JAK-STAT Pathway Inhibition Partially Restores Intestinal Homeostasis in - and -Intestinal Epithelial Cell-Deficient Mice.

We have previously reported that histone deacetylase epigenetic regulator and deletion in intestinal epithelial cells (IEC) disrupts mucosal tissue architecture and barrier, causing chronic inflammation. In this study, proteome and transcriptome analysis revealed the importance of signaling pathways induced upon genetic IEC- and deletion. Indeed, Gene Ontology biological process analysis of enriched deficient IEC RNA and proteins identified common pathways, including lipid metabolic and oxidation-reduction process, cell adhesion, and antigen processing and presentation, related to immune responses, correlating with dysregulation of major histocompatibility complex (MHC) class II genes.

HDAC1 and HDAC2 independently regulate common and specific intrinsic responses in murine enteroids.

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.

A SILAC-Based Method for Quantitative Proteomic Analysis of Intestinal Organoids.

Organoids have the potential to bridge 3D cell culture to tissue physiology by providing a model resembling in vivo organs. Long-term growing organoids were first isolated from intestinal crypt cells and recreated the renewing intestinal epithelial niche. Since then, this technical breakthrough was applied to many other organs, including prostate, liver, kidney and pancreas.

Loss of histone deacetylase Hdac1 disrupts metabolic processes in intestinal epithelial cells.

By using acetyl-CoA as a substrate, acetyltransferases and histone deacetylases regulate protein acetylation by adding or removing an acetyl group on lysines. Nuclear-located Hdac1 is a regulator of intestinal homeostasis. We have previously shown that Hdac1 define specific intestinal epithelial cell basal and inflammatory-dependent gene expression patterns and control cell proliferation.

Distinct Roles for Intestinal Epithelial Cell-Specific Hdac1 and Hdac2 in the Regulation of Murine Intestinal Homeostasis.

The intestinal epithelium responds to and transmits signals from the microbiota and the mucosal immune system to insure intestinal homeostasis. These interactions are in part conveyed by epigenetic modifications, which respond to environmental changes. Protein acetylation is an epigenetic signal regulated by histone deacetylases, including Hdac1 and Hdac2.

The histone deacetylase Hdac1 regulates inflammatory signalling in intestinal epithelial cells.

Background: It has recently been found that both nuclear epithelial-expressed histone deacetylases Hdac1 and Hdac2 are important to insure intestinal homeostasis and control the mucosal inflammatory response in vivo. In addition, HDAC inhibitors modulate epithelial cell inflammatory responses in cancer cells. However, little is known of the specific role of different HDAC, notably Hdac1, in the regulation of inflammatory gene expression in intestinal epithelial cells (IEC).

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

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.

HDAC1 and HDAC2 restrain the intestinal inflammatory response by regulating intestinal epithelial cell differentiation.

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).

The histone H3K27 methylation mark regulates intestinal epithelial cell density-dependent proliferation and the inflammatory response.

Polycomb-group proteins form multimeric protein complexes involved in transcriptional silencing. The Polycomb Repressive complex 2 (PRC2) contains the Suppressor of Zeste-12 protein (Suz12) and the histone methyltransferase Enhancer of Zeste protein-2 (Ezh2). This complex, catalyzing the di- and tri-methylation of histone H3 lysine 27, is essential for embryonic development and stem cell renewal.

P2Y(2) receptor expression is regulated by C/EBPβ during inflammation in intestinal epithelial cells.

Inflammatory bowel diseases are characterized by relapses and remission periods during which numerous factors, including stress factors and nucleotides, are mobilized to re-establish intestinal mucosal homeostasis. We have previously found that expression of the P2Y(2) nucleotide receptor is increased in colonic tissue isolated from inflammatory bowel disease patients as well as in a mouse model of colitis, and that P2Y(2) transcription is regulated in part by nuclear factor κB (NF-κB) p65. Transcription factor DNA-binding site analysis identified three potential CCAAT/enhancer-binding protein β (C/EBPβ) binding sites in the P2Y(2) proximal promoter.

GATA-4 modulates C/EBP-dependent transcriptional activation of acute phase protein genes.

C/EBP transcription factors are involved in the regulation of the intestinal epithelial cell response to inflammatory stimuli. GATA transcription factors modulate C/EBP-dependent transcriptional activation in various cell types. We thus determined whether GATA-4 whose expression is restricted to epithelial cells, modulate C/EBP transcriptional activity and C/EBP-dependent acute phase protein expression in intestinal epithelial cells.

Regulation of C/EBPdelta-dependent transactivation by histone deacetylases in intestinal epithelial cells.

The C/EBPdelta transcription factor is involved in the positive regulation of the intestinal epithelial cell acute phase response. C/EBPdelta regulation by histone deacetylases (HDACs) during the course of inflammation remains to be determined. Our aim was to examine the effect of HDACs on C/EBPdelta-dependent regulation of haptoglobin, an acute phase protein induced in intestinal epithelial cells in response to pro-inflammatory cytokines.