Regulation of intestinal serotonin transporter expression via epigenetic mechanisms: role of HDAC2

Abstract

The serotonin (5-HT) transporter (SERT) facilitates clearance of extracellular 5-HT by its uptake and internalization. Decreased expression of SERT and consequent high 5-HT levels have been implicated in various diarrheal disorders. Thus, appropriate regulation of SERT is critical for maintenance of 5-HT homeostasis in health and disease. Previous studies demonstrated that SERT is regulated via posttranslational and transcriptional mechanisms. However, the role of epigenetic mechanisms in SERT regulation is not known. Current studies investigated the effects of histone deacetylase (HDAC) inhibition on SERT expression and delineated the mechanisms. Treatment of Caco-2 cells with the pan-HDAC inhibitors butyrate (5 mM) and trichostatin (TSA, 1 μM) decreased SERT mRNA and protein levels. Butyrate- or TSA-induced decrease in SERT was associated with decreased activity of human SERT (hSERT) promoter 1 (upstream of exon 1a), but not hSERT promoter 2 (upstream of exon 2). Butyrate + TSA did not show an additive effect on SERT expression, indicating that mechanisms involving histone hyperacetylation may be involved. Chromatin immunoprecipitation assays demonstrated enrichment of the hSERT promoter 1 (flanking nt -250/+2) with tetra-acetylated histone H3 or H4, which was increased (~3-fold) by butyrate. Interestingly, specific inhibition of HDAC2 (but not HDAC1) utilizing small interfering RNA decreased SERT mRNA and protein levels. The decrease in SERT expression by HDAC inhibition was recapitulated in an in vivo model. SERT mRNA levels were decreased in the ileum and colon of mice fed pectin (increased availability of butyrate) compared with controls fed a fiber-free diet (~50-60%). Our results identify a novel role of HDAC2 as a regulator of SERT gene expression in intestinal epithelial cells.

Downregulation of serotonin reuptake transporter gene expression in healing colonic mucosa in presence of remaining low‐grade inflammation in ulcerative colitis

“…Foley et al reported that interferon‐γ and tumor necrosis factor‐α downregulated SERT expression in colonic epithelial cells in vitro , while another report also demonstrated that enteropathogenic E. coli infection inhibits intestinal SERT function and expression . Moreover, Gill et al indicated a novel mechanism of downregulation of intestinal SERT by epigenetic mechanisms involving histone deacetylase2 inhibition . Although SERT expression may be regulated by such mechanisms, additional details should be clarified by further examinations.…”

SRARP and HSPB7 are epigenetically regulated gene pairs that function as tumor suppressors and predict clinical outcome in malignancies

“…Control experiments were performed by the addition of DMSO solvent (Sigma-Aldrich) and following the same procedure. Cell line treatments with histone deacetylase (HDAC) inhibitor trichostatin A (TSA) (Selleck Chemicals, Houston, TX, USA) were carried out at 1 lM concentration for 24 h as previously published (Gill et al, 2013). Control experiments were treated by the addition of solvent alone.…”

Expression of serotonin, chromogranin-A, serotonin receptor-2B, tryptophan hydroxylase-1, and serotonin reuptake transporter in the intestine of dogs with chronic enteropathy

“…Some prior publications have suggested that SERT is down-regulated in some inflammatory or diarrheal motility disorders. 9,18 We hypothesized that SERT expression would be altered in the group of dogs with chronic enteropathy. It has previously been reported that mRNA-encoding SERT and SERT protein are diminished in an animal model of colitis.…”