Keloid may induce severe impairment of life quality for the patients,although keloid is a cutaneous benign tumor.Collagen triple helix repeat containing protein 1 (Cthrc1) was identified as a novel gene that was origi...Keloid may induce severe impairment of life quality for the patients,although keloid is a cutaneous benign tumor.Collagen triple helix repeat containing protein 1 (Cthrc1) was identified as a novel gene that was originally found in adventitial fibroblasts after arterial injury.To address the role of Cthrcl in keloid,the expression level of Cthrcl was assessed in normal skin and keloid tissue,as well as in normal fibroblasts (NFs)and keloid fibroblasts (KFs)by using quantitative PCR,Western blotting and immunohistochemical analysis.The results showed that Cthrcl was increased in keloid tissue and KFs as compared with normal skin and NFs.Meanwhile,CCK8 and Transwell assays found the cellular proliferation and migration of KFs were increased as compared with NFs.Further,to verify the function of Cthrcl in NFs and K.Fs,we increased Cthrcl expression by transfecting lentivirns (LV) vectors LV-Cthrcl.The cellular proliferation and migration,collagen synthesis and the influence on TGF-β and YAP signaling were tested.The cellular proliferation and migration were increased in NFs-Cthrcl as compared with NFs-control.Meanwhile,YAP expression and nuclear-location was increased in NFs-Cthrcl.On the contrary,when Cthrcl was overexpressed in KFs,the cellular migration was suppressed and YAP expression was reduced and transferred to cytoplasm in KFs-Cthrcl as compared with KFs-control.But the expression level of collagen I was decreased and pSmad2/3 nucleus transfer was suppressed in both NFs-Cthrc1 and KFs-Cthrc1 by using Western blotting and immunofluorescence.Increased Cthrcl activated NFs by promoting YAP nucleus translocation,whereas suppressed KFs by inhibiting YAP nucleus translocation.Enhanced Cthrcl decreased collagen I in both NFs and KFs by inhibiting TGF-β/Smad pathway.In conclusion,Cthrcl may play a role in the pathogenesis of keloid by inhibiting collagen synthesis and fibroblasts migration via suppressing TGF-β/Smad pathway and YAP nucleus translocation.展开更多
Histone H3 Lys36(H3K36)methylation and its associated modifiers are crucial for DNA double-strand break(DSB)repair,but the mechanism governing whether and how different H3K36 methylation forms impact repair pathways i...Histone H3 Lys36(H3K36)methylation and its associated modifiers are crucial for DNA double-strand break(DSB)repair,but the mechanism governing whether and how different H3K36 methylation forms impact repair pathways is unclear.Here,we unveil the distinct roles of H3K36 dimethylation(H3K36me2)and H3K36 trimethylation(H3K36me3)in DSB repair via non-homologous end joining(NHEJ)or homologous recombination(HR).Yeast cells lacking H3K36me2 or H3K36me3 exhibit reduced NHEJ or HR efficiency.y Ku70 and Rfa1 bind H3K36me2-or H3K36me3-modified peptides and chromatin,respectively.Disrupting these interactions impairs y Ku70 and Rfa1 recruitment to damaged H3K36me2-or H3K36me3-rich loci,increasing DNA damage sensitivity and decreasing repair efficiency.Conversely,H3K36me2-enriched intergenic regions and H3K36me3-enriched gene bodies independently recruit y Ku70 or Rfa1 under DSB stress.Importantly,human KU70 and RPA1,the homologs of y Ku70 and Rfa1,exclusively associate with H3K36me2 and H3K36me3 in a conserved manner.These findings provide valuable insights into how H3K36me2 and H3K36me3 regulate distinct DSB repair pathways,highlighting H3K36 methylation as a critical element in the choice of DSB repair pathway.展开更多
The Tibet ASγexperiment just reported their measurement of sub-PeV diffuse gamma-ray emission from the Galactic disk,with the highest energy up to 957 TeV.These diffuse gamma rays are most likely the hadronic origin ...The Tibet ASγexperiment just reported their measurement of sub-PeV diffuse gamma-ray emission from the Galactic disk,with the highest energy up to 957 TeV.These diffuse gamma rays are most likely the hadronic origin by cosmic ray(CR)interaction with interstellar gas in the galaxy.This measurement provides direct evidence to the hypothesis that the Galactic Cosmic Rays(GCRs)can be accelerated beyond PeV energies.In this work,we try to explain the sub-PeV diffuse gamma-ray spectrum with different CR propagation models.We find that there is a tension between the sub-PeV diffuse gamma-ray and the local CR spectrum.To describe the sub-PeV diffuse gamma-ray flux,it generally requires larger local CR flux than measurement in the knee region.We further calculate the PeV neutrino flux from the CR propagation model.Even all of these sub-PeV diffuse gamma rays originate from the propagation,the Galactic Neutrinos(GNs)only account for less than∼15%of observed flux,most of which are still from extragalactic sources.展开更多
The Tibet ASγexperiment just reported their measurement of sub-PeV diffuse gamma-ray emission from the Galactic disk,with the highest energy up to 957 TeV.These diffuse gamma rays are most likely the hadronic origin ...The Tibet ASγexperiment just reported their measurement of sub-PeV diffuse gamma-ray emission from the Galactic disk,with the highest energy up to 957 TeV.These diffuse gamma rays are most likely the hadronic origin by cosmic ray(CR)interaction with interstellar gas in the galaxy.This measurement provides direct evidence to the hypothesis that the Galactic Cosmic Rays(GCRs)can be accelerated beyond PeV energies.In this work,we try to explain the sub-PeV diffuse gamma-ray spectrum with different CR propagation models.We find that there is a tension between the sub-PeV diffuse gamma-ray and the local CR spectrum.To describe the sub-PeV diffuse gamma-ray flux,it generally requires larger local CR flux than measurement in the knee region.We further calculate the PeV neutrino flux from the CR propagation model.Even all of these sub-PeV diffuse gamma rays originate from the propagation,the Galactic Neutrinos(GNs)only account for less than~15%of observed flux,most of which are still from extragalactic sources.展开更多
The minichromosome maintenance complex(MCM)DNA helicase is an important replicative factor during DNA replication.The proper chromatin loading of MCM is a key step to ensure replication initiation during S phase.Becau...The minichromosome maintenance complex(MCM)DNA helicase is an important replicative factor during DNA replication.The proper chromatin loading of MCM is a key step to ensure replication initiation during S phase.Because replication initiation is regulated by multiple biological cues,additional changes to MCM may provide better understanding towards this event.Here,we report that histidine methyltransferase SETD3 promotes DNA replication in a manner dependent on enzymatic activity.Nascent-strand sequencing(NS-seq)shows that SETD3 regulates replication initiation,as depletion of SETD3 attenuates early replication origins firing.Biochemical studies reveal that SETD3 binds MCM mainly during S phase,which is required for the CDT1-mediated chromatin loading of MCM.This MCM loading relies on histidine-459 methylation(H459me)on MCM7 which is catalyzed by SETD3.Impairment of H459 methylation attenuates DNA synthesis and chromatin loading of MCM.Furthermore,we show that CDK2 phosphorylates SETD3 at Serine-21 during the G1/S phase,which is required for DNA replication and cell cycle progression.These findings demonstrate a novel mechanism by which SETD3 methylates MCM to regulate replication initiation.展开更多
基金This work was supported by the National Natural Science Foundation of China (No.81472886 and No. 81172588).
文摘Keloid may induce severe impairment of life quality for the patients,although keloid is a cutaneous benign tumor.Collagen triple helix repeat containing protein 1 (Cthrc1) was identified as a novel gene that was originally found in adventitial fibroblasts after arterial injury.To address the role of Cthrcl in keloid,the expression level of Cthrcl was assessed in normal skin and keloid tissue,as well as in normal fibroblasts (NFs)and keloid fibroblasts (KFs)by using quantitative PCR,Western blotting and immunohistochemical analysis.The results showed that Cthrcl was increased in keloid tissue and KFs as compared with normal skin and NFs.Meanwhile,CCK8 and Transwell assays found the cellular proliferation and migration of KFs were increased as compared with NFs.Further,to verify the function of Cthrcl in NFs and K.Fs,we increased Cthrcl expression by transfecting lentivirns (LV) vectors LV-Cthrcl.The cellular proliferation and migration,collagen synthesis and the influence on TGF-β and YAP signaling were tested.The cellular proliferation and migration were increased in NFs-Cthrcl as compared with NFs-control.Meanwhile,YAP expression and nuclear-location was increased in NFs-Cthrcl.On the contrary,when Cthrcl was overexpressed in KFs,the cellular migration was suppressed and YAP expression was reduced and transferred to cytoplasm in KFs-Cthrcl as compared with KFs-control.But the expression level of collagen I was decreased and pSmad2/3 nucleus transfer was suppressed in both NFs-Cthrc1 and KFs-Cthrc1 by using Western blotting and immunofluorescence.Increased Cthrcl activated NFs by promoting YAP nucleus translocation,whereas suppressed KFs by inhibiting YAP nucleus translocation.Enhanced Cthrcl decreased collagen I in both NFs and KFs by inhibiting TGF-β/Smad pathway.In conclusion,Cthrcl may play a role in the pathogenesis of keloid by inhibiting collagen synthesis and fibroblasts migration via suppressing TGF-β/Smad pathway and YAP nucleus translocation.
基金supported by the National Key Research and Development Program of China(2019YFA0802501)the National Natural Science Foundation of China(32270617,31971231)+1 种基金the Fundamental Research Funds for the Central Universities(2042022dx0003)the Application Fundamental Frontier Foundation of Wuhan(2020020601012225)。
文摘Histone H3 Lys36(H3K36)methylation and its associated modifiers are crucial for DNA double-strand break(DSB)repair,but the mechanism governing whether and how different H3K36 methylation forms impact repair pathways is unclear.Here,we unveil the distinct roles of H3K36 dimethylation(H3K36me2)and H3K36 trimethylation(H3K36me3)in DSB repair via non-homologous end joining(NHEJ)or homologous recombination(HR).Yeast cells lacking H3K36me2 or H3K36me3 exhibit reduced NHEJ or HR efficiency.y Ku70 and Rfa1 bind H3K36me2-or H3K36me3-modified peptides and chromatin,respectively.Disrupting these interactions impairs y Ku70 and Rfa1 recruitment to damaged H3K36me2-or H3K36me3-rich loci,increasing DNA damage sensitivity and decreasing repair efficiency.Conversely,H3K36me2-enriched intergenic regions and H3K36me3-enriched gene bodies independently recruit y Ku70 or Rfa1 under DSB stress.Importantly,human KU70 and RPA1,the homologs of y Ku70 and Rfa1,exclusively associate with H3K36me2 and H3K36me3 in a conserved manner.These findings provide valuable insights into how H3K36me2 and H3K36me3 regulate distinct DSB repair pathways,highlighting H3K36 methylation as a critical element in the choice of DSB repair pathway.
基金supported by the National Key Research and Development Program of China(No.2016YFA0400200)the National Natural Science Foundation of China(Nos.U1738209,11875264,11635011,U2031110).
文摘The Tibet ASγexperiment just reported their measurement of sub-PeV diffuse gamma-ray emission from the Galactic disk,with the highest energy up to 957 TeV.These diffuse gamma rays are most likely the hadronic origin by cosmic ray(CR)interaction with interstellar gas in the galaxy.This measurement provides direct evidence to the hypothesis that the Galactic Cosmic Rays(GCRs)can be accelerated beyond PeV energies.In this work,we try to explain the sub-PeV diffuse gamma-ray spectrum with different CR propagation models.We find that there is a tension between the sub-PeV diffuse gamma-ray and the local CR spectrum.To describe the sub-PeV diffuse gamma-ray flux,it generally requires larger local CR flux than measurement in the knee region.We further calculate the PeV neutrino flux from the CR propagation model.Even all of these sub-PeV diffuse gamma rays originate from the propagation,the Galactic Neutrinos(GNs)only account for less than∼15%of observed flux,most of which are still from extragalactic sources.
基金supported by the National Key Research and Development Program of China(No.2016YFA0400200)the National Natural Science Foundation of China(Nos.U1738209,11875264,11635011,and U2031110)。
文摘The Tibet ASγexperiment just reported their measurement of sub-PeV diffuse gamma-ray emission from the Galactic disk,with the highest energy up to 957 TeV.These diffuse gamma rays are most likely the hadronic origin by cosmic ray(CR)interaction with interstellar gas in the galaxy.This measurement provides direct evidence to the hypothesis that the Galactic Cosmic Rays(GCRs)can be accelerated beyond PeV energies.In this work,we try to explain the sub-PeV diffuse gamma-ray spectrum with different CR propagation models.We find that there is a tension between the sub-PeV diffuse gamma-ray and the local CR spectrum.To describe the sub-PeV diffuse gamma-ray flux,it generally requires larger local CR flux than measurement in the knee region.We further calculate the PeV neutrino flux from the CR propagation model.Even all of these sub-PeV diffuse gamma rays originate from the propagation,the Galactic Neutrinos(GNs)only account for less than~15%of observed flux,most of which are still from extragalactic sources.
基金supported by the National Key Research and Development program of China(2023YF0913403)the National Natural Science Foundation of China(32200584,31971231)+1 种基金the Fundamental Research Funds for the Central Universities(2042022dx0003,2042022kf1048)the China Postdoctoral Science Foundation(2021M702526).
文摘The minichromosome maintenance complex(MCM)DNA helicase is an important replicative factor during DNA replication.The proper chromatin loading of MCM is a key step to ensure replication initiation during S phase.Because replication initiation is regulated by multiple biological cues,additional changes to MCM may provide better understanding towards this event.Here,we report that histidine methyltransferase SETD3 promotes DNA replication in a manner dependent on enzymatic activity.Nascent-strand sequencing(NS-seq)shows that SETD3 regulates replication initiation,as depletion of SETD3 attenuates early replication origins firing.Biochemical studies reveal that SETD3 binds MCM mainly during S phase,which is required for the CDT1-mediated chromatin loading of MCM.This MCM loading relies on histidine-459 methylation(H459me)on MCM7 which is catalyzed by SETD3.Impairment of H459 methylation attenuates DNA synthesis and chromatin loading of MCM.Furthermore,we show that CDK2 phosphorylates SETD3 at Serine-21 during the G1/S phase,which is required for DNA replication and cell cycle progression.These findings demonstrate a novel mechanism by which SETD3 methylates MCM to regulate replication initiation.
