Histone H2A monoubiquitination is associated with transcriptional repression and needs to be removed by deubiquitinases to facilitate gene transcription in eukaryotes.However,the deubiquitinase responsible for genome-...Histone H2A monoubiquitination is associated with transcriptional repression and needs to be removed by deubiquitinases to facilitate gene transcription in eukaryotes.However,the deubiquitinase responsible for genome-wide H2A deubiquitination in plants has yet to be identified.In this study,we found that the previously identified PWWP-EPCR-ARID-TRB(PEAT)complex components interact with both the ubiquitin-specific protease UBP5 and the redundant histone acetyltransferases HAM1 and HAM2(HAM1/2)to form a larger version of PEAT complex in Arabidopsis thaliana.UBP5 functions as an H2A deubiquitinase in a nucleosome substrate-dependent manner in vitro and mediates H2A deubiquitination at the whole-genome level in vivo.HAM1/2 are shared subunits of the PEAT complex and the conserved NuA4 histone acetyltransferase com-plex,and are responsible for histone H4K5 acetylation.Within the PEAT complex,the PWWP components(PWWP1,PWWP2,and PWWP3)directly interact with UBP5 and are necessary for UBP5-mediated H2A deu-biquitination,while the EPCR components(EPCR1 and EPCR2)directly interact with HAM1/2 and are required for HAM1/2-mediated H4K5acetylation.Collectively,our study not onlyidentifies dual roles of thePEAT com-plex in H2A deubiquitination and H4K5 acetylation but also illustrates how these processes collaborate at the whole-genome level to regulate the transcription and development in plants.展开更多
Neuroblastoma(NB)is the most common extracranial solid tumor in children.Despite treatment advances,the survival rates of high-risk NB patients remain low.This highlights the urgent need for a deeper understanding of ...Neuroblastoma(NB)is the most common extracranial solid tumor in children.Despite treatment advances,the survival rates of high-risk NB patients remain low.This highlights the urgent need for a deeper understanding of the molecular mechanisms driving NB progression to support the development of new therapeutic strategies.In this study,we demonstrated that the reduced levels of DNAJC12,a protein involved in metabolic regulation,are associated with poor prognosis in NB patients.Our data indicate that low DNAJC12 expression activates glycolysis in NB cells,leading to increased lactic acid production and histone H4 lysine 5 lactylation(H4K5la).Elevated H4K5la upregulates the transcription of COL1A1,a gene implicated in cell metastasis.Immunohistochemistry staining of NB patient samples confirmed that high H4K5la levels correlate with poor clinical outcomes.Furthermore,we showed that inhibiting glycolysis,reducing H4K5la,or targeting COL1A1 can mitigate the invasive behavior of NB cells.These findings reveal a critical link between metabolic reprogramming and epigenetic modifications in the context of NB progression,suggesting that H4K5la could serve as a novel diagnostic and prognostic marker,and shed light on identifying new therapeutic targets within metabolic pathways for the treatment of this aggressive pediatric cancer.展开更多
基金supported by the National Natural Science Foundation of China(grant number:32025003).
文摘Histone H2A monoubiquitination is associated with transcriptional repression and needs to be removed by deubiquitinases to facilitate gene transcription in eukaryotes.However,the deubiquitinase responsible for genome-wide H2A deubiquitination in plants has yet to be identified.In this study,we found that the previously identified PWWP-EPCR-ARID-TRB(PEAT)complex components interact with both the ubiquitin-specific protease UBP5 and the redundant histone acetyltransferases HAM1 and HAM2(HAM1/2)to form a larger version of PEAT complex in Arabidopsis thaliana.UBP5 functions as an H2A deubiquitinase in a nucleosome substrate-dependent manner in vitro and mediates H2A deubiquitination at the whole-genome level in vivo.HAM1/2 are shared subunits of the PEAT complex and the conserved NuA4 histone acetyltransferase com-plex,and are responsible for histone H4K5 acetylation.Within the PEAT complex,the PWWP components(PWWP1,PWWP2,and PWWP3)directly interact with UBP5 and are necessary for UBP5-mediated H2A deu-biquitination,while the EPCR components(EPCR1 and EPCR2)directly interact with HAM1/2 and are required for HAM1/2-mediated H4K5acetylation.Collectively,our study not onlyidentifies dual roles of thePEAT com-plex in H2A deubiquitination and H4K5 acetylation but also illustrates how these processes collaborate at the whole-genome level to regulate the transcription and development in plants.
基金supported by grants from the Fun-damental Research Funds for the Central Universities(YG2022ZD021)the Natural Science Foundation of Shanghai(22ZR1440200 and 23410760900)+1 种基金the Science and Technology Development Fund of Shanghai Pudong New Area(PKJ2022-Y01 and PKJ2022-Y03)the Science and Technology Commission of Shanghai Municipality(202140143).
文摘Neuroblastoma(NB)is the most common extracranial solid tumor in children.Despite treatment advances,the survival rates of high-risk NB patients remain low.This highlights the urgent need for a deeper understanding of the molecular mechanisms driving NB progression to support the development of new therapeutic strategies.In this study,we demonstrated that the reduced levels of DNAJC12,a protein involved in metabolic regulation,are associated with poor prognosis in NB patients.Our data indicate that low DNAJC12 expression activates glycolysis in NB cells,leading to increased lactic acid production and histone H4 lysine 5 lactylation(H4K5la).Elevated H4K5la upregulates the transcription of COL1A1,a gene implicated in cell metastasis.Immunohistochemistry staining of NB patient samples confirmed that high H4K5la levels correlate with poor clinical outcomes.Furthermore,we showed that inhibiting glycolysis,reducing H4K5la,or targeting COL1A1 can mitigate the invasive behavior of NB cells.These findings reveal a critical link between metabolic reprogramming and epigenetic modifications in the context of NB progression,suggesting that H4K5la could serve as a novel diagnostic and prognostic marker,and shed light on identifying new therapeutic targets within metabolic pathways for the treatment of this aggressive pediatric cancer.
