Cells need to coordinate gene expression with their metabolic states to maintain cell homeostasis and growth.However,how cells transduce nutrient availability to appropriate gene expression response via histone modifi...Cells need to coordinate gene expression with their metabolic states to maintain cell homeostasis and growth.However,how cells transduce nutrient availability to appropriate gene expression response via histone modifications remains largely unknown.Here,we report that glucose specifically induces histone H3K4 trimethylation(H3K4me3),an evolutionarily conserved histone covalent modification associated with active gene transcription,and that glycolytic enzymes and metabolites are required for this in?duction.Although glycolysis supplies S-adenosylmethionine for histone methyltransferase Setl to catalyze H3K4me3,glucose induces H3K4me3 primarily by inhibiting histone demethylase Jhd2-catalyzed H3K4 demethylation.Glycolysis provides acetyl-CoA to stimulate histone acetyltransferase Gcn5 to acetylate H3K14,which then inhibits the binding of Jhd2 to chromatin to increase H3K4me3.By repressing Jhd2-mediated H3K4 demethylation,glycolytic enzymes regulate gene expression and cell survival during chronological aging.Thus,our results elucidate how cells reprogram their gene expression programs in response to glucose availability via histone modifications.展开更多
Despite therapy with potent antiviral agents,chronic hepatitis B(CHB)patients remain at high risk of hepatocellular carcinoma(HCC).While metabolites have been rediscovered as active drivers of biological processes inc...Despite therapy with potent antiviral agents,chronic hepatitis B(CHB)patients remain at high risk of hepatocellular carcinoma(HCC).While metabolites have been rediscovered as active drivers of biological processes including carcinogenesis,the specific metabolites modulating HCC risk in CHB patients are largely unknown.Here,we demonstrate that baseline plasma from CHB patients who later developed HCC during follow-up exhibits growth-promoting properties in a case-control design nested within a large-scale,prospective cohort.Metabolomics analysis reveals a reduction in long-chain acylcarnitines(LCACs)in the baseline plasma of patients with HCC development.LCACs preferentially inhibit the proliferation of HCC cells in vitro at a physiological concentration and prevent the occurrence of HCC in vivo without hepatorenal toxicity.Uptake and metabolism of circulating LCACs increase the intracellular level of acetyl coenzyme A,which upregulates histone H3 Lys14 acetylation at the promoter region of KLF6 gene and thereby activates KLF6/p21 pathway.Indeed,blocking LCAC metabolism attenuates the difference in KLF6/p21 expression induced by baseline plasma of HCC/non-HCC patients.The deficiency of circulating LCACs represents a driver of HCC in CHB patients with viral control.These insights provide a promising direction for developing therapeutic strategies to reduce HCC risk further in the antiviral era.展开更多
基金supported by grants from the National Natural Science Foundation of China(31970578,31872812,31671335,and 31600046)the Natural Science Foundation of Hubei Province(2017CFA066).
文摘Cells need to coordinate gene expression with their metabolic states to maintain cell homeostasis and growth.However,how cells transduce nutrient availability to appropriate gene expression response via histone modifications remains largely unknown.Here,we report that glucose specifically induces histone H3K4 trimethylation(H3K4me3),an evolutionarily conserved histone covalent modification associated with active gene transcription,and that glycolytic enzymes and metabolites are required for this in?duction.Although glycolysis supplies S-adenosylmethionine for histone methyltransferase Setl to catalyze H3K4me3,glucose induces H3K4me3 primarily by inhibiting histone demethylase Jhd2-catalyzed H3K4 demethylation.Glycolysis provides acetyl-CoA to stimulate histone acetyltransferase Gcn5 to acetylate H3K14,which then inhibits the binding of Jhd2 to chromatin to increase H3K4me3.By repressing Jhd2-mediated H3K4 demethylation,glycolytic enzymes regulate gene expression and cell survival during chronological aging.Thus,our results elucidate how cells reprogram their gene expression programs in response to glucose availability via histone modifications.
基金supported by National Key Research and Development Program of China(2022YFC2304800)National Natural Science Foundation of China(U22A20274 and 82203305)+1 种基金Guangdong Basic and Applied Basic Research Foundation of Guangzhou Joint Fund(2022B1515120039,China)Science and Technology Projects in Guangzhou(2024B03J0326,China).
文摘Despite therapy with potent antiviral agents,chronic hepatitis B(CHB)patients remain at high risk of hepatocellular carcinoma(HCC).While metabolites have been rediscovered as active drivers of biological processes including carcinogenesis,the specific metabolites modulating HCC risk in CHB patients are largely unknown.Here,we demonstrate that baseline plasma from CHB patients who later developed HCC during follow-up exhibits growth-promoting properties in a case-control design nested within a large-scale,prospective cohort.Metabolomics analysis reveals a reduction in long-chain acylcarnitines(LCACs)in the baseline plasma of patients with HCC development.LCACs preferentially inhibit the proliferation of HCC cells in vitro at a physiological concentration and prevent the occurrence of HCC in vivo without hepatorenal toxicity.Uptake and metabolism of circulating LCACs increase the intracellular level of acetyl coenzyme A,which upregulates histone H3 Lys14 acetylation at the promoter region of KLF6 gene and thereby activates KLF6/p21 pathway.Indeed,blocking LCAC metabolism attenuates the difference in KLF6/p21 expression induced by baseline plasma of HCC/non-HCC patients.The deficiency of circulating LCACs represents a driver of HCC in CHB patients with viral control.These insights provide a promising direction for developing therapeutic strategies to reduce HCC risk further in the antiviral era.
