Identification of an upstream promoter of the human somatostatin receptor, hSSTR2, which is controlled by epigenetic modifications.
Somatostatin is a neuropeptide that inhibits exocrine and endocrine secretions of several hormones and negatively regulates cell proliferation. These events are mediated through somatostatin engagement on one of five G protein-coupled receptors named SSTR1 to STTR5. Somatostatin binding to SSTR2 mediates predominantly antisecretory and antiproliferative effects; two important biological activities in the gastroenteropancreatic endocrine and exocrine system. Herein we demonstrate novel regulatory sequences for human (h) SSTR2 transcription. By genomic DNA sequence analysis, we reveal two CpG islands located 3.8 kb upstream from the transcription start site. We identify a novel transcription start site and a promoter region within one of these CpG islands. We demonstrate that two epigenetic modifications, DNA methylation and histone acetylation, regulate the activation of hSSTR2 upstream promoter. Furthermore, we show that the transcription from this upstream promoter region directly correlates to hSSTR2 mRNA expression in various human cell lines. A combined treatment of a demethylating agent, 5-aza-2-deoxycytidine and a histone deacetylase inhibitor, trichostatin A, leads to increased expression of hSSTR2 mRNA in cell lines in which the CpG island is methylated. The epigenetic regulation of this promoter region results in differential expression of hSSTR2 mRNA in human cell lines. This study reveals the existence of a novel upstream promoter for the hSSTR2 gene that is regulated by epigenetic modifications, suggesting for complex control of the hSSTR2 transcription.
Torrisani
Jérôme
J
Institut National de la Santé et de la Recherche Médicale Unité 858, I2MR Institut de Médecine Moléculaire de Rangueil, Département Cancers Epithéliaux, Angiogénèse, et Signalisation, 31432 Toulouse Cedex 4, France.
Hanoun
Naïma
N
Laurell
Henrik
H
Lopez
Frédéric
F
Maoret
Jean-José
JJ
Souque
Anny
A
Susini
Christiane
C
Cordelier
Pierre
P
Buscail
Louis
L
D001483:Base Sequence; D002843:Chromatin / Q000235:genetics / Q000648:ultrastructure; D002886:Chromosomes, Human, Pair 17; D019175:DNA Methylation; D015226:Dinucleoside Phosphates; D005091:Exons; D017930:Genes, Reporter; D006801:Humans; D008156:Luciferases / Q000235:genetics; D008969:Molecular Sequence Data; D010957:Plasmids; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics*; D017481:Receptors, Somatostatin / Q000235:genetics*; D017384:Sequence Deletion; D012689:Sequence Homology, Nucleic Acid
D002843:Chromatin; D015226:Dinucleoside Phosphates; D008156:Luciferases; D012333:RNA, Messenger; D017481:Receptors, Somatostatin; C015772:CpG dinucleotide; C093733:somatostatin receptor 2