TY - JOUR
T1 - Abnormal DNA Methylation Induced by Hyperglycemia Reduces CXCR4 Gene Expression in CD34+ Stem Cells
AU - Vigorelli, Vera
AU - Resta, Jessica
AU - Bianchessi, Valentina
AU - Lauri, Andrea
AU - Bassetti, Beatrice
AU - Agrifoglio, Marco
AU - Pesce, Maurizio
AU - Polvani, Gianluca
AU - Bonalumi, Giorgia
AU - Cavallotti, Laura
AU - Alamanni, Francesco
AU - Genovese, Stefano
AU - Pompilio, Giulio
AU - Vinci, Maria Cristina
PY - 2019/5/7
Y1 - 2019/5/7
N2 - Background: CD34+ stem/progenitor cells are involved in vascular homeostasis and in neovascularization of ischemic tissues. The number of circulating CD34+ stem cells is a predictive biomarker of adverse cardiovascular outcomes in diabetic patients. Here, we provide evidence that hyperglycemia can be “memorized” by the stem cells through epigenetic changes that contribute to onset and maintenance of their dysfunction in diabetes mellitus. Methods and Results: Cord-blood–derived CD34+ stem cells exposed to high glucose displayed increased reactive oxygen species production, overexpression of p66shc gene, and downregulation of antioxidant genes catalase and manganese superoxide dismutase when compared with normoglycemic cells. This altered oxidative state was associated with impaired migration ability toward stromal-cell–derived factor 1 alpha and reduced protein and mRNA expression of the C-X-C chemokine receptor type 4 (CXCR4) receptor. The methylation analysis by bisulfite Sanger sequencing of the CXCR4 promoter revealed a significant increase in DNA methylation density in high-glucose CD34+ stem cells that negatively correlated with mRNA expression (Pearson r=−0.76; P=0.004). Consistently, we found, by chromatin immunoprecipitation assay, a more transcriptionally inactive chromatin conformation and reduced RNA polymerase II engagement on the CXCR4 promoter. Notably, alteration of CXCR4 DNA methylation, as well as transcriptional and functional defects, persisted in high-glucose CD34+ stem cells despite recovery in normoglycemic conditions. Importantly, such an epigenetic modification was thoroughly confirmed in bone marrow CD34+ stem cells isolated from sternal biopsies of diabetic patients undergoing coronary bypass surgery. Conclusions: CD34+ stem cells “memorize” the hyperglycemic environment in the form of epigenetic modifications that collude to alter CXCR4 receptor expression and migration.
AB - Background: CD34+ stem/progenitor cells are involved in vascular homeostasis and in neovascularization of ischemic tissues. The number of circulating CD34+ stem cells is a predictive biomarker of adverse cardiovascular outcomes in diabetic patients. Here, we provide evidence that hyperglycemia can be “memorized” by the stem cells through epigenetic changes that contribute to onset and maintenance of their dysfunction in diabetes mellitus. Methods and Results: Cord-blood–derived CD34+ stem cells exposed to high glucose displayed increased reactive oxygen species production, overexpression of p66shc gene, and downregulation of antioxidant genes catalase and manganese superoxide dismutase when compared with normoglycemic cells. This altered oxidative state was associated with impaired migration ability toward stromal-cell–derived factor 1 alpha and reduced protein and mRNA expression of the C-X-C chemokine receptor type 4 (CXCR4) receptor. The methylation analysis by bisulfite Sanger sequencing of the CXCR4 promoter revealed a significant increase in DNA methylation density in high-glucose CD34+ stem cells that negatively correlated with mRNA expression (Pearson r=−0.76; P=0.004). Consistently, we found, by chromatin immunoprecipitation assay, a more transcriptionally inactive chromatin conformation and reduced RNA polymerase II engagement on the CXCR4 promoter. Notably, alteration of CXCR4 DNA methylation, as well as transcriptional and functional defects, persisted in high-glucose CD34+ stem cells despite recovery in normoglycemic conditions. Importantly, such an epigenetic modification was thoroughly confirmed in bone marrow CD34+ stem cells isolated from sternal biopsies of diabetic patients undergoing coronary bypass surgery. Conclusions: CD34+ stem cells “memorize” the hyperglycemic environment in the form of epigenetic modifications that collude to alter CXCR4 receptor expression and migration.
KW - cardiovascular complications
KW - CD34 stem cells
KW - CXCR4
KW - diabetes mellitus
KW - DNA methylation
KW - histone modifications
KW - metabolic memory
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U2 - 10.1161/JAHA.118.010012
DO - 10.1161/JAHA.118.010012
M3 - Article
C2 - 31018749
AN - SCOPUS:85065290656
VL - 8
JO - Journal of the American Heart Association
JF - Journal of the American Heart Association
SN - 2047-9980
IS - 9
M1 - e010012
ER -