Summary Epigenetic gene variants, termed epialleles, can broaden genetic and phenotypic diversity in eukaryotes. Here, we identify a natural epiallele of OsAK1, which encodes a rice adenylate kinase. The Epiak1 plants...Summary Epigenetic gene variants, termed epialleles, can broaden genetic and phenotypic diversity in eukaryotes. Here, we identify a natural epiallele of OsAK1, which encodes a rice adenylate kinase. The Epiak1 plants show albino in young leaf and panicle with abnormal chloroplast structures.展开更多
Polycomb group(Pc G)proteins are crucial chromatin regulators during development.H2 AK119 ub1(H2 Aub)and H3 K27 me3 are catalyzed by Polycomb-repressive complex 1 and 2(PRC1/2)respectively,and they largely overlap in ...Polycomb group(Pc G)proteins are crucial chromatin regulators during development.H2 AK119 ub1(H2 Aub)and H3 K27 me3 are catalyzed by Polycomb-repressive complex 1 and 2(PRC1/2)respectively,and they largely overlap in the genome due to mutual recruitment of the two complexes.However,it is unclear whether PRC1/H2 Aub and PRC2/H3 K27 me3 can also function independently.By developing an ultra-sensitive carrier-DNA-assisted chromatin immunoprecipitation sequencing method termed CATCH-Seq,we generated allelic H2 Aub profiles in mouse gametes and early embryos.Our results revealed an unexpected genomewide decoupling of H2 Aub and H3 K27 me3 in mouse preimplantation embryos,where H2 Aub but not H3 K27 me3 was enriched at Pc G targets while only H3 K27 me3 was deposited in the broad distal domains associated with DNA methylation-independent non-canonical imprinting.These observations suggest that H2 Aub represses future bivalent genes during early embryogenesis without H3 K27 me3,but it is not required for the maintenance of non-canonical imprinting,which is mediated by maternal H3 K27 me3.Thus,our study reveals the distinct depositions and independent functions of H2 Aub and H3 K27 me3 during early mammalian development.展开更多
Epigenetic regulation has been attracting increasing attention due to its role in cell differentiation and behaviors.However,the epigenetic mechanisms that regulate human dendritic cell(DC)differentiation and developm...Epigenetic regulation has been attracting increasing attention due to its role in cell differentiation and behaviors.However,the epigenetic mechanisms that regulate human dendritic cell(DC)differentiation and development remain poorly understood.Our previous studies show that extracellular heat shock protein 70-like protein(HSP70L1)is a potent adjuvant of Th1 responses via stimulating DCs when released from cells;however,the role of intracellular HSP70L1 in DC differentiation and maturation remains unknown.Herein,we demonstrate that intracellular HSP70L1 inhibits human DC maturation by suppressing MHC and costimulatory molecule expression,in contrast to the adjuvant activity of extracellular HSP70L1.The stability of intracellular HSP70L1 is dependent on DNAJC2,a known epigenetic regulator.Mechanistically,intracellular HSP70L1 inhibits the recruitment of Ash1l to and maintains the repressive H3K27me3 and H2AK119Ub1 modifications on the promoter regions of costimulatory,MHC and STAT3 genes.Thus,intracellular HSP70L1 is an inhibitor of human DC maturation.Our results provide new insights into the epigenetic regulation of cell development by intracellular HSP70L1.展开更多
Background: LncRNA AK044604(regulator of insulin sensitivity and autophagy, Risa) and autophagy-related factors Sirt1 and GSK3β play important roles in diabetic nephropathy(DN). In this study, we sought to explore th...Background: LncRNA AK044604(regulator of insulin sensitivity and autophagy, Risa) and autophagy-related factors Sirt1 and GSK3β play important roles in diabetic nephropathy(DN). In this study, we sought to explore the effect of Risa on Sirt1/GSK3β-induced podocyte injury.Methods: Diabetic db/db mice received Risa-inhibition adeno-associated virus(AAV) via tail vein injection, and intraperitoneal injection of lithium chloride(LiCl). Blood, urine, and kidney tissue samples were collected and analyzed at different time points. Immortalized mouse podocyte cells(MPCs) were cultured and treated with Risa-inhibition lentivirus(LV), EX-527, and LiCl. MPCs were collected under different stimulations as noted. The effects of Risa on podocyte autophagy were examined by qRT-PCR, Western blotting analysis, transmission electron microscopy,Periodic Acid-Schiff staining, and immunofluorescence staining.Results: Risa and activated GSK3β were overexpressed, but Sirt1 was downregulated in DN mice and high glucosetreated MPCs(P<0.001, db/m vs. db/db, NG or HM vs. HG), which was correlated with poor prognosis. Risa overexpression attenuated Sirt1-mediated downstream autophagy levels and aggravated podocyte injury by inhibiting the expression of Sirt1(P<0.001, db/m vs. db/db, NG or HM vs. HG). In contrast, Risa suppression enhanced Sirt1-induced autophagy and attenuated podocyte injury, which could be abrogated by EX-527(P<0.001, db/db+Risa-AAV vs. db/db, HG+Risa-LV vs. HG). Furthermore, LiCl treatment could restore GSK3β-mediated autophagy of podocytes(P<0.001, db/db+LiCl vs. db/db, HG+LiCl vs. HG), suggesting that Risa overexpression aggravated podocyte injury by decreasing autophagy.Conclusions: Risa could inhibit autophagy by regulating the Sirt1/GSK3β axis, thereby aggravating podocyte injury in DN. Risa may serve as a therapeutic target for the treatment of DN.展开更多
基金supported by Genetically Modified Breeding Major Projects (grant no.2016ZX08009001005 to X.Song)The National Key Research Program of China (2016YFD0100904 to X.Cao)+1 种基金the National Natural Science Foundation of China (No.31161140348 to P.Hu, 31521064 to S.Tang and 31300987 to X.Song)the State Key Laboratory of Plant Genomics
文摘Summary Epigenetic gene variants, termed epialleles, can broaden genetic and phenotypic diversity in eukaryotes. Here, we identify a natural epiallele of OsAK1, which encodes a rice adenylate kinase. The Epiak1 plants show albino in young leaf and panicle with abnormal chloroplast structures.
基金supported by the National Natural Science Foundation of China(32022023 and 31871478)the National Key Research and Development Programs of China(2017YFC1001500)Zhejiang Provincial Natural Science Foundation of China(LR18C060001)。
文摘Polycomb group(Pc G)proteins are crucial chromatin regulators during development.H2 AK119 ub1(H2 Aub)and H3 K27 me3 are catalyzed by Polycomb-repressive complex 1 and 2(PRC1/2)respectively,and they largely overlap in the genome due to mutual recruitment of the two complexes.However,it is unclear whether PRC1/H2 Aub and PRC2/H3 K27 me3 can also function independently.By developing an ultra-sensitive carrier-DNA-assisted chromatin immunoprecipitation sequencing method termed CATCH-Seq,we generated allelic H2 Aub profiles in mouse gametes and early embryos.Our results revealed an unexpected genomewide decoupling of H2 Aub and H3 K27 me3 in mouse preimplantation embryos,where H2 Aub but not H3 K27 me3 was enriched at Pc G targets while only H3 K27 me3 was deposited in the broad distal domains associated with DNA methylation-independent non-canonical imprinting.These observations suggest that H2 Aub represses future bivalent genes during early embryogenesis without H3 K27 me3,but it is not required for the maintenance of non-canonical imprinting,which is mediated by maternal H3 K27 me3.Thus,our study reveals the distinct depositions and independent functions of H2 Aub and H3 K27 me3 during early mammalian development.
基金We thank Yanfeng Li for the technical assistance.This work was supported by grants from the National Key R&D Program of China(2018YFA0507401)the National Natural Science Foundation of China(31670875 and 31470858).
文摘Epigenetic regulation has been attracting increasing attention due to its role in cell differentiation and behaviors.However,the epigenetic mechanisms that regulate human dendritic cell(DC)differentiation and development remain poorly understood.Our previous studies show that extracellular heat shock protein 70-like protein(HSP70L1)is a potent adjuvant of Th1 responses via stimulating DCs when released from cells;however,the role of intracellular HSP70L1 in DC differentiation and maturation remains unknown.Herein,we demonstrate that intracellular HSP70L1 inhibits human DC maturation by suppressing MHC and costimulatory molecule expression,in contrast to the adjuvant activity of extracellular HSP70L1.The stability of intracellular HSP70L1 is dependent on DNAJC2,a known epigenetic regulator.Mechanistically,intracellular HSP70L1 inhibits the recruitment of Ash1l to and maintains the repressive H3K27me3 and H2AK119Ub1 modifications on the promoter regions of costimulatory,MHC and STAT3 genes.Thus,intracellular HSP70L1 is an inhibitor of human DC maturation.Our results provide new insights into the epigenetic regulation of cell development by intracellular HSP70L1.
基金supported by grants from the Joint construction project of Henan Province(SB201901015)the General Program of the National Natural Science Foundation of China General Project(81970633)+2 种基金the Major public welfare special projects in Henan Province(201300310600)the National Natural Science Young Scientists Foundation of China(81800648)the Excellent Young Scientists Fund Program of the Natural Science Foundation of Henan Province(202300410363)。
文摘Background: LncRNA AK044604(regulator of insulin sensitivity and autophagy, Risa) and autophagy-related factors Sirt1 and GSK3β play important roles in diabetic nephropathy(DN). In this study, we sought to explore the effect of Risa on Sirt1/GSK3β-induced podocyte injury.Methods: Diabetic db/db mice received Risa-inhibition adeno-associated virus(AAV) via tail vein injection, and intraperitoneal injection of lithium chloride(LiCl). Blood, urine, and kidney tissue samples were collected and analyzed at different time points. Immortalized mouse podocyte cells(MPCs) were cultured and treated with Risa-inhibition lentivirus(LV), EX-527, and LiCl. MPCs were collected under different stimulations as noted. The effects of Risa on podocyte autophagy were examined by qRT-PCR, Western blotting analysis, transmission electron microscopy,Periodic Acid-Schiff staining, and immunofluorescence staining.Results: Risa and activated GSK3β were overexpressed, but Sirt1 was downregulated in DN mice and high glucosetreated MPCs(P<0.001, db/m vs. db/db, NG or HM vs. HG), which was correlated with poor prognosis. Risa overexpression attenuated Sirt1-mediated downstream autophagy levels and aggravated podocyte injury by inhibiting the expression of Sirt1(P<0.001, db/m vs. db/db, NG or HM vs. HG). In contrast, Risa suppression enhanced Sirt1-induced autophagy and attenuated podocyte injury, which could be abrogated by EX-527(P<0.001, db/db+Risa-AAV vs. db/db, HG+Risa-LV vs. HG). Furthermore, LiCl treatment could restore GSK3β-mediated autophagy of podocytes(P<0.001, db/db+LiCl vs. db/db, HG+LiCl vs. HG), suggesting that Risa overexpression aggravated podocyte injury by decreasing autophagy.Conclusions: Risa could inhibit autophagy by regulating the Sirt1/GSK3β axis, thereby aggravating podocyte injury in DN. Risa may serve as a therapeutic target for the treatment of DN.
