Expression and CpG island methylation pattern of MMP-2 and MMP-9 genes in patients with congenital factor XIII deficiency and intracranial hemorrhage

Abstract

Objectives: Congenital factor XIII (FXIII) deficiency is a rare severe bleeding disorder. Intracranial hemorrhage (ICH) is the leading cause of mortality and morbidity in FXIII deficiency. However, its pathogenesis is not well understood yet. In this study, we investigated the expression and CpG island methylation status of matrix metalloproteinase-2 (MMP-2) and MMP-9 in patients with FXIII deficiency and ICH. Methods: Forty patients with FXIII deficiency including twenty patients with ICH, and twenty without ICH were recruited as case and control groups, respectively. Methylation status was determined by bisulfite sequencing polymerase chain reaction (PCR), and gene expression was assessed by quantitative real-time PCR. Results and discussion: We found an unmethylated pattern for both MMP-2 and MMP-9 genes in the case group. Both genes were partially methylated in the control group, while the percentage of methylated CpGs was significantly higher in MMP-9 than MMP-2 (P = 0.001). Furthermore, higher expression of MMP-9 (in both the mRNA and protein levels) was found in the case than control group (P = 0.008 and P = 0.009, respectively). On the other hand, there was no significant difference in MMP-2 expression level (neither mRNA nor protein) between the two groups (P = 0.12 and P = 0.25, respectively). Conclusion: Our findings indicated that MMP-9 over-expression might be related to ICH in FXIII deficiency, and gene methylation effectively regulates its expression. Future researches will expand our understanding of the pathogenesis of ICH in congenital FXIII deficiency.

Expression and methylation status of vascular endothelial growth factor and thrombospondin-1 genes in congenital factor XIII-deficient patients with intracranial hemorrhage

“…Peripheral blood was collected 24-48 h after ICH [21]. DNA was extracted using the QIAamp DNA Mini kit (QIAGEN, Hilden, Germany), and treated with sodium bisulfite using EpiTect Bisulfite Kit (QIAGEN) according to the manufacturer's protocol.…”

A Mechanistic Investigation of the Relationship Between Extramural Vascular Invasion (EMVI) and CpG Island Methylator Phenotype (CIMP) in Rectal Cancer

“…As the promotor motifs in the promotor regions in MMP2 and the two TIMPs are highly overlapping but the effects of demethylation not convergent, promotor demethylation affecting transcription is not occurring at the identified activator motifs but may be occurring at another upstream site. CpG islands and differential methylation in approximation to MMPs and TIMPs have been associated with a variety of diseases, including cancer, stroke, clotting disorders, and placental defects [657][658][659] . Although epigenetic events have previously been identified in metalloproteinase transcription, including the MMP2/TIMP2/MT1-MMP axis, CpG islands are not well characterised in relation to MMPs and TIMPs, and these genes do not contribute to the classical CIMP classification systems, although some of the ADAM group of proteinases are included in a limited number panels (see Chapter 1, Table 1.2) 592,660,661 .…”