Regulation of tryptophan hydroxylase-2 gene expression by a bipartite RE-1 silencer of transcription/neuron restrictive silencing factor (REST/NRSF) binding motif.
Tryptophan hydroxylase-2 (TPH2) is the rate-limiting enzyme in raphe serotonin biosynthesis, and polymorphisms of TPH2 are implicated in vulnerability to psychiatric disorders. Dynamic transcription regulation of TPH2 may underlie differences in vulnerability. We identified a transcription element in the TPH2 promoter that resembles the binding motif for RE-1 silencer of transcription (REST; also known as NRSF) transcription factor. REST limits tissue expression of non-neuronal genes through a canonical 21-bp motif called the NRSE (neuron-restrictive silencing element). The NRSE in TPH2 is a novel bipartite variant interrupted by a 6-base insertion. We confirmed that this bipartite NRSE permits transcriptional repression by REST identical to canonical NRSE in rat C6-glioma cells. Synthetic permutations of the motif revealed considerable flexibility in the juxtaposition of the two halves of bipartite NRSE. Computational analysis revealed many bipartite NRSE variants conserved between mouse and human genomes. A subgroup of these was found to bind REST by chromatin immunoprecipitation. Messenger RNAs for TPH2 and potassium channel H6, another gene with a bipartite NRSE, were up-regulated by dominant-negative REST in C6-glioma cells. These findings, which indicate that TPH2 expression is part of the developmental program regulated by REST and suggest that many previously unrecognized genes may be regulated by REST through the novel motif, have implications for the mechanism of REST action.
Patel
Paresh D
PD
Molecular and Behavioral Neuroscience Institute, University of Michigan Medical Center, Ann Arbor, Michigan 48109-2200. Electronic address: pdpatel@umich.edu.
Bochar
Daniel A
DA
Department of Biological Chemistry, University of Michigan Medical Center, Ann Arbor, Michigan 48109-0606.
Turner
David L
DL
Molecular and Behavioral Neuroscience Institute, University of Michigan Medical Center, Ann Arbor, Michigan 48109-2200; Department of Biological Chemistry, University of Michigan Medical Center, Ann Arbor, Michigan 48109-0606.
Meng
Fan
F
Molecular and Behavioral Neuroscience Institute, University of Michigan Medical Center, Ann Arbor, Michigan 48109-2200.
Mueller
Helena M
HM
Molecular and Behavioral Neuroscience Institute, University of Michigan Medical Center, Ann Arbor, Michigan 48109-2200.
Pontrello
Crystal G
CG
Program in Neuroscience, University of California, Riverside, California 92521.
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D045744:Cell Line, Tumor; D004285:Dogs; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D062551:NAV1.2 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000235:genetics; D011401:Promoter Regions, Genetic; D051381:Rats; D012097:Repressor Proteins / Q000737:chemistry / Q000502:physiology*; D015222:Sodium Channels / Q000235:genetics; D014157:Transcription Factors / Q000737:chemistry / Q000502:physiology*; D014365:Tryptophan Hydroxylase / Q000235:genetics*; D000099229:RE1-Silencing Transcription Factor
D062551:NAV1.2 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; D012097:Repressor Proteins; D015222:Sodium Channels; D014157:Transcription Factors; D014365:Tryptophan Hydroxylase; D000099229:RE1-Silencing Transcription Factor; C568251:SCN2A protein, human; C568253:Scn2A protein, rat; C000654500:Scn2a protein, mouse; C494784:TPH2 protein, human