DNA Methylation and Gene Expression of Matrix Metalloproteinase 9 Gene in Deficit and Non-deficit Schizophrenia

Abstract

The biological pathology of deficit schizophrenia (DS) remains unclear. Matrix metalloproteinase 9 (MMP9) might be associated with neural plasticity and glutamate regulation, involved in schizophrenia pathogenesis. This study explores gene expression and DNA methylation of MMP9 in peripheral blood mononuclear cells (PBMCs) and their relationship with clinical symptoms in DS and non-deficit schizophrenia (NDS). Pyrosequencing was used to determine DNA methylation at CpG sites in exon 4 and exon 5 of MMP9 in 51 DS patients, 53 NDS patients and 50 healthy subjects (HC). RT-qPCR was used to detect MMP9 expression. Clinical symptoms were assessed by BPRS, SANS and SAPS scales. MMP9 expression in PBMCs was significantly higher in DS than NDS and HC subjects. Compared to NDS patients, DS patients had significantly lower DNA methylation at individual CpG sites in exon 4 and exon 5 of MMP9. Correlation analysis showed that DNA methylation in exon 4 was negatively correlated with gene expression in DS group. Positive correlation was found between MMP9 expression and negative symptoms in total schizophrenic patients. The social amotivation factor of SANS and negative syndrome of BPRS was negatively correlated with DNA methylation of CpG5-1 in DS patients but not in NDS patients. DS patients showed a specific abnormality of peripheral MMP9 expression and DNA methylation, indicating a pathological mechanism underlying DS as a specific subgroup of schizophrenia.

The association of matrix metalloproteinase 9 (MMP9) with hippocampal volume in schizophrenia: a preliminary MRI study

“…Previous research suggested that negative symptoms may indicate neuronal damage [40] and that predominantly negative symptoms are associated with neurodevelopmental abnormalities [41]. Additionally, our finding is in line with recently published studies reporting that MMP9 mRNA expression is more pronounced in deficit schizophrenia [38,42]. Last, it has previously been demonstrated that MMP9 influences hippocampal and prefrontal N-methyl-D-aspartate receptor (NMDA) activity [38,42].…”

“…Our finding of elevated MMP9 plasma levels is in line with previous studies demonstrating higher peripheral activity of MMP9 [37] and its increased blood concentration [24,25] in patients with schizophrenia. It has been proposed that abnormal MMP9 levels might be a useful peripheral biomarker of schizophrenia [24], potentially discriminating patients from healthy individuals [38]. Indeed, given MMP9 distribution and upregulation of this protein might explain several processes that are disturbed throughout the lifespan in schizophrenia.…”

Predicting novel genomic regions linked to genetic disorders using GWAS and chromosome conformation data – a case study of schizophrenia

“…Gao et al . 39 reported a specific abnormality in peripheral expression of the matrix metalloproteinase 9 gene, MMP9 , and its methylation, indicating a potentially different pathological mechanism underlying a specific subgroup of schizophrenia, which includes deficit schizophrenia patients. In turn, gene expression profiling of the dorsolateral and medial orbitofrontal cortex in schizophrenia patients 40 identified seven novel genes, including KAT7 and EVI2A , and previously reported gene TARDBP (all residing within cluster 1) that are differentially expressed in several brain regions, including prefrontal cortical regions, in patients with SCZ.…”

Şizofrenide Epigenetik Bakış Açısı: DNA Metilasyon Modelleri

“…Archives Medical Review Journal Another recent study on the gene SLC6A4 encoding the serotonin transporter (5-HTT) found significant hypermethylation at one CpG site in male patients with SZ 65 . A recent study by Gao et al showed that MMP9, which plays a role in the regulation of the extracellular matrix, is hypomethylated in SZ patients with deficiency compared to non-deficient SZ patients 66 . In a recent study conducted in 2020, CpG regions in FAM63B were found to be significantly hypomethylated in blood samples from SZ patients 67 .…”