Regulation of Mammalian Epithelial Differentiation and Intestine Development by Class I Histone Deacetylases

Abstract

The biochemical mechanisms underlying epigenetic control of gene expression are increasingly well known. In contrast, the contributions of individual modifications toward activation of lineage-specific genes during vertebrate development are poorly understood. Class II histone deacetylases (HDACs), which show restricted tissue distribution, regulate muscle-specific gene expression, in part through interactions with myogenic transcription factors. We have combined gene expression profiling with manipulation of fetal mouse intestinal tissue to define roles for other regulatory factors. We found that in the developing mouse intestine class I HDACs are confined to the prospective epithelium and that their levels decline coincidently with activation of differentiation genes, suggesting a functional relationship between these events. Overexpression of wild-type but not of mutant HDACs 1 and 2 in fetal intestine explants reverses expression of certain maturation markers. HDAC inhibitors, including the selective class I antagonist valproic acid, activate the same genes prematurely and accelerate cytodifferentiation. Chromatin immunoprecipitation of freshly isolated organs reveals early HDAC2 occupancy at differentiation gene promoters and corresponding histone hypoacetylation that reverses as HDAC levels fall. Thus, modulation of endogenous class I HDAC levels represents a previously unappreciated mechanism to enable onset of tissue-restricted gene expression in a developing mammalian organ.

Ketogenesis contributes to intestinal cell differentiation

“…Inhibition of HDACs contributes to intestinal cell differentiation. 13,18 In our current study, we show that βHB inhibits HDACs in intestinal cells. Indeed, βHB acts as an endogenous inhibitor of HDACs in vitro and in vivo.…”

“…16 Recently, βHB has also been shown to act as an endogenous inhibitor of HDACs, 17 which are known to regulate intestinal epithelial differentiation. 18 Circulating concentrations of βHB can increase to as much as 6-8 mM during prolonged fasting and caloric restriction 16,17 when the liver switches to fatty acid oxidation, and even to 25 mM in diabetic ketoacidosis. These nutritional states are associated with altered intestinal integrity, 19 but it is unknown whether ketone bodies have a role in the maintenance of intestinal homeostasis.…”

HDACs and HDAC inhibitors in colon cancer

“…Indeed, direct evidence for such a role in vivo was elegantly demonstrated by the transient overexpression of HDAC1 and HDAC2 in fetal mouse intestinal explants, which resulted in abnormal intestinal development and differentiation. 61 Likewise, intestinal cell number and thickness of the intestinal mucosa were reduced in HDAC2 mutant compared to wild type mice, 52 consistent with a reduction in the proliferative capacity of the intestinal epithelium.…”

Proper expression of the Gcn5 histone acetyltransferase is required for neural tube closure in mouse embryos

“…The phenotypes of mouse mutants deficient for particular HATs or HDACs confirm the importance of these enzymes during embryogenesis. For example, class I HDACs limit tissue differentiation (Tou et al, 2004) and class II HDACs are central modulators of cell proliferation and growth (Zhang et al, 2002;Chang et al, 2004;Vega et al, 2004). Disruption of genes encoding the p300, CBP, or Gcn5 HATs causes embryos to die at midgestation (Yao et al, 1998;Xu et al, 2000).…”