goblet secretory cells, which sustain physical and chemical protection barriers, and increased intermediate secretory cell precursor numbers. Furthermore, IEC Hdac1- and Hdac2-dependent common and specific biological processes were identified, including oxidation-reduction, inflammatory responses, and lipid-related metabolic processes, as well as canonical pathways and upstream regulators related to environment-dependent signaling through steroid receptor pathways, among others. These findings uncover unrecognized regulatory similarities and differences between Hdac1 and Hdac2 in IEC, and demonstrate how HDAC1 and HDAC2 may complement each other to regulate the intrinsic IEC phenotype.
Highlights
The small intestinal epithelium is composed of a single row of epithelial cells divided in proliferative crypt and differentiated villus compartments[1]
In contrast to mice with one Hdac[1] allele without Hdac[2], villin-Cre mice with one allele of Hdac[2] without Hdac[1] display homeostatic defects similar to double villin-Cre Hdac[1] and Hdac[2] knockout phenotypic alterations[35]. These results suggest that HDAC1 and HDAC2 display redundant and specific functions in intestinal epithelial cells that could alter IEC interactions with the environment, leading to modifications in intestinal homeostasis
While there were no statistical differences in enteroid size, as assessed by surface area measurement (Fig. 2A; p > 0.1, one-way ANOVA), loss of Hdac[1] or Hdac[2] resulted in differences in enteroid structure, as determined by enhanced crypt budding per enteroid (Fig. 2B,C)
Summary
The small intestinal epithelium is composed of a single row of epithelial cells divided in proliferative crypt and differentiated villus compartments[1]. In contrast to mice with one Hdac[1] allele without Hdac[2], villin-Cre mice with one allele of Hdac[2] without Hdac[1] display homeostatic defects similar to double villin-Cre Hdac[1] and Hdac[2] knockout phenotypic alterations[35] These results suggest that HDAC1 and HDAC2 display redundant and specific functions in intestinal epithelial cells that could alter IEC interactions with the environment, leading to modifications in intestinal homeostasis. We identify IEC Hdac1- and Hdac2-dependent common and specific biological processes, including oxidation-reduction and lipid-related metabolic processes, as well as canonical pathways and upstream regulators related to environment-dependent signaling through steroid receptor pathways, among others. These findings uncover unrecognized regulatory similarities and differences between Hdac[1] and Hdac[2] in IEC, and demonstrate how HDAC1 and HDAC2 may complement each other to regulate the intrinsic IEC phenotype
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