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Polycomblike protein PHF1b: a transcriptional sensor for GABA receptor activity
- Source :
- BMC Pharmacology & Toxicology
- Publication Year :
- 2013
- Publisher :
- Springer Science and Business Media LLC, 2013.
-
Abstract
- Background The γ-aminobutyric acid (GABA) type A receptor (GABAAR) contains the recognition sites for a variety of agents used in the treatment of brain disorders, including anxiety and epilepsy. A better understanding of how receptor expression is regulated in individual neurons may provide novel opportunities for therapeutic intervention. Towards this goal we have studied transcription of a GABAAR subunit gene (GABRB1) whose activity is autologously regulated by GABA via a 10 base pair initiator-like element (β1-INR). Methods By screening a human cDNA brain library with a yeast one-hybrid assay, the Polycomblike (PCL) gene product PHD finger protein transcript b (PHF1b) was identified as a β1-INR associated protein. Promoter/reporter assays in primary rat cortical cells demonstrate that PHF1b is an activator at GABRB1, and chromatin immunoprecipitation assays reveal that presence of PHF1 at endogenous Gabrb1 is regulated by GABAAR activation. Results PCL is a member of the Polycomb group required for correct spatial expression of homeotic genes in Drosophila. We now show that PHF1b recognition of β1-INR is dependent on a plant homeodomain, an adjacent helix-loop-helix, and short glycine rich motif. In neurons, it co-immunoprecipitates with SUZ12, a key component of the Polycomb Repressive Complex 2 (PRC2) that regulates a number of important cellular processes, including gene silencing via histone H3 lysine 27 trimethylation (H3K27me3). Conclusions The observation that chronic exposure to GABA reduces PHF1 binding and H3K27 monomethylation, which is associated with transcriptional activation, strongly suggests that PHF1b may be a molecular transducer of GABAAR function and thus GABA-mediated neurotransmission in the central nervous system.
- Subjects :
- Male
Transcription, Genetic
Receptor expression
Polycomb-Group Proteins
Neocortex
Biology
Hippocampus
Rats, Sprague-Dawley
Gene product
03 medical and health sciences
0302 clinical medicine
Two-Hybrid System Techniques
Chlorocebus aethiops
SUZ12
Animals
Humans
Gene silencing
Pharmacology (medical)
Transcription factor
Cells, Cultured
gamma-Aminobutyric Acid
030304 developmental biology
Neurons
Pharmacology
0303 health sciences
Receptors, GABA-A
Molecular biology
Rats
DNA-Binding Proteins
Protein Subunits
PHD finger
COS Cells
Homeotic gene
Chromatin immunoprecipitation
030217 neurology & neurosurgery
Research Article
Transcription Factors
Subjects
Details
- ISSN :
- 20506511
- Volume :
- 14
- Database :
- OpenAIRE
- Journal :
- BMC Pharmacology and Toxicology
- Accession number :
- edsair.doi.dedup.....b718ffe2d4e1a098a3f49f8683db9c6d