Epigenetics of Epileptogenesis-Evoked Upregulation of Matrix Metalloproteinase-9 in Hippocampus

Abstract

Enhanced levels of Matrix Metalloproteinase-9 (MMP-9) have been implicated in the pathogenesis of epilepsy in humans and rodents. Lack of Mmp-9 impoverishes, whereas excess of Mmp-9 facilitates epileptogenesis. Epigenetic mechanisms driving the epileptogenesis-related upregulation of MMP-9 expression are virtually unknown. The aim of this study was to reveal these mechanisms. We analyzed hippocampi extracted from adult and pediatric patients with temporal lobe epilepsy as well as from partially and fully pentylenetetrazole kindled rats. We used a unique approach to the analysis of the kindling model results (inclusion in the analysis of rats being during kindling, and not only a group of fully kindled animals), which allowed us to separate the molecular effects exerted by the epileptogenesis from those related to epilepsy and epileptic activity. Consequently, it allowed for a disclosure of molecular mechanisms underlying causes, and not consequences, of epilepsy. Our data show that the epileptogenesis-evoked upregulation of Mmp-9 expression is regulated by removal from Mmp-9 gene proximal promoter of the two, interweaved potent silencing mechanisms–DNA methylation and Polycomb Repressive Complex 2 (PRC2)-related repression. Demethylation depends on a gradual dissociation of the DNA methyltransferases, Dnmt3a and Dnmt3b, and on progressive association of the DNA demethylation promoting protein Gadd45β to Mmp-9 proximal gene promoter in vivo. The PRC2-related mechanism relies on dissociation of the repressive transcription factor YY1 and the dissipation of the PRC2-evoked trimethylation on Lys27 of the histone H3 from the proximal Mmp-9 promoter chromatin in vivo. Moreover, we show that the DNA hydroxymethylation, a new epigenetic DNA modification, which is localized predominantly in the gene promoters and is particularly abundant in the brain, is not involved in a regulation of MMP-9 expression during the epileptogenesis in the rat hippocampus as well as in the hippocampi of pediatric and adult epileptic patients. Additionally, we have also found that despite of its transient nature, the histone modification H3S10ph is strongly and gradually accumulated during epileptogenesis in the cell nuclei and in the proximal Mmp-9 gene promoter in the hippocampus, which suggests that H3S10ph can be involved in DNA demethylation in mammals, and not only in Neurospora. The study identifies MMP-9 as the first protein coding gene which expression is regulated by DNA methylation in human epilepsy. We present a detailed epigenetic model of the epileptogenesis-evoked upregulation of MMP-9 expression in the hippocampus. To our knowledge, it is the most complex and most detailed mechanism of epigenetic regulation of gene expression ever revealed for a particular gene in epileptogenesis. Our results also suggest for the first time that dysregulation of DNA methylation found in epilepsy is a cause rather than a consequence of this condition.

The Novel HDAC8 Inhibitor WK2-16 Attenuates Lipopolysaccharide-Activated Matrix Metalloproteinase-9 Expression in Human Monocytic Cells and Improves Hypercytokinemia In Vivo

“…The transcriptional regulator Yin Yang 1 (YY1) plays an important role in MMP-9 expression in brain neurons [ 30 , 31 ]. Furthermore, it was reported that HDAC8 inhibition represses the transcriptional activity of YY1 [ 37 ].…”

“…Several transcription factors have also been described to be involved in MMP-9 expression, including NF-κB, AP-1, SP-1 and Ets [ 29 ]. MMP-9 could also be regulated negatively by transcription factor Yin Yang1 (YY1) in rat non-depolarized brain neurons [ 30 , 31 ]. However, it remains unclear whether HDAC8 inhibition influences the function of transcription factors on MMP-9 and pro-inflammatory cytokine expression in monocytic cells.…”

c-Fos and neuronal plasticity: the aftermath of Kaczmarek’s theory

“…Moreover, MMP-9 is an essential regulator of dendritic spine dynamics (Jasinska et al 2016, Kondratiuk et al 2016, Michaluk et al 2011, Szepesi et al 2013, 2014. In addition to its role in brain physiology, MMP-9 was shown to be implicated in aberrant plasticity and contributes to various brain disorders, such as epilepsy, alcoholism, stress, and schizophrenia (Lepeta et al 2017, Pijet et al 2018, Samochowiec et al 2010, Wilczynski et al 2008, Zybura-Broda et al 2016).…”

Od c-Fos do MMP-9 w kontroli plastyczności synaptycznej zdrowego i chorego umysłu, spojrzenie osobiste

“…Recently, Pijet et al [117] have employed traumatic brain injury-evoked epileptogenesis, clinically relevant mouse model, to demonstrate important contribution of MMP-9 to epilepsy development. Most interestingly, elevated MMP-9 was found in human epileptic brain samples [118][119][120][121]. Furthermore, Zybura-Broda et al [121] implicated progressive increase in MMP-9 levels, possibly dependent on its gene promoter demethylation, in human epilepsy and rat epileptogenesis.…”