title: Polycomblike protein PHF1b: a transcriptional sensor for GABA receptor activity.
abstract: BACKGROUND
  The γ-aminobutyric acid (GABA) type A receptor (GABA(A)R) 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 GABA(A)R subunit gene (GABRB1) whose activity is autologously regulated by GABA via a 10 base pair initiator-like element (β(1)-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 β(1)-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 GABA(A)R 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 β(1)-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 GABA(A)R function and thus GABA-mediated neurotransmission in the central nervous system.
authors.affiliation: Department of Pharmacology & Experimental Therapeutics, Laboratory of Translational Epilepsy, Boston University School of Medicine, Boston, MA 02118, USA.
authors.forename: Shamol
authors.initials: S
authors.lastname: Saha
authors.forename: Yinghui
authors.initials: Y
authors.lastname: Hu
authors.forename: Stella C
authors.initials: SC
authors.lastname: Martin
authors.forename: Sabita
authors.initials: S
authors.lastname: Bandyopadhyay
authors.forename: Shelley J
authors.initials: SJ
authors.lastname: Russek
authors.forename: David H
authors.initials: DH
authors.lastname: Farb
mesh_terms: D000818:Animals; D019556:COS Cells; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D008297:Male; D019579:Neocortex / Q000166:cytology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D063146:Polycomb-Group Proteins; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D020798:Two-Hybrid System Techniques; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology*
chemical_list: D004268:DNA-Binding Proteins; C546264:GABRB1 protein, human; C112309:PHF1 protein, human; D063146:Polycomb-Group Proteins; D021122:Protein Subunits; D011963:Receptors, GABA-A; D014157:Transcription Factors; D005680:gamma-Aminobutyric Acid