Yy1 Regulates Senp1 Contributing to AMPA Receptor GluR1 Expression Following Neuronal Depolarization

J Biomed Sci. 2019 Oct 20;26(1):79. doi: 10.1186/s12929-019-0582-1.

Abstract

Background: Neuronal activity-induced changes in gene expression patterns are important mediators of neuronal plasticity. Many neuronal genes can be activated or inactivated in response to neuronal depolarization. Mechanisms that activate gene transcription are well established, but activity-dependent mechanisms that silence transcription are less understood. It is also not clear what is the significance of inhibiting these genes during neuronal activity.

Methods: Quantitative Real Time-PCR, western blot and immunofluorescence staining were performed to examine the expression of Senp1 and GluR1 in mouse cortical neurons. The alterations of Yy1 phosphorylation upon neuronal depolarization and the interaction of Yy1 with Brd4 were studied by protein co-immunoprecipitation. The regulators of Yy1 phosphorylation were identified by phosphatase inhibitors. Chromatin immunoprecipitation, in vitro DNA binding assay, luciferase assay and gene knockdown experiments were used to validate the roles of Yy1 and its phosphorylation as well as Brd4 in regulating Senp1 expression.

Results: We report that neuronal depolarization deactivates the transcription of the SUMO protease Senp1, an important component regulating synaptic transmission, scaling, and plasticity, through Yy1. In un-stimulated neurons, Senp1 transcription is activated by a Yy1-Brd4 transcription factor protein complex assembled on the Senp1 promoter. Upon membrane depolarization, however, Yy1 is dephosphorylated and the Yy1-Brd4 complex is evicted from the Senp1 promoter, reducing Senp1 transcription levels. Both Yy1 and Senp1 promote the expression of AMPA receptor subunit GluR1, a pivotal component in learning and memory.

Conclusions: These results reveal an axis of Yy1/Brd4-Senp1 which regulates the expression of GluR1 during neuronal depolarization. This implicates a regulation mechanism in silencing gene expression upon neuronal activity.

Keywords: Brd4; GluR1; Neuronal membrane depolarization; Phosphorylation; Senp1; Yy1.

MeSH terms

  • Animals
  • Cysteine Endopeptidases / genetics*
  • Cysteine Endopeptidases / metabolism
  • Embryo, Mammalian / physiology
  • Gene Expression Regulation / genetics*
  • Mice, Inbred C57BL
  • Neurons / physiology*
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Receptors, AMPA / genetics*
  • Receptors, AMPA / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • YY1 Transcription Factor / genetics*
  • YY1 Transcription Factor / metabolism

Substances

  • Brd4 protein, mouse
  • Nuclear Proteins
  • Receptors, AMPA
  • Transcription Factors
  • YY1 Transcription Factor
  • Yy1 protein, mouse
  • Cysteine Endopeptidases
  • Senp1 protein, mouse
  • glutamate receptor ionotropic, AMPA 1