The timing of floral transition is critical to reproductive success in angiosperms and is genetically controlled by a network of flowering genes. In Arabidopsis, expression of certain flowering genes is regulated by v...The timing of floral transition is critical to reproductive success in angiosperms and is genetically controlled by a network of flowering genes. In Arabidopsis, expression of certain flowering genes is regulated by various chromatin modifications, among which are two central regulators of flowering, namely FLOWERING LOCUS C （FLC） and FLOWERING LOCUS T（FT）. Recent studies have revealed that a number of chromatin-modifying components are involved in activation or repression of FLC expression. Activation of FLC expression is associated with various ＇active＇ chromatln modifications including acetylation of core histone tails, histone H3 lysine-4 （H3K4） methylation, H2B monoubiquitination, H3 lysine-36 （H3K36） di- and tri-methylation and deposition of the histone variant H2A.Z, whereas various ＇repressive＇ histone mod- ifications are associated with FLC repression, including histone deacetylation, H3K4 demethylation, histone H3 lysine-9 （H3K9） and H3 lysine-27 （H3K27） methylation, and histone arginine methylation. In addition, recent studies have revealed that Polycomb group gene-mediated transcriptional-silencing mechanism not only represses FLC expression, but also directly represses FTexpression. Regulation of FLC expression provides a paradigm for control of the expression of other developmental genes in plants through chromatin mechanisms.展开更多
Histone lysine methylation plays an important role in heterochromatin formation and reprogramming of gene expression. SET-domain-containing proteins are shown to have histone lysine methyltransferase activities. A lar...Histone lysine methylation plays an important role in heterochromatin formation and reprogramming of gene expression. SET-domain-containing proteins are shown to have histone lysine methyltransferase activities. A large number of SET-domain genes are identified in plant genomes. The function of most SET-domain genes is not known. In this work, we studied the 12 rice （Oryza sativa） homologs of Su（var）3-9, the histone H3 lysine 9 （H3K9） methyltransferase identified in Drosophila. Several rice SUVHs （i.e. SDG714, SDG727, and SDG710） were found to have an antagonistic func- tion to the histone H3K9 demethylase JMJ706, as down-regulation of these genes could partially complement the jmj706 phenotype and reduced histone H3K9 methylation. Down-regulation of a rice Su（var）3-9 homolog （SUVH）, namely SDG728, decreased H3K9 methylation and altered seed morphology. Overexpression of the gene increased H3K9 methylation. SDG728 and other SUVH genes were found to be involved in the repression of retrotransposons such as Tos17 and a Tyl-copia element. Analysis of histone methylation suggested that SDG728-mediated H3K9 methylation may play an important role in retrotransposon repression.展开更多
The scope of paternal contributions during early embryonic development has long been considered limited. Dramatic changes in chromatin structure throughout spermatogenesis have been thought to leave the sperm void of ...The scope of paternal contributions during early embryonic development has long been considered limited. Dramatic changes in chromatin structure throughout spermatogenesis have been thought to leave the sperm void of complex layers of epigenetic regulation over the DNA blueprint, thus leaving the balance of that regulation to the oocyte. However, recent work in the fields of epigenetics and male factor infertility has placed this long-held, and now controversial dogma, in a new light. Elegant studies investigating chromatin and epigenetic modifications in the developing sperm cell have provided new insights that may establish a more critical role for the paternal epigenome in the developing embryo. DNA methylation, histone tail modifications, targeted histone retention and protamine incorporation into the chromatin have great influence in the developing sperm cell. Perturbations in the establishment and/or maintenance of any of these epigenetic marks have been demonstrated to affect fertility status, ranging in severity from mild to catastrophic. Sperm require this myriad of chromatin structural changes not only to serve a protective role to DNA throughout spermatogenesis and future delivery to the egg, but also, it appears, to contribute to the developmental program of the future embryo. This review will focus on our current understanding of the epigenetics of sperm. We will discuss sperm-specific chromatin modifications that result in genes essential to development being poised for activation early in embryonic development, the disruption of which may result in reduced fecundity.展开更多
Dynamic regulation of histone methylation/demethylation plays an important role during development. Mutations and truncations in human plant homeodomain （PHD） finger protein 8 （PHF8） are associated with X-linked m...Dynamic regulation of histone methylation/demethylation plays an important role during development. Mutations and truncations in human plant homeodomain （PHD） finger protein 8 （PHF8） are associated with X-linked mental retardation and facial anomalies, such as a long face, broad nasal tip, cleft lip/cleft palate and large hands, yet its molecular function and structural basis remain unclear. Here, we report the crystal structures of the catalytic core of PHF8 with or without α-ketoglutarate （α-KG） at high resolution. Biochemical and structural studies reveal that PHF8 is a novel histone demethylase specific for di- and mono-methylated histone H3 lysine 9 （H3K9me2/1）, but not for H3K9me3. Our analyses also reveal how human PHF8 discriminates between methylation states and achieves sequence specificity for methylated H3K9. The in vitro demethylation assay also showed that the F279S mutant observed in clinical patients possesses no demethylation activity, suggesting that loss of enzymatic activity is crucial for pathogenesis of PHF8 patients. Taken together, these results will shed light on the molecular mechanism underlying PHF8-associated developmental and neurological diseases.展开更多
Polycomb group （PcG） and trithorax group （trxG） proteins have been shown to act antagonistically to epigenetically regulate gene expression in eukaryotes. The trxG proteins counteract PcG-mediated floral repressio...Polycomb group （PcG） and trithorax group （trxG） proteins have been shown to act antagonistically to epigenetically regulate gene expression in eukaryotes. The trxG proteins counteract PcG-mediated floral repression in Arabidopsis, but their roles in other developmental processes are poorly understood. We investigated the interactions between the trxG genes, ARABIDOPSIS HOMOLOG OF TRITHORAX1 （ATX1） and ULTRAPETALA1 （ULT1）, and the PcG gene EMBRYONIC FLOWER 1 （EMF1） during early development. Unexpectedly, we found that mutations in the trxG genes failed to rescue the early-flowering phenotype of emfl mutants. Instead, emfl atxl ultl seedlings showed a novel swollen root phenotype and massive deregulation of gene expression. Greater ectopic expression of seed master regulatory genes in emfl atxl ultl triple than in emfl single mutants indicates that PcG and trxG factors together repress seed gene expression after germination. Furthermore, we found that the widespread gene derepression is asso- ciated with reduced levels of H3K27me3, an epigenetic repressive mark of gene expression, and with globally altered chromatin organization. EMF1, ATXl, and ULT1 are able to bind the chromatin of seed genes and ULT1 can physically interact with ATX1 and EMF1, suggesting that the trxG and EMF1 proteins directly associate at target gene loci for EMFl-mediated gene silencing. Thus, while ATXl, ULT1, and EMF1 interact antagonistically to regulate flowering, they work together to maintain chromatin integrity and prevent precocious seed gene expression after germination.展开更多
Classical methyl-CpG binding proteins contain the conserved DNA binding motif methyl-cytosine binding domain(MBD), which preferentially binds to methylated CpG dinucleotides. These proteins serve as transcriptional re...Classical methyl-CpG binding proteins contain the conserved DNA binding motif methyl-cytosine binding domain(MBD), which preferentially binds to methylated CpG dinucleotides. These proteins serve as transcriptional repressors,mediating gene silencing via DNA cytosine methylation. Mutations in methyl-CpG binding protein 2 (MeCP2) have beenlinked to the human mental retardation disorder Rett syndrome, suggesting an important role for methyl-CpG bindingproteins in brain development and function. This mini-review summarizes the recent advances in studying the diversefunctions of MeCP2 as a prototype for other methyl-CpG binding proteins in the development and function of thevertebrate nervous system.展开更多
Epigenomic imbalance drives abnormal transcriptional processes,promoting the onset and progression of cancer.Although defective gene regulation generally affects carcinogenesis and tumor suppression networks,tumor imm...Epigenomic imbalance drives abnormal transcriptional processes,promoting the onset and progression of cancer.Although defective gene regulation generally affects carcinogenesis and tumor suppression networks,tumor immunogenicity and immune cells involved in antitumor responses may also be affected by epigenomic changes,which may have significant implications for the development and application of epigenetic therapy,cancer immunotherapy,and their combinations.Herein,we focus on the impact of epigenetic regulation on tumor immune cell function and the role of key abnormal epigenetic processes,DNA methylation,histone post-translational modification,and chromatin structure in tumor immunogenicity,and introduce these epigenetic research methods.We emphasize the value of small-molecule inhibitors of epigenetic modulators in enhancing antitumor immune responses and discuss the challenges of developing treatment plans that combine epigenetic therapy and immuno-therapy through the complex interaction between cancer epigenetics and cancer immunology.展开更多
The developmental transition to flowering in many plants is timed by changing seasons,which enables plants to flower at a season that is favorable for seed production.Many plants grown at high latitudes perceive the s...The developmental transition to flowering in many plants is timed by changing seasons,which enables plants to flower at a season that is favorable for seed production.Many plants grown at high latitudes perceive the seasonal cues of changing day length and/or winter cold(prolonged cold exposure),to regulate the expression of flowering-regulatory genes through the photoperiod pathway and/or vernalization pathway,and thus align flowering with a particular season.Recent studies in the model flowering plant Arabidopsis thaliana have revealed that diverse transcription factors engage various chromatin modifiers to regulate several key flowering-regulatory genes including FLOWERING LOCUS C(FLC)and FLOWERING LOCUS T(FT)in response to seasonal signals.Here,we summarize the current understanding of molecular and chromatin-regulatory or epigenetic mechanisms underlying the vernalization response and photoperiodic control of flowering in Arabidopsis.Moreover,the conservation and divergence of regulatory mechanisms for seasonal flowering in crops and other plants are briefly discussed.展开更多
Meiosis is a key event in gametogenesis that generates new combinations of genetic information and is required to reduce the chro- mosome content of the gametes. Meiotic chromosomes undergo a number of specialised eve...Meiosis is a key event in gametogenesis that generates new combinations of genetic information and is required to reduce the chro- mosome content of the gametes. Meiotic chromosomes undergo a number of specialised events during prophase to allow meiotic recombination, homologous chromosome synapsis and reductional chromosome segregation to occur. In mammalian cells, DNA phys- ically associates with histones to form chromatin, which can be modified by methylation, phosphorylation, ubiquitination and acetylation to help regulate higher order chromatin structure, gene expression, and chromosome organisation. Recent studies have identified some of the enzymes responsible for generating chromatin modifications in meiotic mammalian cells, and shown that these chromatin modifying enzymes are required for key meiosis-specific events that occur during meiotic prophase. This review will discuss the role of chromatin modifications in meiotic recombination, homologous chromosome synapsis and regulation of meiotic gene expression in mammals.展开更多
文摘The timing of floral transition is critical to reproductive success in angiosperms and is genetically controlled by a network of flowering genes. In Arabidopsis, expression of certain flowering genes is regulated by various chromatin modifications, among which are two central regulators of flowering, namely FLOWERING LOCUS C （FLC） and FLOWERING LOCUS T（FT）. Recent studies have revealed that a number of chromatin-modifying components are involved in activation or repression of FLC expression. Activation of FLC expression is associated with various ＇active＇ chromatln modifications including acetylation of core histone tails, histone H3 lysine-4 （H3K4） methylation, H2B monoubiquitination, H3 lysine-36 （H3K36） di- and tri-methylation and deposition of the histone variant H2A.Z, whereas various ＇repressive＇ histone mod- ifications are associated with FLC repression, including histone deacetylation, H3K4 demethylation, histone H3 lysine-9 （H3K9） and H3 lysine-27 （H3K27） methylation, and histone arginine methylation. In addition, recent studies have revealed that Polycomb group gene-mediated transcriptional-silencing mechanism not only represses FLC expression, but also directly represses FTexpression. Regulation of FLC expression provides a paradigm for control of the expression of other developmental genes in plants through chromatin mechanisms.
文摘Histone lysine methylation plays an important role in heterochromatin formation and reprogramming of gene expression. SET-domain-containing proteins are shown to have histone lysine methyltransferase activities. A large number of SET-domain genes are identified in plant genomes. The function of most SET-domain genes is not known. In this work, we studied the 12 rice （Oryza sativa） homologs of Su（var）3-9, the histone H3 lysine 9 （H3K9） methyltransferase identified in Drosophila. Several rice SUVHs （i.e. SDG714, SDG727, and SDG710） were found to have an antagonistic func- tion to the histone H3K9 demethylase JMJ706, as down-regulation of these genes could partially complement the jmj706 phenotype and reduced histone H3K9 methylation. Down-regulation of a rice Su（var）3-9 homolog （SUVH）, namely SDG728, decreased H3K9 methylation and altered seed morphology. Overexpression of the gene increased H3K9 methylation. SDG728 and other SUVH genes were found to be involved in the repression of retrotransposons such as Tos17 and a Tyl-copia element. Analysis of histone methylation suggested that SDG728-mediated H3K9 methylation may play an important role in retrotransposon repression.
文摘The scope of paternal contributions during early embryonic development has long been considered limited. Dramatic changes in chromatin structure throughout spermatogenesis have been thought to leave the sperm void of complex layers of epigenetic regulation over the DNA blueprint, thus leaving the balance of that regulation to the oocyte. However, recent work in the fields of epigenetics and male factor infertility has placed this long-held, and now controversial dogma, in a new light. Elegant studies investigating chromatin and epigenetic modifications in the developing sperm cell have provided new insights that may establish a more critical role for the paternal epigenome in the developing embryo. DNA methylation, histone tail modifications, targeted histone retention and protamine incorporation into the chromatin have great influence in the developing sperm cell. Perturbations in the establishment and/or maintenance of any of these epigenetic marks have been demonstrated to affect fertility status, ranging in severity from mild to catastrophic. Sperm require this myriad of chromatin structural changes not only to serve a protective role to DNA throughout spermatogenesis and future delivery to the egg, but also, it appears, to contribute to the developmental program of the future embryo. This review will focus on our current understanding of the epigenetics of sperm. We will discuss sperm-specific chromatin modifications that result in genes essential to development being poised for activation early in embryonic development, the disruption of which may result in reduced fecundity.
基金Supplementary information is linked to the online version of the paper on the Cell Research website.Acknowledgments We thank Dr Dawei Li （China Agricultural University） for generously providing us with the experimental conditions during the early stages of this project. We thank Dr Ruiming Xu （Institute of Biophysics, Chinese Academy of Sciences） for critical reading of this manuscript and advice. We thank Dr Pinchao Mei （Chinese Academy of Medical Sciences and Peking Union Medical College）, Xinqi Liu （Nankai University） and Jiemin Wong （East China Normal University） for discussions and advice. The synchrotronradiation experiments were performed at Shanghai Synchrotron Radiation Facility （SSRF） and NE3A in the Photon Factory. Z.C. is supported by the National Basic Research Program of China （973 Program, 2009CB825501）, the National Natural Science Foundation of China （30870494 and 90919043）, the New Century Excellent Talents in University （NCET-07-0808） and the Innovative Project of SKLAB. S. H. is supported by the National Key Laboratory Special Fund 2060204. Z. D. is supported by the National Natural Science Foundation of China （J0730639）.
文摘Dynamic regulation of histone methylation/demethylation plays an important role during development. Mutations and truncations in human plant homeodomain （PHD） finger protein 8 （PHF8） are associated with X-linked mental retardation and facial anomalies, such as a long face, broad nasal tip, cleft lip/cleft palate and large hands, yet its molecular function and structural basis remain unclear. Here, we report the crystal structures of the catalytic core of PHF8 with or without α-ketoglutarate （α-KG） at high resolution. Biochemical and structural studies reveal that PHF8 is a novel histone demethylase specific for di- and mono-methylated histone H3 lysine 9 （H3K9me2/1）, but not for H3K9me3. Our analyses also reveal how human PHF8 discriminates between methylation states and achieves sequence specificity for methylated H3K9. The in vitro demethylation assay also showed that the F279S mutant observed in clinical patients possesses no demethylation activity, suggesting that loss of enzymatic activity is crucial for pathogenesis of PHF8 patients. Taken together, these results will shed light on the molecular mechanism underlying PHF8-associated developmental and neurological diseases.
基金This work was supported by Beijing Natural Science Foundation （grant 5182028 to L.P.）, the Agricultural Science and Technology Innovation Program, CAAS, China （to L.P.）, the National Science Foundation, USA （NSF grant lOS 0956409 to Z.R.So）, and the National Science Council, Taiwan, China （grant NSC 98-2311-B-001-001-MY3 to L.O.C.）.
文摘Polycomb group （PcG） and trithorax group （trxG） proteins have been shown to act antagonistically to epigenetically regulate gene expression in eukaryotes. The trxG proteins counteract PcG-mediated floral repression in Arabidopsis, but their roles in other developmental processes are poorly understood. We investigated the interactions between the trxG genes, ARABIDOPSIS HOMOLOG OF TRITHORAX1 （ATX1） and ULTRAPETALA1 （ULT1）, and the PcG gene EMBRYONIC FLOWER 1 （EMF1） during early development. Unexpectedly, we found that mutations in the trxG genes failed to rescue the early-flowering phenotype of emfl mutants. Instead, emfl atxl ultl seedlings showed a novel swollen root phenotype and massive deregulation of gene expression. Greater ectopic expression of seed master regulatory genes in emfl atxl ultl triple than in emfl single mutants indicates that PcG and trxG factors together repress seed gene expression after germination. Furthermore, we found that the widespread gene derepression is asso- ciated with reduced levels of H3K27me3, an epigenetic repressive mark of gene expression, and with globally altered chromatin organization. EMF1, ATXl, and ULT1 are able to bind the chromatin of seed genes and ULT1 can physically interact with ATX1 and EMF1, suggesting that the trxG and EMF1 proteins directly associate at target gene loci for EMFl-mediated gene silencing. Thus, while ATXl, ULT1, and EMF1 interact antagonistically to regulate flowering, they work together to maintain chromatin integrity and prevent precocious seed gene expression after germination.
文摘Classical methyl-CpG binding proteins contain the conserved DNA binding motif methyl-cytosine binding domain(MBD), which preferentially binds to methylated CpG dinucleotides. These proteins serve as transcriptional repressors,mediating gene silencing via DNA cytosine methylation. Mutations in methyl-CpG binding protein 2 (MeCP2) have beenlinked to the human mental retardation disorder Rett syndrome, suggesting an important role for methyl-CpG bindingproteins in brain development and function. This mini-review summarizes the recent advances in studying the diversefunctions of MeCP2 as a prototype for other methyl-CpG binding proteins in the development and function of thevertebrate nervous system.
基金supported by the Startup Foundation for Junior Faculty,Nankai University(Grant No.:63191439)the National Natural Science Foundation of China(Grant Nos.:32100418,3210040345)+1 种基金The Health Commission Foundation of China(Grant No.:2018ZX10712001-017)the Chongqing Medical College Natural Fund(Grant Nos.:ygz2019302 and ygz2019305).
文摘Epigenomic imbalance drives abnormal transcriptional processes,promoting the onset and progression of cancer.Although defective gene regulation generally affects carcinogenesis and tumor suppression networks,tumor immunogenicity and immune cells involved in antitumor responses may also be affected by epigenomic changes,which may have significant implications for the development and application of epigenetic therapy,cancer immunotherapy,and their combinations.Herein,we focus on the impact of epigenetic regulation on tumor immune cell function and the role of key abnormal epigenetic processes,DNA methylation,histone post-translational modification,and chromatin structure in tumor immunogenicity,and introduce these epigenetic research methods.We emphasize the value of small-molecule inhibitors of epigenetic modulators in enhancing antitumor immune responses and discuss the challenges of developing treatment plans that combine epigenetic therapy and immuno-therapy through the complex interaction between cancer epigenetics and cancer immunology.
基金Research in the Plant Environmental Epigenetics laboratory is supported in part by the National Natural Science Foundation of China(31830049)the National Key Research and Development Program of China(2017YFA0503803)the Chinese Academy of Sciences(XDB27030202)。
文摘The developmental transition to flowering in many plants is timed by changing seasons,which enables plants to flower at a season that is favorable for seed production.Many plants grown at high latitudes perceive the seasonal cues of changing day length and/or winter cold(prolonged cold exposure),to regulate the expression of flowering-regulatory genes through the photoperiod pathway and/or vernalization pathway,and thus align flowering with a particular season.Recent studies in the model flowering plant Arabidopsis thaliana have revealed that diverse transcription factors engage various chromatin modifiers to regulate several key flowering-regulatory genes including FLOWERING LOCUS C(FLC)and FLOWERING LOCUS T(FT)in response to seasonal signals.Here,we summarize the current understanding of molecular and chromatin-regulatory or epigenetic mechanisms underlying the vernalization response and photoperiodic control of flowering in Arabidopsis.Moreover,the conservation and divergence of regulatory mechanisms for seasonal flowering in crops and other plants are briefly discussed.
基金supported by a Medical Research Council (MRC)intramural program grant to I.R.A.at the MRC Human Genetics Unit in UK
文摘Meiosis is a key event in gametogenesis that generates new combinations of genetic information and is required to reduce the chro- mosome content of the gametes. Meiotic chromosomes undergo a number of specialised events during prophase to allow meiotic recombination, homologous chromosome synapsis and reductional chromosome segregation to occur. In mammalian cells, DNA phys- ically associates with histones to form chromatin, which can be modified by methylation, phosphorylation, ubiquitination and acetylation to help regulate higher order chromatin structure, gene expression, and chromosome organisation. Recent studies have identified some of the enzymes responsible for generating chromatin modifications in meiotic mammalian cells, and shown that these chromatin modifying enzymes are required for key meiosis-specific events that occur during meiotic prophase. This review will discuss the role of chromatin modifications in meiotic recombination, homologous chromosome synapsis and regulation of meiotic gene expression in mammals.
