The acetylome regulators Hdac1 and Hdac2 differently modulate intestinal epithelial cell dependent homeostatic responses in experimental colitis

Abstract

Histone deacetylases (Hdac) remove acetyl groups from proteins, influencing global and specific gene expression. Hdacs control inflammation, as shown by Hdac inhibitor-dependent protection from dextran sulfate sodium (DSS)-induced murine colitis. Although tissue-specific Hdac knockouts show redundant and specific functions, little is known of their intestinal epithelial cell (IEC) role. We have shown previously that dual Hdac1/Hdac2 IEC-specific loss disrupts cell proliferation and determination, with decreased secretory cell numbers and altered barrier function. We thus investigated how compound Hdac1/Hdac2 or Hdac2 IEC-specific deficiency alters the inflammatory response. Floxed Hdac1 and Hdac2 and villin-Cre mice were interbred. Compound Hdac1/Hdac2 IEC-deficient mice showed chronic basal inflammation, with increased basal disease activity index (DAI) and deregulated Reg gene colonic expression. DSS-treated dual Hdac1/Hdac2 IEC-deficient mice displayed increased DAI, histological score, intestinal permeability, and inflammatory gene expression. In contrast to double knockouts, Hdac2 IEC-specific loss did not affect IEC determination and growth, nor result in chronic inflammation. However, Hdac2 disruption protected against DSS colitis, as shown by decreased DAI, intestinal permeability and caspase-3 cleavage. Hdac2 IEC-specific deficient mice displayed increased expression of IEC gene subsets, such as colonic antimicrobial Reg3b and Reg3g mRNAs, and decreased expression of immune cell function-related genes. Our data show that Hdac1 and Hdac2 are essential IEC homeostasis regulators. IEC-specific Hdac1 and Hdac2 may act as epigenetic sensors and transmitters of environmental cues and regulate IEC-mediated mucosal homeostatic and inflammatory responses. Different levels of IEC Hdac activity may lead to positive or negative outcomes on intestinal homeostasis during inflammation.

Epigenomic regulation of host–microbiota interactions

“…However, in contrast to IEC-specific HDAC3 or double HDAC1/2 knockout mice, IEC-specific deletion of HDAC2 alone protected mice from experimental colitis [60], suggesting differential roles for specific HDACs and sensitivity to alterations in levels of HDAC activity in IECs. Whether expression of HDAC1/2 or other classes of HDACs mediate commensal bacteria-dependent regulation of IEC-intrinsic gene expression and intestinal homeostasis remains to be determined.…”

Molecular pathways controlling barrier function in IBD

“…New insights have been facilitated by novel technologies such as conditional gene targeting in IECs, new methods for studying IECs in vitro (intestinal organoid cultures) and detailed analyses of patient samples. [8][9][10] On the basis of these new studies we are beginning to understand the complexity of IEC function and cytokine-induced alterations in IBD. However, deciphering the molecular mechanisms that control mucosal homeostasis is the dawn of a new era in our understanding of IBD pathophysiology.…”

Loss of histone deacetylase HDAC1 induces cell death in Drosophila epithelial cells through JNK and Hippo signaling

“…These results show that activation of JNK signaling also contributes to Rpd3 RNAi -induced apoptosis and clone elimination. Interestingly, loss of HDAC1 and HDAC2 in mouse guts caused upregulation of genes related to inflammation (Turgeon et al, 2013; Turgeon et al, 2014). Since JNK pathway plays important roles in inflammation, it will be interesting to study whether JNK signaling is induced and contributes to HDAC1 and HDAC2 inactivation-induced inflammation in mice.…”