Yin Yang 1 Is a Critical Repressor of Matrix Metalloproteinase-9 Expression in Brain Neurons

Marcin Rylski,Renata Amborska,Katarzyna Zybura,Barbara Mioduszewska,Piotr Michaluk,Jacek Jaworski,Leszek Kaczmarek

doi:10.1074/jbc.m804540200

Abstract

Membrane depolarization controls long lasting adaptive neuronal changes in brain physiology and pathology. Such responses are believed to be gene expression-dependent. Notably, however, only a couple of gene repressors active in nondepolarized neurons have been described. In this study, we show that in the unstimulated rat hippocampus in vivo, as well as in the nondepolarized brain neurons in primary culture, the transcriptional regulator Yin Yang 1 (YY1) is bound to the proximal Mmp-9 promoter and strongly represses Mmp-9 transcription. Furthermore, we demonstrate that monoubiquitinated and CtBP1 (C-terminal binding protein 1)-bound YY1 regulates Mmp-9 mRNA synthesis in rat brain neurons controlling its transcription apparently via HDAC3-dependent histone deacetylation. In conclusion, our data suggest that YY1 exerts, via epigenetic mechanisms, a control over neuronal expression of MMP-9. Because MMP-9 has recently been shown to play a pivotal role in physiological and pathological neuronal plasticity, YY1 may be implicated in these phenomena as well.

Highlights

In this study we set out to search for these transcriptional repressors
We have found a strong enrichment of the Ϫ187/Ϫ13-bp proximal Mmp-9 promoter fragments, whereas the distal Mmp-9 promoter DNA and the downstream one were not present in amounts higher than those found in controls (Fig. 1B)
We show that in the unstimulated rat hippocampus in vivo, as well as in the nondepolarized brain neurons in primary culture, the transcriptional regulator Yin Yang 1 (YY1) is bound to the Ϫ333/Ϫ322-bp site of the Mmp-9 promoter and strongly represses Mmp-9 transcription

Summary

Introduction

In this study we set out to search for these transcriptional repressors. We focused on a regulation of Mmp-9 that codes for an extracellular matrix protease involved in physiological and pathological extracellular matrix remodeling. Its expression levels in those cells are very low, which points toward a presence of an efficient mechanism(s) repressing its transcription in unstimulated neurons (10). Molecular mechanisms directly controlling MMP-9 transcription in physiology and pathology of neurons remain unknown. Using the DNase I footprinting, a method for an identification of novel DNA regulatory proteins (17, 18), we have analyzed the rat Mmp-9 promoter fragments overlapping the Ϫ557/ϩ18-bp region of the gene in unstimulated neurons to look for repressive transcription factors. We have identified YY1, a transcription factor belonging to a Polycomb group of proteins (PcGs), as a potential Mmp-9 gene repressor.

Methods

Results

Conclusion