Cited by 9Epigenetics and DNA MethylationGenomics and Chromatin DynamicsNeuroscience and Neuropharmacology Research

Polycomblike protein PHF1b: a transcriptional sensor for GABA receptor activity

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Saha, Shamol, Hu, Yinghui, Martin, Stella C, Bandyopadhyay, Sabita, Russek, Shelley J, Farb, David H·2013·BMC Pharmacology and Toxicology

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.

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  • The PHF1b isoform promotes transcription of GABRB1, which encodes GABA type A receptor, resulting in regulation of GABA-mediated neurotransmission in the central nervous system, in particular in neocortical and hippocampal neurons.

    “the PHF1b isoform promotes the transcription of GABRB1, which encodes GABA type A receptor (GABAAR); this results in the regulation of GABA-mediated neurotransmission in the central nervous system, in particular in neocortical and hippocampal neurons92.”

    From Distinct selective forces and Neanderthal introgression shaped genetic diversity at genes involved in neurodevelopmental disorders (2017) · cites this paper as [92]

    The Background and Discussion report that PHF1b stimulates GABRB1 promoter activity, and the Results show PHF1 binding at the Gabrb1 promoter in rat neocortical and hippocampal neurons. But GABRB1 encodes a GABA-A receptor β1 subunit, not the entire receptor. The Conclusions say PHF1b *may* transduce GABA-A receptor activity and thus affect CNS neurotransmission; they do not establish the claimed downstream regulation as a demonstrated result. (LLM, conf=0.87)

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  1. Korhonen P Huotari V Soininen H Salminen A Glutamate-induced changes in the DNA-binding complexes of transcription factor YY1 in cultured hippocampal and cerebellar granule cells Brain Res Mol Brain Res 1997 52 330 333 9495557

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Authors
Saha, S., Hu, Y., Martin, S. C., Bandyopadhyay, S., Russek, S. J., & Farb, D. H.
Affiliations
Boston University (US)
Corresponding author
Russek, Shelley J
Venue
BMC Pharmacology and Toxicology
Published
2013-07-23
Volume
14
Issue
1
Pages
37-37
ISSN
2050-6511 (ISSN-L)
OpenAlex
W1990026602
Cited by
9
References
83
Citations by year
2024: 1 · 2022: 2 · 2020: 1 · 2018: 1 · 2017: 2 · 2016: 1 · 2015: 1
FWCI
0.30
Type
journal article
Language
en
Open access
Locations
  • BMC Pharmacology and Toxicology (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • School of Medicine, Boston University
  • National Institutes of Health
  • National Institute on Alcohol Abuse and Alcoholism (R01AA011697, R01 AA11697-09)
  • National Institute of Neurological Disorders and Stroke (R01NS050393, R01 NS050393-010A)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
GABAA receptor, GABRB1, transcriptional regulation, plant homeodomain, SUZ12, polycomb repressive complex 2, H3K27 methylation, cortical neurons, GABA signaling
MeSH terms
Animals, Cells, Cultured, Chlorocebus aethiops, DNA-Binding Proteins, gamma-Aminobutyric Acid, Hippocampus, Humans, Male, Neurons, Receptors, GABA-A, Transcription Factors, Transcription, Genetic, Rats, Sprague-Dawley, COS Cells, Neocortex, Two-Hybrid System Techniques, Protein Subunits, Rats, Polycomb-Group Proteins

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