LSD1 （KDM1 under the new nomenclature） was the first identified lysine-specific histone demethylase belonging to the flavin-dependent amine oxidase family. Here, we report that AOF1 （KDM1B under the new nomenclatur...LSD1 （KDM1 under the new nomenclature） was the first identified lysine-specific histone demethylase belonging to the flavin-dependent amine oxidase family. Here, we report that AOF1 （KDM1B under the new nomenclature）, a mammalian protein related to LSD1, also possesses histone demethylase activity with specificity for H3K4mel and H3K4me2. Like LSD1, the highly conserved SWIRM domain is required for its enzymatic activity. However, AOF1 differs from LSD1 in several aspects. First, AOF1 does not appear to form stable protein complexes containing histone deacetylases. Second, AOF1 is found to localize to chromosomes during the mitotic phase of the cell cycle, whereas LSD1 does not. Third, AOF1 represses transcription when tethered to DNA and this repression activity is independent of its demethylase activity. Structural and functional analyses identified its unique N-terminal Zf-CW domain as essential for the demethylase activity-independent repression function. Collectively, our study identifies AOF1 as the second histone demethylase in the family of flavin-dependent amine oxidases and reveals a demethylase-independent repression function of AOF1.展开更多
Bone tissue engineering may be hindered by underlying osteoporosis because of a decreased osteogenic ability of autologous seed cells and an unfavorably changed microenvironment in these patients. Epigenetic regulatio...Bone tissue engineering may be hindered by underlying osteoporosis because of a decreased osteogenic ability of autologous seed cells and an unfavorably changed microenvironment in these patients. Epigenetic regulation plays an important role in the developmental origins of osteoporosis; however, few studies have investigated the potential of epigenetic therapy to improve or rescue the osteogenic ability of bone marrow mesenchymal stem cells(BMMSCs) under osteoporotic conditions. Here, we investigated pargyline, an inhibitor of lysine-specific demethylase 1(LSD1), which mainly catalyzes the demethylation of the di- and mono-methylation of H3K4. We demonstrated that 1.5 mmol·Lpargyline was the optimal concentration for the osteogenic differentiation of human BMMSCs. Pargyline rescued the osteogenic differentiation ability of mouse BMMSCs under osteoporotic conditions by enhancing the dimethylation level of H3K4 at the promoter regions of osteogenesis-related genes. Moreover, pargyline partially rescued or prevented the osteoporotic conditions in aged or ovariectomized mouse models, respectively. By introducing the concept of epigenetic therapy into the field of osteoporosis, this study demonstrated that LSD1 inhibitors could improve the clinical practice of MSC-based bone tissue engineering and proposes their novel use to treat osteoporosis.展开更多
ZHOU Bai-Bin *,1,2 WEI Yong-De 1 LI Zhong-Hua 1 ( 1 Department of Applied Chemistry,Ha rbin Institute of Technology ￡?Harbin￡±￡ì￡°￡°￡°￡±￡(c)( 2 Department of Chemistry,Harbin Norm...ZHOU Bai-Bin *,1,2 WEI Yong-De 1 LI Zhong-Hua 1 ( 1 Department of Applied Chemistry,Ha rbin Institute of Technology ￡?Harbin￡±￡ì￡°￡°￡°￡±￡(c)( 2 Department of Chemistry,Harbin Normal University￡?Harbin￡±￡ì￡°￡°￡?￡°￡(c) The air-solid interface reaction of Ce,Lu with K10 H 3[Gd (SiMo 4 W￡*O￡3￡1￡(c) 2]through chemistry-heated permeation is reported for the fi rst time￡(r)The permeated complex is characterized by ICP and the result shows tha t the mini mum Ce,Lu can permeate into the inner sph ere of K 10 H ￡3 ￡?Gd ￡¨SiMo ￡′ W ￡* O ￡3￡1 ￡(c) 2]The IR ,XRD patterns give the eviden ce that after permeation the comple x still keeps the Keggin structure,howe ver,its crystal structure is different from the complex before permeation￡(r)The cond uctivity of the permeated complex has been measured with the four-electr ode method and the data show that the co nductivity of the complex after permeation is 10 6 times higher than that of the sample before permeation and reaches ￡′￡(r)84 6×10 -1 S·cm -1 ￡(r)These indicate that the permeated c omplex is a good solid electrolyte and further appli cations are also expected￡(r)展开更多
Two new Gd Ⅲ complexes with nitrilotriacetic acid(nta) and trans-1,2-cyclohexanediaminetetraacetic acid(Cydta) ligands were synthesized. Their crystal structures were determined by single-crystal X-ray structure anal...Two new Gd Ⅲ complexes with nitrilotriacetic acid(nta) and trans-1,2-cyclohexanediaminetetraacetic acid(Cydta) ligands were synthesized. Their crystal structures were determined by single-crystal X-ray structure analyses. The crystal data are as follows: K 3[Gd Ⅲ(nta) 2·(H 2O)]·6H 2O, monoclinic system, C2/c space group, a=1.534 81(15) nm, b=1.292 05(12) nm, c=2.610 8(3) nm, β=96.244(2)°, V=5.146 7(9) nm 3, Z=8, M=776.87, D c=2.005 g/cm 3, μ= 3.149 mm -1 and \{F(000)=\}3 080, R=0.024 5, wR=0.064 3 for 4 455 unique reflections and R= 0.028 9, wR=0.067 2 for all 10 305 reflections. The Gd ⅢN 2O 7 part in the [Gd Ⅲ(nta) 2(H 2O)] 3- anion is a pseudo-monocapped square antiprismatic nine-coordination structure.(NH 4)[Gd Ⅲ(Cydta)(H 2O) 2]·5H 2O, triclinic system, P1 space group, a=0.866 2(3) nm, b=1.006 7(3) nm, c= 1.444 8(5) nm, α= 88.282(5)°, β=75\^190(5)°, γ=88.317(4)°, V=1.217 2(7) nm 3, Z=2, M=643.69, D c=1.756 g/cm 3, μ=2.798 mm -1 and F(000)=650, R=0.030 3, wR=0.080 9 for 4 273 unique reflections and R=0.033 2, wR=0.082 5 for all 5 062 reflections. The Gd ⅢN 2O 6 part in the [Gd Ⅲ(Cydta)(H 2O) 2] - anion has a pseudo-square antiprismatic eight-coordination structure.展开更多
目的:探讨检测肝癌组织中组蛋白第三亚基四号赖氨酸的三甲基化(H3K4me3)蛋白的表达与肿瘤病理特点和肝癌患者生存预后的相关性。方法:免疫组化和Western-blot检测H3K4me3和组蛋白甲基转移酶(SET and MYND domain-containing protein 3,S...目的:探讨检测肝癌组织中组蛋白第三亚基四号赖氨酸的三甲基化(H3K4me3)蛋白的表达与肿瘤病理特点和肝癌患者生存预后的相关性。方法:免疫组化和Western-blot检测H3K4me3和组蛋白甲基转移酶(SET and MYND domain-containing protein 3,SMYD3)在肝癌组织(n=168)和细胞株中的表达。此外,实验结果还在另外一个肝癌组织芯片(n=147)中进行验证。H3K4me3表达的最佳分界点(optimal cut-point)由X-tile程序确定,患者的预后由Kaplan-meier生存曲线描述。结果:H3K4me3高表达于肝癌细胞系和肝癌组织,其高表达与肝癌尤其是早期TNM1/2期患者的较差总体生存显著相关。单因素和多因素分析均提示H3K4me3表达水平是患者预后的独立危险因素。此外,H3K4me3和SMYD3在两组肝癌组织中均存在正相关表达。结论:H3K4me3表达水平能成为肝癌患者术后生存的预测因子,其高表达可能与SMYD3有关。展开更多
基金We thank Dr Ramin Shiekhattar （Wistar Institute, USA） for the baculoviruses expressing Flag-LSD1 and Drs Jianguo Song and Degui Chen （Shanghai Institute of Biochemistry and Cell Biol- ogy, China） for anti-HDAC1 antibody and H3K36me2 antibody, respectively. This study was partially supported by grants from the National Natural Science Foundation of China （90919025, 30871381）, the Ministry of Science and Technology of China （2009CB918402, 2009CB825601） and the Research Platform for Cell Signaling Networks from the Science and Technology Com- mission of Shanghai Municipality （06DZ22923）.
文摘LSD1 （KDM1 under the new nomenclature） was the first identified lysine-specific histone demethylase belonging to the flavin-dependent amine oxidase family. Here, we report that AOF1 （KDM1B under the new nomenclature）, a mammalian protein related to LSD1, also possesses histone demethylase activity with specificity for H3K4mel and H3K4me2. Like LSD1, the highly conserved SWIRM domain is required for its enzymatic activity. However, AOF1 differs from LSD1 in several aspects. First, AOF1 does not appear to form stable protein complexes containing histone deacetylases. Second, AOF1 is found to localize to chromosomes during the mitotic phase of the cell cycle, whereas LSD1 does not. Third, AOF1 represses transcription when tethered to DNA and this repression activity is independent of its demethylase activity. Structural and functional analyses identified its unique N-terminal Zf-CW domain as essential for the demethylase activity-independent repression function. Collectively, our study identifies AOF1 as the second histone demethylase in the family of flavin-dependent amine oxidases and reveals a demethylase-independent repression function of AOF1.
基金supported by grants from the National Natural Science Foundation of China(81200763 to WG and 81070809 to YZ)the Program for New Century Excellent Talents(NCET)at the University from Ministry of Education of China(NCET-11-0026)+1 种基金the PKU School of Stomatology for Talented Young Investigators(PKUSS20150107)the Construction Program for the National Key Clinical Specialty from the National Health and Family Planning Commission of China(2011)
文摘Bone tissue engineering may be hindered by underlying osteoporosis because of a decreased osteogenic ability of autologous seed cells and an unfavorably changed microenvironment in these patients. Epigenetic regulation plays an important role in the developmental origins of osteoporosis; however, few studies have investigated the potential of epigenetic therapy to improve or rescue the osteogenic ability of bone marrow mesenchymal stem cells(BMMSCs) under osteoporotic conditions. Here, we investigated pargyline, an inhibitor of lysine-specific demethylase 1(LSD1), which mainly catalyzes the demethylation of the di- and mono-methylation of H3K4. We demonstrated that 1.5 mmol·Lpargyline was the optimal concentration for the osteogenic differentiation of human BMMSCs. Pargyline rescued the osteogenic differentiation ability of mouse BMMSCs under osteoporotic conditions by enhancing the dimethylation level of H3K4 at the promoter regions of osteogenesis-related genes. Moreover, pargyline partially rescued or prevented the osteoporotic conditions in aged or ovariectomized mouse models, respectively. By introducing the concept of epigenetic therapy into the field of osteoporosis, this study demonstrated that LSD1 inhibitors could improve the clinical practice of MSC-based bone tissue engineering and proposes their novel use to treat osteoporosis.
文摘ZHOU Bai-Bin *,1,2 WEI Yong-De 1 LI Zhong-Hua 1 ( 1 Department of Applied Chemistry,Ha rbin Institute of Technology ￡?Harbin￡±￡ì￡°￡°￡°￡±￡(c)( 2 Department of Chemistry,Harbin Normal University￡?Harbin￡±￡ì￡°￡°￡?￡°￡(c) The air-solid interface reaction of Ce,Lu with K10 H 3[Gd (SiMo 4 W￡*O￡3￡1￡(c) 2]through chemistry-heated permeation is reported for the fi rst time￡(r)The permeated complex is characterized by ICP and the result shows tha t the mini mum Ce,Lu can permeate into the inner sph ere of K 10 H ￡3 ￡?Gd ￡¨SiMo ￡′ W ￡* O ￡3￡1 ￡(c) 2]The IR ,XRD patterns give the eviden ce that after permeation the comple x still keeps the Keggin structure,howe ver,its crystal structure is different from the complex before permeation￡(r)The cond uctivity of the permeated complex has been measured with the four-electr ode method and the data show that the co nductivity of the complex after permeation is 10 6 times higher than that of the sample before permeation and reaches ￡′￡(r)84 6×10 -1 S·cm -1 ￡(r)These indicate that the permeated c omplex is a good solid electrolyte and further appli cations are also expected￡(r)
文摘Two new Gd Ⅲ complexes with nitrilotriacetic acid(nta) and trans-1,2-cyclohexanediaminetetraacetic acid(Cydta) ligands were synthesized. Their crystal structures were determined by single-crystal X-ray structure analyses. The crystal data are as follows: K 3[Gd Ⅲ(nta) 2·(H 2O)]·6H 2O, monoclinic system, C2/c space group, a=1.534 81(15) nm, b=1.292 05(12) nm, c=2.610 8(3) nm, β=96.244(2)°, V=5.146 7(9) nm 3, Z=8, M=776.87, D c=2.005 g/cm 3, μ= 3.149 mm -1 and \{F(000)=\}3 080, R=0.024 5, wR=0.064 3 for 4 455 unique reflections and R= 0.028 9, wR=0.067 2 for all 10 305 reflections. The Gd ⅢN 2O 7 part in the [Gd Ⅲ(nta) 2(H 2O)] 3- anion is a pseudo-monocapped square antiprismatic nine-coordination structure.(NH 4)[Gd Ⅲ(Cydta)(H 2O) 2]·5H 2O, triclinic system, P1 space group, a=0.866 2(3) nm, b=1.006 7(3) nm, c= 1.444 8(5) nm, α= 88.282(5)°, β=75\^190(5)°, γ=88.317(4)°, V=1.217 2(7) nm 3, Z=2, M=643.69, D c=1.756 g/cm 3, μ=2.798 mm -1 and F(000)=650, R=0.030 3, wR=0.080 9 for 4 273 unique reflections and R=0.033 2, wR=0.082 5 for all 5 062 reflections. The Gd ⅢN 2O 6 part in the [Gd Ⅲ(Cydta)(H 2O) 2] - anion has a pseudo-square antiprismatic eight-coordination structure.
文摘目的:探讨检测肝癌组织中组蛋白第三亚基四号赖氨酸的三甲基化(H3K4me3)蛋白的表达与肿瘤病理特点和肝癌患者生存预后的相关性。方法:免疫组化和Western-blot检测H3K4me3和组蛋白甲基转移酶(SET and MYND domain-containing protein 3,SMYD3)在肝癌组织(n=168)和细胞株中的表达。此外,实验结果还在另外一个肝癌组织芯片(n=147)中进行验证。H3K4me3表达的最佳分界点(optimal cut-point)由X-tile程序确定,患者的预后由Kaplan-meier生存曲线描述。结果:H3K4me3高表达于肝癌细胞系和肝癌组织,其高表达与肝癌尤其是早期TNM1/2期患者的较差总体生存显著相关。单因素和多因素分析均提示H3K4me3表达水平是患者预后的独立危险因素。此外,H3K4me3和SMYD3在两组肝癌组织中均存在正相关表达。结论:H3K4me3表达水平能成为肝癌患者术后生存的预测因子,其高表达可能与SMYD3有关。
