Recent studies have suggested that abnormal acidification of lysosomes induces autophagic accumulation of amyloid-βin neurons,which is a key step in senile plaque formation.Therefore,resto ring normal lysosomal funct...Recent studies have suggested that abnormal acidification of lysosomes induces autophagic accumulation of amyloid-βin neurons,which is a key step in senile plaque formation.Therefore,resto ring normal lysosomal function and rebalancing lysosomal acidification in neurons in the brain may be a new treatment strategy for Alzheimer's disease.Microtubule acetylation/deacetylation plays a central role in lysosomal acidification.Here,we show that inhibiting the classic microtubule deacetylase histone deacetylase 6 with an histone deacetylase 6 shRNA or thehistone deacetylase 6 inhibitor valproic acid promoted lysosomal reacidification by modulating V-ATPase assembly in Alzheimer's disease.Fu rthermore,we found that treatment with valproic acid markedly enhanced autophagy.promoted clearance of amyloid-βaggregates,and ameliorated cognitive deficits in a mouse model of Alzheimer's disease.Our findings demonstrate a previously unknown neuroprotective mechanism in Alzheimer's disease,in which histone deacetylase 6 inhibition by valproic acid increases V-ATPase assembly and lysosomal acidification.展开更多
Background: SIRT1 histone deacetylase acts on many epigenetic and non-epigenetic targets. It is thought that SIRT1 is involved in oocyte maturation;therefore, the importance of the ooplasmic SIRT1 pool for the further...Background: SIRT1 histone deacetylase acts on many epigenetic and non-epigenetic targets. It is thought that SIRT1 is involved in oocyte maturation;therefore, the importance of the ooplasmic SIRT1 pool for the further fate of mature oocytes has been strongly suggested. We hypothesised that SIRT1 plays the role of a signalling molecule in mature oocytes through selected epigenetic and non-epigenetic regulation.Results: We observed SIRT1 re-localisation in mature oocytes and its association with spindle microtubules.In mature oocytes, SIRT1 distribution shows a spindle-like pattern, and spindle-specific SIRT1 action decreasesα-tubulin acetylation. Based on the observation of the histone code in immature and mature oocytes, we suggest that SIRT1 is mostly predestined for an epigenetic mode of action in the germinal vesicles(GVs) of immature oocytes. Accordingly, BML-278-driven trimethylation of lysine K9 in histone H3 in mature oocytes is considered to be a result of GV epigenetic transformation.Conclusions: Taken together, our observations point out the dual spatiotemporal SIRT1 action in oocytes,which can be readily switched from the epigenetic to non-epigenetic mode of action depending on the progress of meiosis.展开更多
The HIV-1 LTR controls the expression of HIV-1 viral genes and thus is critical for viral propagation and pathology. Numerous host factors have been shown to participate in the regulation of the LTR promoter. Among th...The HIV-1 LTR controls the expression of HIV-1 viral genes and thus is critical for viral propagation and pathology. Numerous host factors have been shown to participate in the regulation of the LTR promoter. Among them is the thyroid hormone (T3) receptor (TR). TR has been shown to bind to the critical region of the promoter that contain the NFbB and Sp1 binding sites. Interestingly, earlier transient transfection studies in tissue culture cells have yielded contradicting conclusions on the role of TR in LTR regulation, likely due to the use of different cell types and/or lack of proper chromatin organization. Here, using the frog oocyte as a model system that allows replication-coupled chromatin assembly, mimicking that in somatic cells, we demonstrate that unliganded heterodimers of TR and RXR (9-cis retinoic acid receptor) repress LTR while the addition of T3 relieves the repression and further activates the promoter. More importantly, we show that chromatin and unliganded TR/RXR synergize to repress the promoter in a histone deacetylase-dependent manner.展开更多
Breast cancer susceptibility gene 1(BRCA1)is a tumor suppressor gene,which is frequently mutated in breast and ovarian cancers.BRCA1 plays a key role in the homologous recombination directed DNA repair,allowing its de...Breast cancer susceptibility gene 1(BRCA1)is a tumor suppressor gene,which is frequently mutated in breast and ovarian cancers.BRCA1 plays a key role in the homologous recombination directed DNA repair,allowing its deficiency to act as a therapeutic target of DNA damaging agents.In this study,we found that inhibition of the classⅠhistone deacetylases(HDAC)exhibited synthetic lethality with BRCA1 deficiency in breast cancer cells.Transcriptome profiling and validation study showed that HDAC inhibition enhanced the expression of thioredoxin interaction protein(TXNIP),causing reactive oxygen species(ROS)-mediated DNA damage.This effect induced preferential apoptosis in BRCA1-/-breast cancer cells where DNA repair system is compromised.Two animal experiments and gene expression-associated patients’survival analysis further confirmed in vivo synthetic lethality between BRCA1 and HDAC.Finally,the combination of inhibitors of HDAC and bromodomain and extra-terminal motif(BET),another BRCA1 synthetic lethality target that also works through oxidative stress-mediated DNA damage,showed a strong anticancer effect in BRCA1-/-breast cancer cells.Together,this study provides a new therapeutic strategy for BRCA1-deficient breast cancer by targeting two epigenetic machineries,HDAC and BET.展开更多
基金supported by the National Natural Science Foundation of China,No.82201582(to QT)Scientific and Technological Research Program of Chongqing Municipal Education Commission,No.KJQN202200457(to QT)+3 种基金General Project of Changqing Natural Science Foundation,No.cstc2021jcyjmsxmX0442(to ZL)CQMU Program for Youth Innovation in Future Medicine,No.W0044(to ZD and GH)Direct Research Project for PhD of Chongqing,No.CSTB2022BSXM-JCX0051(to ZL)the Project of the Top-Notch Talent Cultivation Program For the Graduate Students of Chongqing Medical University,No.BJRC202310(to CG)。
文摘Recent studies have suggested that abnormal acidification of lysosomes induces autophagic accumulation of amyloid-βin neurons,which is a key step in senile plaque formation.Therefore,resto ring normal lysosomal function and rebalancing lysosomal acidification in neurons in the brain may be a new treatment strategy for Alzheimer's disease.Microtubule acetylation/deacetylation plays a central role in lysosomal acidification.Here,we show that inhibiting the classic microtubule deacetylase histone deacetylase 6 with an histone deacetylase 6 shRNA or thehistone deacetylase 6 inhibitor valproic acid promoted lysosomal reacidification by modulating V-ATPase assembly in Alzheimer's disease.Fu rthermore,we found that treatment with valproic acid markedly enhanced autophagy.promoted clearance of amyloid-βaggregates,and ameliorated cognitive deficits in a mouse model of Alzheimer's disease.Our findings demonstrate a previously unknown neuroprotective mechanism in Alzheimer's disease,in which histone deacetylase 6 inhibition by valproic acid increases V-ATPase assembly and lysosomal acidification.
基金supported by the Charles University Research Fund(Progres Q39)the National Sustainability Programme I(NPU I)Nr.LO1503 provided by the Ministry of Education+5 种基金Youth and Sports of the Czech Republic(MEYS CR)project No.SVV 02690 awarded by MEYS CRthe project No.CZ.02.1.01/0.0/0.0/16_019/0000787 “Fighting Infectious Diseases”awarded by MEYS CR and financed from The European Regional Development Fundsupported by the National Agency of Agriculture Sciences(NAZV QJ1510138)the Czech Ministry of Agriculture(MZe RO 0718)
文摘Background: SIRT1 histone deacetylase acts on many epigenetic and non-epigenetic targets. It is thought that SIRT1 is involved in oocyte maturation;therefore, the importance of the ooplasmic SIRT1 pool for the further fate of mature oocytes has been strongly suggested. We hypothesised that SIRT1 plays the role of a signalling molecule in mature oocytes through selected epigenetic and non-epigenetic regulation.Results: We observed SIRT1 re-localisation in mature oocytes and its association with spindle microtubules.In mature oocytes, SIRT1 distribution shows a spindle-like pattern, and spindle-specific SIRT1 action decreasesα-tubulin acetylation. Based on the observation of the histone code in immature and mature oocytes, we suggest that SIRT1 is mostly predestined for an epigenetic mode of action in the germinal vesicles(GVs) of immature oocytes. Accordingly, BML-278-driven trimethylation of lysine K9 in histone H3 in mature oocytes is considered to be a result of GV epigenetic transformation.Conclusions: Taken together, our observations point out the dual spatiotemporal SIRT1 action in oocytes,which can be readily switched from the epigenetic to non-epigenetic mode of action depending on the progress of meiosis.
文摘The HIV-1 LTR controls the expression of HIV-1 viral genes and thus is critical for viral propagation and pathology. Numerous host factors have been shown to participate in the regulation of the LTR promoter. Among them is the thyroid hormone (T3) receptor (TR). TR has been shown to bind to the critical region of the promoter that contain the NFbB and Sp1 binding sites. Interestingly, earlier transient transfection studies in tissue culture cells have yielded contradicting conclusions on the role of TR in LTR regulation, likely due to the use of different cell types and/or lack of proper chromatin organization. Here, using the frog oocyte as a model system that allows replication-coupled chromatin assembly, mimicking that in somatic cells, we demonstrate that unliganded heterodimers of TR and RXR (9-cis retinoic acid receptor) repress LTR while the addition of T3 relieves the repression and further activates the promoter. More importantly, we show that chromatin and unliganded TR/RXR synergize to repress the promoter in a histone deacetylase-dependent manner.
基金supported by the Multi-Year Research Grant of the University of Macao,China(MYRG2017-00176-FHS to Joong Sup Shim).
文摘Breast cancer susceptibility gene 1(BRCA1)is a tumor suppressor gene,which is frequently mutated in breast and ovarian cancers.BRCA1 plays a key role in the homologous recombination directed DNA repair,allowing its deficiency to act as a therapeutic target of DNA damaging agents.In this study,we found that inhibition of the classⅠhistone deacetylases(HDAC)exhibited synthetic lethality with BRCA1 deficiency in breast cancer cells.Transcriptome profiling and validation study showed that HDAC inhibition enhanced the expression of thioredoxin interaction protein(TXNIP),causing reactive oxygen species(ROS)-mediated DNA damage.This effect induced preferential apoptosis in BRCA1-/-breast cancer cells where DNA repair system is compromised.Two animal experiments and gene expression-associated patients’survival analysis further confirmed in vivo synthetic lethality between BRCA1 and HDAC.Finally,the combination of inhibitors of HDAC and bromodomain and extra-terminal motif(BET),another BRCA1 synthetic lethality target that also works through oxidative stress-mediated DNA damage,showed a strong anticancer effect in BRCA1-/-breast cancer cells.Together,this study provides a new therapeutic strategy for BRCA1-deficient breast cancer by targeting two epigenetic machineries,HDAC and BET.
