DNA methylation is a reversible process catalyzed by the ten-eleven translocation(TET)family of enzymes(TET1,TET2,TET3)that convert 5-methylcytosine(5mC)to 5-hydroxymethylcytosine(5hmC).Altered patterns of 5hmC and 5m...DNA methylation is a reversible process catalyzed by the ten-eleven translocation(TET)family of enzymes(TET1,TET2,TET3)that convert 5-methylcytosine(5mC)to 5-hydroxymethylcytosine(5hmC).Altered patterns of 5hmC and 5mC are widely reported in human cancers and loss of 5hmC correlates with poor prognosis.展开更多
As a dioxygenase. Ten-Eleven Translocation 2 （TET2） catalyzes subsequent steps of 5-methylcytosine （5mC） oxidation. TET2 plays a critical role in the self-renewal, proliferation, and differentiation of hei-natopoi...As a dioxygenase. Ten-Eleven Translocation 2 （TET2） catalyzes subsequent steps of 5-methylcytosine （5mC） oxidation. TET2 plays a critical role in the self-renewal, proliferation, and differentiation of hei-natopoietic stem cells, but its impact on mature hematopoietic cells is not well-characterized. Here we show that Tet2 plays an essential role in osteoclastogenesis. Dele- tion of Tet2 impairs the differentiation of osteoclast precursor cells （macrophages） and their matu- ration into bone-resorbing osteoclasts in vitro. Furthermore, Tet2 / mice exhibit mild osteopetrosis, accompanied by decreased number of osteoclasts in vivo. Tet2 loss in macrophages results in the altered expression of a set of genes implicated in osteoclast differentiation, such as Cehpa, Mafb, and Nfkbiz. Tet2 deletion also leads to a genome-wide alteration in the level of 5-hydroxymethylcytosine （ShmC） and altered expression of a specific subset of macrophage genes associated with osteoclast differentiation. Furthermore, Tet2 interacts with Runxl and negatively modulates its transcriptional activity. Our studies demonstrate a novel molecular mechanism controlling osteoclast differentiation and function by Tet2, that is, through interactions with Runxl and the maintenance of genomie 5hmC. Targeting Tet2 and its pathway could be a potential therapeutic strategy for the prevention and t,＇eatment of abnormal bone mass caused by the deregulation of osteoclast activities.展开更多
Conversion of 5-methylcytosine(5mC)to 5-hydroxymethylcytosine(5hmC)by ten-eleven translocation(TET)family proteins leads to the accumulation of 5hmC in the central nervous system;however,the role of 5hmC in the postna...Conversion of 5-methylcytosine(5mC)to 5-hydroxymethylcytosine(5hmC)by ten-eleven translocation(TET)family proteins leads to the accumulation of 5hmC in the central nervous system;however,the role of 5hmC in the postnatal brain and how its levels and target genes are regulated by TETs remain elusive.We have generated mice that lack all three Tet genes specifically in postnatal excitatory neurons.These mice exhibit significantly reduced 5hmC levels,altered dendritic spine morphology within brain regions crucial for cognition,and substantially impaired spatial and associative memories.Transcriptome profiling combined with epigenetic mapping reveals that a subset of genes,which display changes in both 5hmC/5mC levels and expression patterns,are involved in synapse-related functions.Our findings provide insight into the role of postnatally accumulated 5hmC in the mouse brain and underscore the impact of 5hmC modification on the expression of genes essential for synapse development and function.展开更多
文摘DNA methylation is a reversible process catalyzed by the ten-eleven translocation(TET)family of enzymes(TET1,TET2,TET3)that convert 5-methylcytosine(5mC)to 5-hydroxymethylcytosine(5hmC).Altered patterns of 5hmC and 5mC are widely reported in human cancers and loss of 5hmC correlates with poor prognosis.
基金supported by grants from the National Institutes of Health (Grant No. CA172408 to MX and FCY, Grant No. HL112294 to MX)the Leukemia & Lymphoma Society (LLS) (SCOR program to SN, FCY, and MX+7 种基金 translational grant to SN)University of Miami Sylvester Comprehensive Cancer Center (SCCC to MX and FCY), the United Statessupported by the Ministry of Science and Technology of China (Grant Nos. 2017YFA0103402to WY)National Natural Science Foundation of China (Grant Nos. 81629001 to MX, 81670102 to ZZ, 81600136 to YC, and 81421002 to WY)CAMS Innovation Fund for Medical Sciences (Grant Nos. 2017-I2M-3-015 to WY and 2016-I2M-1-017 to YC)Tianjin Application Foundation and Advanced Technology Research Program (Grant Nos. 16JCYBJC25200 to ZZ and 17JCQNJC09800 to YC)SKLEH-Pilot Research Grand (Grant No. ZK16-3 to ZZ)Peking Union Medical College Youth Fund (Grant No. 3332016092 to YC), China
文摘As a dioxygenase. Ten-Eleven Translocation 2 （TET2） catalyzes subsequent steps of 5-methylcytosine （5mC） oxidation. TET2 plays a critical role in the self-renewal, proliferation, and differentiation of hei-natopoietic stem cells, but its impact on mature hematopoietic cells is not well-characterized. Here we show that Tet2 plays an essential role in osteoclastogenesis. Dele- tion of Tet2 impairs the differentiation of osteoclast precursor cells （macrophages） and their matu- ration into bone-resorbing osteoclasts in vitro. Furthermore, Tet2 / mice exhibit mild osteopetrosis, accompanied by decreased number of osteoclasts in vivo. Tet2 loss in macrophages results in the altered expression of a set of genes implicated in osteoclast differentiation, such as Cehpa, Mafb, and Nfkbiz. Tet2 deletion also leads to a genome-wide alteration in the level of 5-hydroxymethylcytosine （ShmC） and altered expression of a specific subset of macrophage genes associated with osteoclast differentiation. Furthermore, Tet2 interacts with Runxl and negatively modulates its transcriptional activity. Our studies demonstrate a novel molecular mechanism controlling osteoclast differentiation and function by Tet2, that is, through interactions with Runxl and the maintenance of genomie 5hmC. Targeting Tet2 and its pathway could be a potential therapeutic strategy for the prevention and t,＇eatment of abnormal bone mass caused by the deregulation of osteoclast activities.
基金supported by the Shanghai Sailing Program(20YF1442200)the Natural Science Foundation of Shanghai(21ZR1455200)+1 种基金the STI2030-Major Project(2022ZD0214200)the National Natural Science Foundation of China(32371075),and the Shanghai Pujiang Program(22PJ1412300).
文摘Conversion of 5-methylcytosine(5mC)to 5-hydroxymethylcytosine(5hmC)by ten-eleven translocation(TET)family proteins leads to the accumulation of 5hmC in the central nervous system;however,the role of 5hmC in the postnatal brain and how its levels and target genes are regulated by TETs remain elusive.We have generated mice that lack all three Tet genes specifically in postnatal excitatory neurons.These mice exhibit significantly reduced 5hmC levels,altered dendritic spine morphology within brain regions crucial for cognition,and substantially impaired spatial and associative memories.Transcriptome profiling combined with epigenetic mapping reveals that a subset of genes,which display changes in both 5hmC/5mC levels and expression patterns,are involved in synapse-related functions.Our findings provide insight into the role of postnatally accumulated 5hmC in the mouse brain and underscore the impact of 5hmC modification on the expression of genes essential for synapse development and function.
