HDAC1 and HDAC2 Restrain the Intestinal Inflammatory Response by Regulating Intestinal Epithelial Cell Differentiation

Abstract

Acetylation and deacetylation of histones and other proteins depends on histone acetyltransferases and histone deacetylases (HDACs) activities, leading to either positive or negative gene expression. HDAC inhibitors have uncovered a role for HDACs in proliferation, apoptosis and inflammation. However, little is known of the roles of specific HDACs in intestinal epithelial cells (IEC). We investigated the consequences of ablating both HDAC1 and HDAC2 in murine IECs. Floxed Hdac1 and Hdac2 homozygous mice were crossed with villin-Cre mice. Mice deficient in both IEC HDAC1 and HDAC2 weighed less and survived more than a year. Colon and small intestinal sections were stained with hematoxylin and eosin, or with Alcian blue and Periodic Acid Schiff for goblet cell identification. Tissue sections from mice injected with BrdU for 2 h, 14 h and 48 h were stained with anti-BrdU. To determine intestinal permeability, 4-kDa FITC-labeled dextran was given by gavage for 3 h. Microarray analysis was performed on total colon RNAs. Inflammatory and IEC-specific gene expression was assessed by Western blot or semi-quantitative RT-PCR and qPCR with respectively total colon protein and total colon RNAs. HDAC1 and HDAC2-deficient mice displayed: 1) increased migration and proliferation, with elevated cyclin D1 expression and phosphorylated S6 ribosomal protein, a downstream mTOR target; 2) tissue architecture defects with cell differentiation alterations, correlating with reduction of secretory Paneth and goblet cells in jejunum and goblet cells in colon, increased expression of enterocytic markers such as sucrase-isomaltase in the colon, increased expression of cleaved Notch1 and augmented intestinal permeability; 3) loss of tissue homeostasis, as evidenced by modifications of claudin 3 expression, caspase-3 cleavage and Stat3 phosphorylation; 4) chronic inflammation, as determined by inflammatory molecular expression signatures and altered inflammatory gene expression. Thus, epithelial HDAC1 and HDAC2 restrain the intestinal inflammatory response, by regulating intestinal epithelial cell proliferation and differentiation.

253 TSC2/mTORC1 Signaling Controls Paneth and Goblet Cell Differentiation in the Intestinal Epithelium

“…37,38 Treatment with rapamycin has been shown to inhibit the polyposis and progression to dysplasia induced by APC mutation. 25 Taken together, our studies and those of others 25,35,36 demonstrate the regulation of intestinal differentiation by mTORC1 signaling.…”

“…36 Furthermore, dysregulated differentiation within the intestinal crypts is associated with the progression of colorectal cancer. 5 We previously demonstrated elevated mTOR activity and overexpression of mTOR complex components in CRC.…”

Plasticity within stem cell hierarchies in mammalian epithelia

“…Do niche signals such as Wnt, therefore, play a role in maintaining an epigenetic state that dictates 'stemness' and do epigenetic mechanisms play a role in dedifferentiation? In the intestine the loss of histone deacetylase enzymes (HDAC1/2) disrupts cell lineage commitment [42]. A recent study on histone marks that permit chromatin accessibility surprisingly showed that many intergenic regulatory regions were prominently marked, with no significant differences, between intestinal stem cells and their progeny committed to the secretory and enterocyte lineages [43].…”

Commensal microbiota-derived signals regulate host immune system through epigenetic modifications

“…Commensal bacteriaderived signals also influence host epigenetic pathways, particularly through DNA and histone methylation [32][33][34][35][36] and histone acetylation and deacetylation [37][38][39][40][41] . The commensal microbiota produces multiple low-molecular-weight byproducts that modify the host cell epigenome and may alter the functional behavior of host cells.…”