Regulation of intestinal serotonin transporter (SERT) expression via epigenetic mechanisms: Role of HDAC2
Gill, RK; Kumar, A; Malhotra, P; Maher, D; Singh, V; Dudeja, PK; Alrefai, WA; Saksena, S
HERO ID
1454439
Reference Type
Journal Article
Year
2013
Language
English
PMID
| HERO ID | 1454439 |
|---|---|
| In Press | No |
| Year | 2013 |
| Title | Regulation of intestinal serotonin transporter (SERT) expression via epigenetic mechanisms: Role of HDAC2 |
| Authors | Gill, RK; Kumar, A; Malhotra, P; Maher, D; Singh, V; Dudeja, PK; Alrefai, WA; Saksena, S |
| Journal | American Journal of Physiology: Cell Physiology |
| Volume | 304 |
| Issue | 4 |
| Page Numbers | C334-C341 |
| Abstract | The serotonin 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 the maintenance of 5-HT homeostasis in health and disease. Previous studies demonstrated that SERT is regulated via both post-translational and transcriptional mechanisms. However, the role of epigenetic mechanisms in SERT regulation is not known. Current studies investigated the effects of HDAC inhibition on SERT expression and delineated the mechanisms. Treatment of Caco-2 cells with pan-HDAC inhibitors, butyrate (5mM) or TSA (1μM) decreased SERT mRNA and protein levels. Decrease in SERT by butyrate or TSA was associated with a decreased activity of hSERTp1 (upstream of exon 1a) but not hSERTp2 (upstream of exon 2). Butyrate and TSA together did not show an additive effect on SERT expression indicating that mechanisms involving histone hyperacetylation may be involved. Chromatin immunoprecipitation assays demonstrated an enrichment of the hSERTp1 (flanking -250/+2 bp) with tetra-acetylated H3 or H4 histones, which was increased (~ three-fold) by butyrate. Interestingly, specific inhibition of HDAC2 (but not HDAC1) utilizing siRNA 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 ileum and colon of pectin (increased availability of butyrate) fed mice compared to controls fed fiber free diet (~50-60%). Our results identify novel role of HDAC2 as a regulator of SERT gene expression in IECs. |
| Doi | 10.1152/ajpcell.00361.2012 |
| Pmid | 23195070 |
| Wosid | WOS:000315142800006 |
| Is Certified Translation | No |
| Dupe Override | No |
| Is Public | Yes |
| Language Text | English |
| Keyword | SERT; histone deacetylase inhibition; trichostatin A; butyrate epigenetics |