The scope and variety of the metabolic intermediates from the mitochondrial tricarboxylic acid(TCA)cycle that are engaged in epigenetic regulation of the chromatin function in the nucleus raise an outstanding question...The scope and variety of the metabolic intermediates from the mitochondrial tricarboxylic acid(TCA)cycle that are engaged in epigenetic regulation of the chromatin function in the nucleus raise an outstanding question about how timely and precise supply/consumption of these metabolites is achieved in the nucleus.We report here the identification of a nonclassical TCA cycle in the nucleus(nTCA cycle).We found that all the TCA cycle-associated enzymes including citrate synthase(CS),aconitase 2(ACO2),isocitrate dehydrogenase 3(IDH3),oxoglutarate dehydrogenase(OGDH),succinyl-CoA synthetase(SCS),fumarate hydratase(FH),and malate dehydrogenase 2(MDH2),except for succinate dehydrogenase(SDH),a component of electron transport chain for generating ATP,exist in the nucleus.We showed that these nuclear enzymes catalyze an incomplete TCA cycle similar to that found in cyanobacteria.We propose that the nTCA cycle is implemented mainly to generate/consume metabolic intermediates,not for energy production.We demonstrated that the nTCA cycle is intrinsically linked to chromatin dynamics and transcription regulation.Together,our study uncovers the existence of a nonclassical TCA cycle in the nucleus that links the metabolic pathway to epigenetic regulation.展开更多
Faithful transmission or restoration of epigenetic information such as repressive histone modifications through generations is crit- ical for the maintenance of cell identity. We report here that chromodomain Y-like p...Faithful transmission or restoration of epigenetic information such as repressive histone modifications through generations is crit- ical for the maintenance of cell identity. We report here that chromodomain Y-like protein （CDYL）, a chromodomain-containing transcription corepressor, is physically associated with chromatin assembly factor 1 （CAF-1） and the repiicative heUcase MCM complex. We showed that CDYL bridges CAF-1 and MCM, facilitating histone transfer and deposition during DNA replication. We demonstrated that CDYI. recruits histone-modifying enzymes G9a, SETDB1, and EZH2 to replication forks, leading to the addition of H3Kgme2/3 and H3K27me2/3 on newly deposited histone H3. Significantly, depletion of CDYL impedes early S phase progres- sion and sensitizes cells to DNA damage. Our data indicate that CDYL plays an important role in the transmission/restoration of repressive histone marks, thereby preserving the epigenetic landscape for the maintenance of cell identity.展开更多
基金This work was supported by a grant(2016YFC1302304 to Y.S.)from the Ministry of Science and Technology of Chinaa grant(Z200020 to L.S.)from the Natural Science Foundation of Beijing+1 种基金a grant(QNBJ2020-2 to L.S.)from National Program for Support of Top-notch Young Professionalsgrants(81530073 and 81730079 to Y.S.,31571340 and 81874158 to L.S.,81972659 to W.S.)from the National Natural Science Foundation of China.
文摘The scope and variety of the metabolic intermediates from the mitochondrial tricarboxylic acid(TCA)cycle that are engaged in epigenetic regulation of the chromatin function in the nucleus raise an outstanding question about how timely and precise supply/consumption of these metabolites is achieved in the nucleus.We report here the identification of a nonclassical TCA cycle in the nucleus(nTCA cycle).We found that all the TCA cycle-associated enzymes including citrate synthase(CS),aconitase 2(ACO2),isocitrate dehydrogenase 3(IDH3),oxoglutarate dehydrogenase(OGDH),succinyl-CoA synthetase(SCS),fumarate hydratase(FH),and malate dehydrogenase 2(MDH2),except for succinate dehydrogenase(SDH),a component of electron transport chain for generating ATP,exist in the nucleus.We showed that these nuclear enzymes catalyze an incomplete TCA cycle similar to that found in cyanobacteria.We propose that the nTCA cycle is implemented mainly to generate/consume metabolic intermediates,not for energy production.We demonstrated that the nTCA cycle is intrinsically linked to chromatin dynamics and transcription regulation.Together,our study uncovers the existence of a nonclassical TCA cycle in the nucleus that links the metabolic pathway to epigenetic regulation.
文摘Faithful transmission or restoration of epigenetic information such as repressive histone modifications through generations is crit- ical for the maintenance of cell identity. We report here that chromodomain Y-like protein （CDYL）, a chromodomain-containing transcription corepressor, is physically associated with chromatin assembly factor 1 （CAF-1） and the repiicative heUcase MCM complex. We showed that CDYL bridges CAF-1 and MCM, facilitating histone transfer and deposition during DNA replication. We demonstrated that CDYI. recruits histone-modifying enzymes G9a, SETDB1, and EZH2 to replication forks, leading to the addition of H3Kgme2/3 and H3K27me2/3 on newly deposited histone H3. Significantly, depletion of CDYL impedes early S phase progres- sion and sensitizes cells to DNA damage. Our data indicate that CDYL plays an important role in the transmission/restoration of repressive histone marks, thereby preserving the epigenetic landscape for the maintenance of cell identity.
