The rapidly increasing prevalence of diabetes mellitus worldwide is one of the most serious and challenging health problems in the 21st century.Mammalian sirtuin 1(SIRT1) has been shown to decrease high-glucose-induce...The rapidly increasing prevalence of diabetes mellitus worldwide is one of the most serious and challenging health problems in the 21st century.Mammalian sirtuin 1(SIRT1) has been shown to decrease high-glucose-induced endothelial cell senescence in vitro and prevent hyperglycemia-induced vascular dysfunction.However,a role for SIRT1 in prevention of hyperglycemia-induced vascular cell senescence in vivo remains unclear.We used endothelium-specific SIRT1 transgenic(SIRT1-Tg) mice and wild-type(WT) mice to construct a 40-week streptozotocin(STZ)-induced diabetic mouse model.In this mode,42.9% of wild-type(WT) mice and 38.5% of SIRT1-Tg mice were successfully established as diabetic.Forty weeks of hyperglycemia induced significant vascular cell senescence in aortas of mice,as indicated by upregulation of expression of senescence-associated markers including p53,p21 and plasminogen activator inhibitor-1(PAI-1).However,SIRT1-Tg diabetic mice displayed dramatically decreased expression of p53,p21 and PAI-1 compared with diabetic WT mice.Moreover,manganese superoxide dismutase expression(MnSOD) was significantly downregulated in the aortas of diabetic WT mice,but was preserved in diabetic SIRT1-Tg mice.Furthermore,expression of the oxidative stress adaptor p66Shc was significantly decreased in aortas of SIRT1-Tg diabetic mice compared with WT diabetic mice.Overall,these findings suggest that SIRT1-mediated inhibition of hyperglycemia-induced vascular cell senescence is mediated at least partly through the reduction of oxidative stress.展开更多
Spatial expression patterns of homeobox(HOX) genes delineate positional identity of primary fibroblasts from different topographic sites. The molecular mechanism underlying the establishing or maintaining of HOX gene ...Spatial expression patterns of homeobox(HOX) genes delineate positional identity of primary fibroblasts from different topographic sites. The molecular mechanism underlying the establishing or maintaining of HOX gene expression pattern remains an attractive developmental issue to be addressed. Our previous work suggested a critical role of CTCF/cohesin-mediated higher-order chromatin structure in RA-induced HOXA activation in human teratocarcinoma NT2/D1 cells. This study investigated the recruitment of CTCF and cohesin, and the higher-order chromatin structure of the HOXA locus in fetal lung and adult foreskin fibroblasts, which display complementary HOXA gene expression patterns. Chromatin contacts between the CTCF-binding sites were observed with lower frequency in human foreskin fibroblasts. This observation is consistent with the lower level of cohesin recruitment and 5′ HOXA gene expression in the same cells. We also showed that CTCF-binding site A56(CBSA56) related chromatin structures exhibit the most notable changes in between the two types of cell, and hence may stand for one of the key CTCF-binding sites for cell-type specific chromatin structure organization. Together, these results imply that CTCF/cohesin coordinates HOXA cluster higher-order chromatin structure and expression during development, and provide insight into the relationship between cell-type specific chromatin organization and the spatial collinearity.展开更多
基金supported by the National Basic Research Program of China (Grant No. 2011CB503902)National Natural Science Foundation of China (Grant Nos. 31028005 and 31021091)
文摘The rapidly increasing prevalence of diabetes mellitus worldwide is one of the most serious and challenging health problems in the 21st century.Mammalian sirtuin 1(SIRT1) has been shown to decrease high-glucose-induced endothelial cell senescence in vitro and prevent hyperglycemia-induced vascular dysfunction.However,a role for SIRT1 in prevention of hyperglycemia-induced vascular cell senescence in vivo remains unclear.We used endothelium-specific SIRT1 transgenic(SIRT1-Tg) mice and wild-type(WT) mice to construct a 40-week streptozotocin(STZ)-induced diabetic mouse model.In this mode,42.9% of wild-type(WT) mice and 38.5% of SIRT1-Tg mice were successfully established as diabetic.Forty weeks of hyperglycemia induced significant vascular cell senescence in aortas of mice,as indicated by upregulation of expression of senescence-associated markers including p53,p21 and plasminogen activator inhibitor-1(PAI-1).However,SIRT1-Tg diabetic mice displayed dramatically decreased expression of p53,p21 and PAI-1 compared with diabetic WT mice.Moreover,manganese superoxide dismutase expression(MnSOD) was significantly downregulated in the aortas of diabetic WT mice,but was preserved in diabetic SIRT1-Tg mice.Furthermore,expression of the oxidative stress adaptor p66Shc was significantly decreased in aortas of SIRT1-Tg diabetic mice compared with WT diabetic mice.Overall,these findings suggest that SIRT1-mediated inhibition of hyperglycemia-induced vascular cell senescence is mediated at least partly through the reduction of oxidative stress.
基金supported by the National Natural Science Foundation of China(31030026)the National Basic Research Program(2011CB-965203)the PUMC Youth funds(3332013138)
文摘Spatial expression patterns of homeobox(HOX) genes delineate positional identity of primary fibroblasts from different topographic sites. The molecular mechanism underlying the establishing or maintaining of HOX gene expression pattern remains an attractive developmental issue to be addressed. Our previous work suggested a critical role of CTCF/cohesin-mediated higher-order chromatin structure in RA-induced HOXA activation in human teratocarcinoma NT2/D1 cells. This study investigated the recruitment of CTCF and cohesin, and the higher-order chromatin structure of the HOXA locus in fetal lung and adult foreskin fibroblasts, which display complementary HOXA gene expression patterns. Chromatin contacts between the CTCF-binding sites were observed with lower frequency in human foreskin fibroblasts. This observation is consistent with the lower level of cohesin recruitment and 5′ HOXA gene expression in the same cells. We also showed that CTCF-binding site A56(CBSA56) related chromatin structures exhibit the most notable changes in between the two types of cell, and hence may stand for one of the key CTCF-binding sites for cell-type specific chromatin structure organization. Together, these results imply that CTCF/cohesin coordinates HOXA cluster higher-order chromatin structure and expression during development, and provide insight into the relationship between cell-type specific chromatin organization and the spatial collinearity.
