Polycomb repressive complex 2(PRC2)contributes to catalyze the methylation of histone H3 at lysine 27 and plays vital roles in transcriptional silencing and growth development in various organisms.In Magnaporthe oryza...Polycomb repressive complex 2(PRC2)contributes to catalyze the methylation of histone H3 at lysine 27 and plays vital roles in transcriptional silencing and growth development in various organisms.In Magnaporthe oryzae,histone H3K27 is found to associate with altered transcription of in planta induced genes.However,it is still unknown whether and how H3K27me3 modification is involved in pathogenicity to rice and stress response.In this study,we found that core subunits of PRC2,Kmt6-Suz12-Eed,were required for fungal pathogenicity to rice in M.oryzae.Kmt6-Suz12-Eed localized in the nuclei and was necessary for the establishment of H3K27me3 modification.With ChIP-seq analysis,9.0%of genome regions enriched with H3K27me3 occupancy,which corresponded to 1033 genes in M.oryzae.Furthermore,deletion of Kmt6,Suz12 or Eed altered genome-wide transcriptional expression,while the de-repression genes in theΔkmt6 strain were highly associated with H3K27me3 occupancy.Notably,plenty of genes which encode effectors and secreted enzymes,secondary metabolite synthesis genes,and cell wall stress-responsive genes were directly occupied with H3K27me3 modification and de-repression in theΔkmt6 strain.These results elaborately explained how PRC2 was required for pathogenicity,which is closely related to effector modulated host immunity and host environment adaption.展开更多
Polycomb Group Proteins(PcG)are a family of epigenetic regulators responsible for the repression of an array of genes important in development and cell fate specification.PcG proteins complex to form two types of epig...Polycomb Group Proteins(PcG)are a family of epigenetic regulators responsible for the repression of an array of genes important in development and cell fate specification.PcG proteins complex to form two types of epigenetic regulators:Polycomb Repressive Complex 1 and 2(PRC1 and PRC2).Although the mechanisms regulating PRC2 recruitment and activity in mammals remain poorly understood,recent work has identified a non-canonical PRC2 in mouse embryonic stem cells(mESC)with unique activities required for repression of PRC2 target genes and necessary for mESC differentiation and somatic cell reprogramming.Here we review the functions of PRC2 in embryonic stem cells and explore the role of the newly identified mESC specific PRC2 regulatory subunits Jarid2(jumonji,AT rich interactive domain 2),Mtf2(metal response element binding transcription factor 2)and esPRC2p48.展开更多
Stem cells are unique cell populations identified in a variety of normal tissues and some cancers. Maintenance of stem cell pools is essential for normal development, tissue homeostasis, and tumorigenesis. Recent stud...Stem cells are unique cell populations identified in a variety of normal tissues and some cancers. Maintenance of stem cell pools is essential for normal development, tissue homeostasis, and tumorigenesis. Recent studies have revealed that Polycomb repressive complexes （PRCs） play a central role in maintaining stem cells by repressing cellular senescence and differentiation. Here, we will review recent findings on dynamic composition of PRC complexes and sub-complexes, how PRCs are recruited to chromatin, and their functional roles in maintaining self- renewal of stem cells. Furthermore, we will discuss how PRCs, CpG islands （CGIs）, the INK4A/ARF/INK4B locus, and developmental genes form a hierarchical regulatory axis that is utilized by a variety of stem cells to maintain their self- renewal and identities.展开更多
Neural activities differentiating bodies versus non-body stimuli have been identified in the occipitotemporal cortex of both humans and nonhuman primates.However,the neural mechanisms of coding the similarity of diffe...Neural activities differentiating bodies versus non-body stimuli have been identified in the occipitotemporal cortex of both humans and nonhuman primates.However,the neural mechanisms of coding the similarity of different individuals’bodies of the same species to support their categorical representations remain unclear.Using electroencephalography(EEG)and magnetoencephalography(MEG),we investigated the temporal and spatial characteristics of neural processes shared by different individual body silhouettes of the same species by quantifying the repetition suppression of neural responses to human and animal(chimpanzee,dog,and bird)body silhouettes showing different postures.Our EEG results revealed significant repetition suppression of the amplitudes of early frontal/central activity at 180–220 ms(P2)and late occipitoparietal activity at 220–320 ms(P270)in response to animal(but not human)body silhouettes of the same species.Our MEG results further localized the repetition suppression effect related to animal body silhouettes in the left supramarginal gyrus and left frontal cortex at 200–440 ms after stimulus onset.Our findings suggest two neural processes that are involved in spontaneous categorical representations of animal body silhouettes as a cognitive basis of human-animal interactions.展开更多
Background:Globally,breast cancer constitutes the predominant malignancy in women.Abnormal regulation of epigenetic factors plays a key role in the development of tumors.Anti-apoptosis is a characteristic of tumor cel...Background:Globally,breast cancer constitutes the predominant malignancy in women.Abnormal regulation of epigenetic factors plays a key role in the development of tumors.Anti-apoptosis is a characteristic of tumor cells.Therefore,exploring and identifying relevant epigenetic factors that regulate the apoptosis of tumor cells is the foundation for clarifying the pathogenesis of tumors and achieving precision antitumor therapy.Method:This study focused on exploring the epigenetic mechanism of FOXK1 in the development of estrogen receptor-positive(ER^(+))breast cancer.We used overexpressing FLAG-FOXK1 MCF-7 cells to perform silver staining mass spectrometry analysis and conducted Co-IP experiments to verify the interactions.ChIP-seq was conducted on MCF-7 cells to examine FOXK1's binding across the genome and its transcriptional target sites.To validate the ChIP-seq results,qChIP,western blotting,and quantitative polymerase chain reaction(qPCR)were performed.Through TUNEL assay,cell counting assay,colony formation assay,and the mouse xenograft models,the effect of FOXK1 on breast cancer progression was detected.Finally,by analyzing online databases,the correlation between FOXK1 and the survival of breast cancer patients was examined.Results:FOXK1 interacts with the REST/CoREST transcriptional corepression complex to transcriptionally inhibit target genes representing the apoptotic pathway.Abnormally high expression of FOXK1 prevents the apoptosis of ER+breast cancer cells in vitro and promotes ER+breast tumor progression in vivo.Furthermore,the expression of FOXK1 is negatively correlated with the survival of ER+breast cancer patients.Conclusion:FOXK1 promotes ER+breast carcinogenesis through anti-apoptosis and acts as a potential target for ER+breast cancer treatment.展开更多
Polycomb group （PCG） complexes are epigenetic regulatory complexes that conduct transcriptional repression of target genes via modifying the chromatin. The two best characterized forms of PCG complexes, polycomb rep...Polycomb group （PCG） complexes are epigenetic regulatory complexes that conduct transcriptional repression of target genes via modifying the chromatin. The two best characterized forms of PCG complexes, polycomb repressive complexes 1 and 2 （PRC1 and PRC2）, are required for maintaining the sternness of embryonic stem cells and many types of adult stem cells. The spectra of target genes for PRCs are dynamically changing with cell differentiation, which is essential for proper decisions on cell fate during developmental processes, Chromobox （CBX） family proteins are canonical components in PRC1, responsible for targeting PRC1 to the chromatin. Recent studies highlight the function specifications among CBX family members in undifferentiated and differentiated stem cells, which reveal the interplay between compositional diversity and functional specificity of PRCI. In this review, we summarize the current knowledge about targeting and functional mechanisms of PRCs, emphasizing the recent breakthroughs related to CBX proteins under a number of physiological and pathological conditions.展开更多
Once thought to be transcriptional noise, large non-coding RNAs （IncRNAs） have recently been demonstrated to be functional molecules. The cell-type-specific expression patterns of lncRNAs suggest that their transcri...Once thought to be transcriptional noise, large non-coding RNAs （IncRNAs） have recently been demonstrated to be functional molecules. The cell-type-specific expression patterns of lncRNAs suggest that their transcription may be regulated epigenetically. Using a custom-designed microarray, here we examine the expression profile of IncRNAs in embryonic stem （ES） cells, lineage-restricted neuronal progenitor cells, and terminally differentiated fibroblasts. In addition, we also analyze the relationship between their expression and their promoter H3K4 and H3K27 methyla- tion patterns. We find that numerous lncRNAs in these cell types undergo changes in the levels of expression and promoter H3K4me3 and H3K27me3. Interestingly, lncRNAs that are expressed at lower levels in ES cells exhibit higher levels of H3K27me3 at their promoters. Consistent with this result, knockdown of the H3K27me3 methyltransferase Ezh2 results in derepression of these IncRNAs in ES cells. Thus, our results establish a role for Ezh2-mediated H3K27 methylation in lncRNA silencing in ES cells and reveal that lncRNAs are subject to epigenetic regulation in a similar manner to that of the protein-coding genes.展开更多
The Polycomb group(PcG) proteins are a family of chromatin regulators and critical for the maintenance of cellular identity. The PcG machinery can be categorized into at least three multi-protein complexes, namely Pol...The Polycomb group(PcG) proteins are a family of chromatin regulators and critical for the maintenance of cellular identity. The PcG machinery can be categorized into at least three multi-protein complexes, namely Polycomb Repressive Complex 1(PRC1), PRC2, and Polycomb Repressive De UBiquitinase(PR-DUB).Their deregulation has been associated with human cancer initiation and progression. Here we review the updated understanding for Pc G proteins in transcription regulation and DNA damage repair and highlight increasing links to the hallmarks in cancer. Accordingly, we discuss some of the recent advances in drug development or strategies against cancers caused by the gain or loss of PcG functions.展开更多
The Polycomb group （PcG） genes repress gene expression mainly through chromatin modifications and regulation of chromatin structure. At present, at/east four protein complexes of PcG proteins are identified, includi...The Polycomb group （PcG） genes repress gene expression mainly through chromatin modifications and regulation of chromatin structure. At present, at/east four protein complexes of PcG proteins are identified, including Polycomb repressive complex 1 （PRC1）, Polycomb repressive complex 2 （PRC2）, PHO-repressive complex （PhoRC） and Polycomb repressive deubiquitinase （PR-DUB）. In this review, the recent discoveries of the composition of the above complexes, as well as their roles in regulating histone modifications and gene silencing are discussed. We mainly focus on the composition of PRC1 and PRC2 complex and recruitment of PcG to target genes and mechanisms of PRC1 and PRC2-mediated gene silencing. Although much progress has been made in understanding gene silencing mediated by PcG proteins, we also discuss several important questions that still remained unanswered, such as the inheritance of histone modifications during cell division.展开更多
B lymphoma Moloney murine leukemia virus insertion region 1 (BMI1), a core member of polycomb repressive complex 1 (PRC1), has been intensely investigated in the field of cancer epigenetics for decades. Widely known a...B lymphoma Moloney murine leukemia virus insertion region 1 (BMI1), a core member of polycomb repressive complex 1 (PRC1), has been intensely investigated in the field of cancer epigenetics for decades. Widely known as a critical regulator in cellular physiology, BMI1 is essential in self-renewal and differentiation in different lineages of stem cells. BMI1 also plays a significant role in cancer etiology for its involvement in pathological progress such as epithelial–mesenchymal transition (EMT) and cancer stem cell maintenance, propagation, and differentiation. Importantly, overexpression of BMI1 is predictive for drug resistance, tumor recurrence, and eventual therapy failure of various cancer subtypes, which renders the pharmacological targeting at BMI1 as a novel and promising therapeutic approach. The study on prostate cancer, a prevalent hormone-related cancer among men, has promoted enormous research advancements in cancer genetics and epigenetics. This review summarizes the role of BMI1 as an oncogenic and epigenetic regulator in tumor initiation, progression, and relapse of prostate cancer.展开更多
Protein O-GlcNAcylation is a monosaccharide post-translational modification maintained by two evolutionarily conserved enzymes, O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). Mutations in human OGT have recently be...Protein O-GlcNAcylation is a monosaccharide post-translational modification maintained by two evolutionarily conserved enzymes, O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). Mutations in human OGT have recently been associated with neurodevelopmental disorders, although the mechanisms linking O-GlcNAc homeostasis to neurodevelopment are not understood. Here, we investigate the effects of perturbing protein O-GlcNAcylation using transgenic Drosophila lines that overexpress a highly active OGA. We reveal that temporal reduction of protein O-GlcNAcylation in early embryos leads to reduced brain size and olfactory learning in adult Drosophila. Downregulation of O-GlcNAcylation induced by the exogenous OGA activity promotes nuclear foci formation of Polycomb-group protein Polyhomeotic and the accumulation of excess K27 trimethylation of histone H3 (H3K27me3) at the mid-blastula transition. These changes interfere with the zygotic expression of several neurodevelopmental genes, particularly short gastrulation (sog), a component of an evolutionarily conserved sog-Decapentaplegic (Dpp) signaling system required for neuroectoderm specification. Our findings highlight the importance of early embryonic O-GlcNAcylation homeostasis for the fidelity of facultative heterochromatin redeployment and initial cell fate commitment of neuronal lineages, suggesting a possible mechanism underpinning OGT-associated intellectual disability.展开更多
Over the past decades,tRNA was found to be a rich hub of RNA modifications such as 1-methyladenosine and 5-methycytosine modifications and others,holding more than half of all modifications occurring in RNA molecules....Over the past decades,tRNA was found to be a rich hub of RNA modifications such as 1-methyladenosine and 5-methycytosine modifications and others,holding more than half of all modifications occurring in RNA molecules.Moreover,tRNA was discovered to be a source of various small noncoding RNA species,such as the stress induced angiogenin cleaved tRNA halves(tiRNA)or the miRNA like tRNA derived fragments.tRNA cleavage under stress was fist discovered in bacteria and later was found to be conserved across different species,including mammals.Under cellular stress conditions,tRNA undergoes conformational changes and angiogenin cleaves it into 3′and 5′halves.5′tiRNA halves were shown to repress protein translations.tRNA cleavage is thought of to be a cytoprotective mechanism by which cells evade apoptosis,however some data hints to the opposite;that tiRNA are cytotoxic or at least related to apoptosis initiation.tRNA cleavage also was shown to be affected by tRNA modifications via different enzymes in the cytosol and mitochondria.In this review,we will highlight the biology of tRNA cleavage,show the evidence of it being cytoprotective or a marker of cell death and shed a light on its role in disease models and human diseases as well as possible future directions in this field of RNA research.展开更多
It has been reported that one of the factors that promotes tumoral progression is the abnormal activation of the epithelial-mesenchymal transition program. This process is associated with tumoral cells acquiring invas...It has been reported that one of the factors that promotes tumoral progression is the abnormal activation of the epithelial-mesenchymal transition program. This process is associated with tumoral cells acquiring invasive and malignant properties and has the transcription factor zinc finger E-box-binding homeobox 1 （ZEB1） as one of its main activators. However, the role of ZEB1 in promoting malignancy in prostate cancer （PC, a） is still unclear. Here, we report that ZEB1 expression correlates with Gleason score in PCa samples and that expression of ZEB1 regulates epithelial-mesenchymal transition and malignant characteristics in PCa cell lines. The results showed that ZEB1 expression is higher in samples of higher malignancy and that overexpression of ZEB1 was able to induce epithelial-mesenchymal transition by upregulating the mesenchymal marker Vimentin and downregulating the epithelial marker E-Cadherin. On the contrary, ZEB 1 silencing repressed Vimentin expression and upregulated E-Cadherin. ZEB1 expression conferred enhanced motility and invasiveness and a higher colony formation capacity to 22Rvl cells whereas DU145 cells with ZEB1 silencing showed a decrease in those same properties. The results showed that ZEB1 could be a key promoter of tumoral progression toward advanced stages of PC, a.展开更多
LSD1 （KDM1 under the new nomenclature） was the first identified lysine-specific histone demethylase belonging to the flavin-dependent amine oxidase family. Here, we report that AOF1 （KDM1B under the new nomenclatur...LSD1 （KDM1 under the new nomenclature） was the first identified lysine-specific histone demethylase belonging to the flavin-dependent amine oxidase family. Here, we report that AOF1 （KDM1B under the new nomenclature）, a mammalian protein related to LSD1, also possesses histone demethylase activity with specificity for H3K4mel and H3K4me2. Like LSD1, the highly conserved SWIRM domain is required for its enzymatic activity. However, AOF1 differs from LSD1 in several aspects. First, AOF1 does not appear to form stable protein complexes containing histone deacetylases. Second, AOF1 is found to localize to chromosomes during the mitotic phase of the cell cycle, whereas LSD1 does not. Third, AOF1 represses transcription when tethered to DNA and this repression activity is independent of its demethylase activity. Structural and functional analyses identified its unique N-terminal Zf-CW domain as essential for the demethylase activity-independent repression function. Collectively, our study identifies AOF1 as the second histone demethylase in the family of flavin-dependent amine oxidases and reveals a demethylase-independent repression function of AOF1.展开更多
Interferon-gamma （IFN-γ） is a major proinflammatory effector and regulatory cytokine produced by activated T cells and NK cells. IFN-γ has been shown to play pivotal roles in fundamental immunological processes su...Interferon-gamma （IFN-γ） is a major proinflammatory effector and regulatory cytokine produced by activated T cells and NK cells. IFN-γ has been shown to play pivotal roles in fundamental immunological processes such as inflammatory reactions, cell-mediated immunity and autoimmunity. A variety of human disorders have now been linked to irregular IFN-γ expression. In order to achieve proper IFN-γ-mediated immunological effects, IFN-γ expression in T cells is subject to both positive and negative regulation. In this study, we report for the first time the negative regulation of IFN-γ expression by Prospero-related Homeobox （Proxl）. In Jurkat T cells and primary human CD4＋ T cells, Proxl expression decreases quickly upon T cell activation, concurrent with a dramatic increase in IFN-γ expression. Reporter analysis and chromatin immunoprecipitation （CHIP） revealed that Proxl associates with and inhibits the transcription activity of IFN-γ promoter in activated Jurkat T cells. Co-immunoprecipitation and GST pull-down assay demonstrated a direct binding between Proxl and the nuclear receptor peroxisome proliferator-activated receptor gamma （PPARγ）, which is also an IFN-γ repressor in T cells. By introducing deletions and mutations into Proxl, we show that the repression of IFN-γ promoter by Proxl is largely dependent upon the physical interaction between Proxl and PPARγ. Furthermore, PPARγ antagonist treatment removes Proxl from IFN-γ promoter and attenuates repression of IFN-γ expression by Proxl. These findings establish Proxl as a new negative regulator of IFN-γ expression in T cells and will aid in the understanding of IFN-γ transcription regulation mechanisms.展开更多
Long non-coding RNA (lncRNA) refers to an over 200 nt functional RNA molecule that will not be translated into protein. Previously thought to be dark matters of the genome, lncRNAs have been gradually recognized as cr...Long non-coding RNA (lncRNA) refers to an over 200 nt functional RNA molecule that will not be translated into protein. Previously thought to be dark matters of the genome, lncRNAs have been gradually recognized as crucial gene regulators. Although tremendous progress has been made in animals and human, the study of lncRNAs in plant is still in its infancy. Here, we reviewed the biogenesis and regulation mechanisms of lncRNAs and summarized the achievements that have been made in plant lncRNA identification and functional characterization. Genome-wide identification has uncovered large amount of lncRNAs in Arabidopsis, Rice, Maize and Wheat, and more information from other plant species will be expected with the aid of deep sequencing technologies. Similar to other species, LncRNA-mediated gene regulation also widely exists in plants, even though only a few functionally characterized examples are available. Up to now, at least four divergent lncRNA-mediated regulation mechanisms have been unraveled, including target mimicry, transcription interference, PRC2 associated histone methylation and DNA methylation. lncRNAs may be involved in the regulation of flowering, male sterility, nutrition metabolism, biotic and abiotic stress response in plants.展开更多
In this study,a modified continuous-flow nitrifying reactor was successfully operated for rapid cultivation of micro-granules and achieving robust nitritation.Results showed that sludge granulation with mean size of c...In this study,a modified continuous-flow nitrifying reactor was successfully operated for rapid cultivation of micro-granules and achieving robust nitritation.Results showed that sludge granulation with mean size of ca.100μm was achieved within three weeks by gradually increasing settling velocity-based selection pressure from 0.48 to 0.9 m/hr.Though Nitrospira like nitrite-oxidizing bacteria(NOB)were enriched in the micro-granules with a ratio between ammonia-oxidizing bacteria(AOB)and NOB of 5.7%/6.5% on day 21,fast nitritation was achieved within one-week by gradually increasing of influent ammonium concentration(from 50 to 200 mg/L).Maintaining ammonium in-excess was the key for repressing NOB in the micro-granules.Interestingly,when the influent ammonium concentration switched back to 50 mg/L still with the residual ammonium of 15–25 mg/L,the nitrite accumulation efficiency increased from 90%to 98%.Experimental results suggested that the NOB repression was intensified by both oxygen and nitrite unavailability in the inner layers of micro-granules.Unexpectedly,continuous operation with ammonium in excess resulted in overproduction of extracellular polysaccharides and overgrowth of some bacteria(e.g.,Nitrosomonas,Arenimonas,and Flavobacterium),which deteriorated the micro-granule stability and drove the micro-granules aggregation into larger ones with irregular morphology.However,efficient nitritation was stably maintained with extremely high ammonium oxidation potential(>50 mg/g VSS/hr)and nearly complete washout of NOB was obtained.This suggested that smooth and spherical granule was not a prerequisite for achieving NOB wash-out and maintaining effective nitritation in the granular reactor.Overall,the microgranules exhibited a great practical potential for high-rate nitritation.展开更多
In order to understand the behavior of ligninolytic enzyme production by white rot fungi Phanerochaete chrysosporium, study on time courses and a mathematical model for the production of lignin peroxidase (LiP) and ma...In order to understand the behavior of ligninolytic enzyme production by white rot fungi Phanerochaete chrysosporium, study on time courses and a mathematical model for the production of lignin peroxidase (LiP) and manganese peroxidase (MnP) of the fungi was undertaken. Based on the Monod-Jacob operon model, the ligninolytic enzyme would be synthesized in the absence of a related repressor. The repressor is assumed to be active in the presence of ammonia nitrogen, and as combined as co-repressor, it causes the inhibition of enzyme synthesis. The model can explain the mechanism of extracellular ligninolytic enzyme production by white rot fungi. The results,as predicted by the model, correspond closely to those observed in experimental studies. In addition, some light is also shed on unmeasured variables, such as the concentrations of repressor and mRNA that are related to the enzyme synthesis.展开更多
Rice grain size is an important trait that affects rice yield and quality, and thus the identification of genes related to grain size is of great significance for improving rice yield and quality. Many genes related t...Rice grain size is an important trait that affects rice yield and quality, and thus the identification of genes related to grain size is of great significance for improving rice yield and quality. Many genes related to grain size, such as DEP1(Huang et al., 2009),GW5(Liu et al., 2017).展开更多
基金the National Natural Science Foundation of China(Grant Nos.32170192 and 32000103)Zhejiang Science and Technology Major Program on Agricultural New Variety Breeding(Grant No.2021C02064)+1 种基金Key Research and Development Project of China National Rice Research Institute(Grant No.CNRRI-2020-04)the Chinese Academy of Agricultural Sciences under the‘Elite Youth’Program and the Agricultural Sciences and Technologies Innovation Program.
文摘Polycomb repressive complex 2(PRC2)contributes to catalyze the methylation of histone H3 at lysine 27 and plays vital roles in transcriptional silencing and growth development in various organisms.In Magnaporthe oryzae,histone H3K27 is found to associate with altered transcription of in planta induced genes.However,it is still unknown whether and how H3K27me3 modification is involved in pathogenicity to rice and stress response.In this study,we found that core subunits of PRC2,Kmt6-Suz12-Eed,were required for fungal pathogenicity to rice in M.oryzae.Kmt6-Suz12-Eed localized in the nuclei and was necessary for the establishment of H3K27me3 modification.With ChIP-seq analysis,9.0%of genome regions enriched with H3K27me3 occupancy,which corresponded to 1033 genes in M.oryzae.Furthermore,deletion of Kmt6,Suz12 or Eed altered genome-wide transcriptional expression,while the de-repression genes in theΔkmt6 strain were highly associated with H3K27me3 occupancy.Notably,plenty of genes which encode effectors and secreted enzymes,secondary metabolite synthesis genes,and cell wall stress-responsive genes were directly occupied with H3K27me3 modification and de-repression in theΔkmt6 strain.These results elaborately explained how PRC2 was required for pathogenicity,which is closely related to effector modulated host immunity and host environment adaption.
基金Hengbin Wang is a Sidney Kimmel Scholar and work in Wang Lab is supported by NIH Grant(GM081489).
文摘Polycomb Group Proteins(PcG)are a family of epigenetic regulators responsible for the repression of an array of genes important in development and cell fate specification.PcG proteins complex to form two types of epigenetic regulators:Polycomb Repressive Complex 1 and 2(PRC1 and PRC2).Although the mechanisms regulating PRC2 recruitment and activity in mammals remain poorly understood,recent work has identified a non-canonical PRC2 in mouse embryonic stem cells(mESC)with unique activities required for repression of PRC2 target genes and necessary for mESC differentiation and somatic cell reprogramming.Here we review the functions of PRC2 in embryonic stem cells and explore the role of the newly identified mESC specific PRC2 regulatory subunits Jarid2(jumonji,AT rich interactive domain 2),Mtf2(metal response element binding transcription factor 2)and esPRC2p48.
文摘Stem cells are unique cell populations identified in a variety of normal tissues and some cancers. Maintenance of stem cell pools is essential for normal development, tissue homeostasis, and tumorigenesis. Recent studies have revealed that Polycomb repressive complexes （PRCs） play a central role in maintaining stem cells by repressing cellular senescence and differentiation. Here, we will review recent findings on dynamic composition of PRC complexes and sub-complexes, how PRCs are recruited to chromatin, and their functional roles in maintaining self- renewal of stem cells. Furthermore, we will discuss how PRCs, CpG islands （CGIs）, the INK4A/ARF/INK4B locus, and developmental genes form a hierarchical regulatory axis that is utilized by a variety of stem cells to maintain their self- renewal and identities.
基金supported by the National Natural Science Foundation of China(32230043 and 32371092)the Ministry of Science and Technology of China(2019YFA0707103)+1 种基金Das Chinesisch-Deutsche Zentrum für Wissenschaftsförderung(M-0093)the High-performance Computing Platform of Peking University.
文摘Neural activities differentiating bodies versus non-body stimuli have been identified in the occipitotemporal cortex of both humans and nonhuman primates.However,the neural mechanisms of coding the similarity of different individuals’bodies of the same species to support their categorical representations remain unclear.Using electroencephalography(EEG)and magnetoencephalography(MEG),we investigated the temporal and spatial characteristics of neural processes shared by different individual body silhouettes of the same species by quantifying the repetition suppression of neural responses to human and animal(chimpanzee,dog,and bird)body silhouettes showing different postures.Our EEG results revealed significant repetition suppression of the amplitudes of early frontal/central activity at 180–220 ms(P2)and late occipitoparietal activity at 220–320 ms(P270)in response to animal(but not human)body silhouettes of the same species.Our MEG results further localized the repetition suppression effect related to animal body silhouettes in the left supramarginal gyrus and left frontal cortex at 200–440 ms after stimulus onset.Our findings suggest two neural processes that are involved in spontaneous categorical representations of animal body silhouettes as a cognitive basis of human-animal interactions.
基金Beijing High-Level Innovation and Entrepreneurship Talent Support Plan,Grant/Award Number:G04070024National Natural Science Foundation of China,Grant/Award Number:82073122。
文摘Background:Globally,breast cancer constitutes the predominant malignancy in women.Abnormal regulation of epigenetic factors plays a key role in the development of tumors.Anti-apoptosis is a characteristic of tumor cells.Therefore,exploring and identifying relevant epigenetic factors that regulate the apoptosis of tumor cells is the foundation for clarifying the pathogenesis of tumors and achieving precision antitumor therapy.Method:This study focused on exploring the epigenetic mechanism of FOXK1 in the development of estrogen receptor-positive(ER^(+))breast cancer.We used overexpressing FLAG-FOXK1 MCF-7 cells to perform silver staining mass spectrometry analysis and conducted Co-IP experiments to verify the interactions.ChIP-seq was conducted on MCF-7 cells to examine FOXK1's binding across the genome and its transcriptional target sites.To validate the ChIP-seq results,qChIP,western blotting,and quantitative polymerase chain reaction(qPCR)were performed.Through TUNEL assay,cell counting assay,colony formation assay,and the mouse xenograft models,the effect of FOXK1 on breast cancer progression was detected.Finally,by analyzing online databases,the correlation between FOXK1 and the survival of breast cancer patients was examined.Results:FOXK1 interacts with the REST/CoREST transcriptional corepression complex to transcriptionally inhibit target genes representing the apoptotic pathway.Abnormally high expression of FOXK1 prevents the apoptosis of ER+breast cancer cells in vitro and promotes ER+breast tumor progression in vivo.Furthermore,the expression of FOXK1 is negatively correlated with the survival of ER+breast cancer patients.Conclusion:FOXK1 promotes ER+breast carcinogenesis through anti-apoptosis and acts as a potential target for ER+breast cancer treatment.
基金Project supported by the Fundamental Research Funds for the Central Universities from Lanzhou University (No.lzujbky-2014-87),China
文摘Polycomb group （PCG） complexes are epigenetic regulatory complexes that conduct transcriptional repression of target genes via modifying the chromatin. The two best characterized forms of PCG complexes, polycomb repressive complexes 1 and 2 （PRC1 and PRC2）, are required for maintaining the sternness of embryonic stem cells and many types of adult stem cells. The spectra of target genes for PRCs are dynamically changing with cell differentiation, which is essential for proper decisions on cell fate during developmental processes, Chromobox （CBX） family proteins are canonical components in PRC1, responsible for targeting PRC1 to the chromatin. Recent studies highlight the function specifications among CBX family members in undifferentiated and differentiated stem cells, which reveal the interplay between compositional diversity and functional specificity of PRCI. In this review, we summarize the current knowledge about targeting and functional mechanisms of PRCs, emphasizing the recent breakthroughs related to CBX proteins under a number of physiological and pathological conditions.
文摘Once thought to be transcriptional noise, large non-coding RNAs （IncRNAs） have recently been demonstrated to be functional molecules. The cell-type-specific expression patterns of lncRNAs suggest that their transcription may be regulated epigenetically. Using a custom-designed microarray, here we examine the expression profile of IncRNAs in embryonic stem （ES） cells, lineage-restricted neuronal progenitor cells, and terminally differentiated fibroblasts. In addition, we also analyze the relationship between their expression and their promoter H3K4 and H3K27 methyla- tion patterns. We find that numerous lncRNAs in these cell types undergo changes in the levels of expression and promoter H3K4me3 and H3K27me3. Interestingly, lncRNAs that are expressed at lower levels in ES cells exhibit higher levels of H3K27me3 at their promoters. Consistent with this result, knockdown of the H3K27me3 methyltransferase Ezh2 results in derepression of these IncRNAs in ES cells. Thus, our results establish a role for Ezh2-mediated H3K27 methylation in lncRNA silencing in ES cells and reveal that lncRNAs are subject to epigenetic regulation in a similar manner to that of the protein-coding genes.
基金supported by the National Key Research and Development Program (2017YFA0504102)the National Natural Science Foundation of China (81772676, 31970579)+3 种基金the Natural Science Foundation of Tianjin Municipal Science and Technology Commission (18JCJQJC48200)Key Research Project of Tianjin Education Commission (2020ZD13)Open grant from the Chinese Academy of Medical Sciences (157-Zk19-02 and Z20-04)the Talent Excellence Program from Tianjin Medical University and Research Project of Tianjin Education Commission。
文摘The Polycomb group(PcG) proteins are a family of chromatin regulators and critical for the maintenance of cellular identity. The PcG machinery can be categorized into at least three multi-protein complexes, namely Polycomb Repressive Complex 1(PRC1), PRC2, and Polycomb Repressive De UBiquitinase(PR-DUB).Their deregulation has been associated with human cancer initiation and progression. Here we review the updated understanding for Pc G proteins in transcription regulation and DNA damage repair and highlight increasing links to the hallmarks in cancer. Accordingly, we discuss some of the recent advances in drug development or strategies against cancers caused by the gain or loss of PcG functions.
基金Supported by the National Key Basic Research Program of China(973 Program)(2011CB504206,2012CB518700)the National Natural Science Foundation of China(91019013,31221061,31200653 and 31370866)Program for New Century Excellent Talents in University(NCET-11-0410)
文摘The Polycomb group （PcG） genes repress gene expression mainly through chromatin modifications and regulation of chromatin structure. At present, at/east four protein complexes of PcG proteins are identified, including Polycomb repressive complex 1 （PRC1）, Polycomb repressive complex 2 （PRC2）, PHO-repressive complex （PhoRC） and Polycomb repressive deubiquitinase （PR-DUB）. In this review, the recent discoveries of the composition of the above complexes, as well as their roles in regulating histone modifications and gene silencing are discussed. We mainly focus on the composition of PRC1 and PRC2 complex and recruitment of PcG to target genes and mechanisms of PRC1 and PRC2-mediated gene silencing. Although much progress has been made in understanding gene silencing mediated by PcG proteins, we also discuss several important questions that still remained unanswered, such as the inheritance of histone modifications during cell division.
文摘B lymphoma Moloney murine leukemia virus insertion region 1 (BMI1), a core member of polycomb repressive complex 1 (PRC1), has been intensely investigated in the field of cancer epigenetics for decades. Widely known as a critical regulator in cellular physiology, BMI1 is essential in self-renewal and differentiation in different lineages of stem cells. BMI1 also plays a significant role in cancer etiology for its involvement in pathological progress such as epithelial–mesenchymal transition (EMT) and cancer stem cell maintenance, propagation, and differentiation. Importantly, overexpression of BMI1 is predictive for drug resistance, tumor recurrence, and eventual therapy failure of various cancer subtypes, which renders the pharmacological targeting at BMI1 as a novel and promising therapeutic approach. The study on prostate cancer, a prevalent hormone-related cancer among men, has promoted enormous research advancements in cancer genetics and epigenetics. This review summarizes the role of BMI1 as an oncogenic and epigenetic regulator in tumor initiation, progression, and relapse of prostate cancer.
基金This project has been supported by the National Natural Science Foundation of China(grants 91853108,92153301,31771589,and 32170821 to K.Y,32101034 to F.C)Department of Science and Technology of Hunan Province(grants 2017RS3013,2017XK2011,2018DK2015,2019SK1012,and 2021JJ10054 to K.Y,and the innovative team program 2019RS1010)+2 种基金Central South University(2018CX032 to K.Y,2019zzts046 to Y.Z,2019zzts339 to X.L,2021zzts497 to H.Y,and the innovation-driven team project 2020CX016)D.M.F.v.A.is supported by Wellcome Trust Investigator Award(110061)a Novo Nordisk Foundation Laureate award(NNF21OC0065969).
文摘Protein O-GlcNAcylation is a monosaccharide post-translational modification maintained by two evolutionarily conserved enzymes, O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). Mutations in human OGT have recently been associated with neurodevelopmental disorders, although the mechanisms linking O-GlcNAc homeostasis to neurodevelopment are not understood. Here, we investigate the effects of perturbing protein O-GlcNAcylation using transgenic Drosophila lines that overexpress a highly active OGA. We reveal that temporal reduction of protein O-GlcNAcylation in early embryos leads to reduced brain size and olfactory learning in adult Drosophila. Downregulation of O-GlcNAcylation induced by the exogenous OGA activity promotes nuclear foci formation of Polycomb-group protein Polyhomeotic and the accumulation of excess K27 trimethylation of histone H3 (H3K27me3) at the mid-blastula transition. These changes interfere with the zygotic expression of several neurodevelopmental genes, particularly short gastrulation (sog), a component of an evolutionarily conserved sog-Decapentaplegic (Dpp) signaling system required for neuroectoderm specification. Our findings highlight the importance of early embryonic O-GlcNAcylation homeostasis for the fidelity of facultative heterochromatin redeployment and initial cell fate commitment of neuronal lineages, suggesting a possible mechanism underpinning OGT-associated intellectual disability.
文摘Over the past decades,tRNA was found to be a rich hub of RNA modifications such as 1-methyladenosine and 5-methycytosine modifications and others,holding more than half of all modifications occurring in RNA molecules.Moreover,tRNA was discovered to be a source of various small noncoding RNA species,such as the stress induced angiogenin cleaved tRNA halves(tiRNA)or the miRNA like tRNA derived fragments.tRNA cleavage under stress was fist discovered in bacteria and later was found to be conserved across different species,including mammals.Under cellular stress conditions,tRNA undergoes conformational changes and angiogenin cleaves it into 3′and 5′halves.5′tiRNA halves were shown to repress protein translations.tRNA cleavage is thought of to be a cytoprotective mechanism by which cells evade apoptosis,however some data hints to the opposite;that tiRNA are cytotoxic or at least related to apoptosis initiation.tRNA cleavage also was shown to be affected by tRNA modifications via different enzymes in the cytosol and mitochondria.In this review,we will highlight the biology of tRNA cleavage,show the evidence of it being cytoprotective or a marker of cell death and shed a light on its role in disease models and human diseases as well as possible future directions in this field of RNA research.
文摘It has been reported that one of the factors that promotes tumoral progression is the abnormal activation of the epithelial-mesenchymal transition program. This process is associated with tumoral cells acquiring invasive and malignant properties and has the transcription factor zinc finger E-box-binding homeobox 1 （ZEB1） as one of its main activators. However, the role of ZEB1 in promoting malignancy in prostate cancer （PC, a） is still unclear. Here, we report that ZEB1 expression correlates with Gleason score in PCa samples and that expression of ZEB1 regulates epithelial-mesenchymal transition and malignant characteristics in PCa cell lines. The results showed that ZEB1 expression is higher in samples of higher malignancy and that overexpression of ZEB1 was able to induce epithelial-mesenchymal transition by upregulating the mesenchymal marker Vimentin and downregulating the epithelial marker E-Cadherin. On the contrary, ZEB 1 silencing repressed Vimentin expression and upregulated E-Cadherin. ZEB1 expression conferred enhanced motility and invasiveness and a higher colony formation capacity to 22Rvl cells whereas DU145 cells with ZEB1 silencing showed a decrease in those same properties. The results showed that ZEB1 could be a key promoter of tumoral progression toward advanced stages of PC, a.
基金We thank Dr Ramin Shiekhattar （Wistar Institute, USA） for the baculoviruses expressing Flag-LSD1 and Drs Jianguo Song and Degui Chen （Shanghai Institute of Biochemistry and Cell Biol- ogy, China） for anti-HDAC1 antibody and H3K36me2 antibody, respectively. This study was partially supported by grants from the National Natural Science Foundation of China （90919025, 30871381）, the Ministry of Science and Technology of China （2009CB918402, 2009CB825601） and the Research Platform for Cell Signaling Networks from the Science and Technology Com- mission of Shanghai Municipality （06DZ22923）.
文摘LSD1 （KDM1 under the new nomenclature） was the first identified lysine-specific histone demethylase belonging to the flavin-dependent amine oxidase family. Here, we report that AOF1 （KDM1B under the new nomenclature）, a mammalian protein related to LSD1, also possesses histone demethylase activity with specificity for H3K4mel and H3K4me2. Like LSD1, the highly conserved SWIRM domain is required for its enzymatic activity. However, AOF1 differs from LSD1 in several aspects. First, AOF1 does not appear to form stable protein complexes containing histone deacetylases. Second, AOF1 is found to localize to chromosomes during the mitotic phase of the cell cycle, whereas LSD1 does not. Third, AOF1 represses transcription when tethered to DNA and this repression activity is independent of its demethylase activity. Structural and functional analyses identified its unique N-terminal Zf-CW domain as essential for the demethylase activity-independent repression function. Collectively, our study identifies AOF1 as the second histone demethylase in the family of flavin-dependent amine oxidases and reveals a demethylase-independent repression function of AOF1.
文摘Interferon-gamma （IFN-γ） is a major proinflammatory effector and regulatory cytokine produced by activated T cells and NK cells. IFN-γ has been shown to play pivotal roles in fundamental immunological processes such as inflammatory reactions, cell-mediated immunity and autoimmunity. A variety of human disorders have now been linked to irregular IFN-γ expression. In order to achieve proper IFN-γ-mediated immunological effects, IFN-γ expression in T cells is subject to both positive and negative regulation. In this study, we report for the first time the negative regulation of IFN-γ expression by Prospero-related Homeobox （Proxl）. In Jurkat T cells and primary human CD4＋ T cells, Proxl expression decreases quickly upon T cell activation, concurrent with a dramatic increase in IFN-γ expression. Reporter analysis and chromatin immunoprecipitation （CHIP） revealed that Proxl associates with and inhibits the transcription activity of IFN-γ promoter in activated Jurkat T cells. Co-immunoprecipitation and GST pull-down assay demonstrated a direct binding between Proxl and the nuclear receptor peroxisome proliferator-activated receptor gamma （PPARγ）, which is also an IFN-γ repressor in T cells. By introducing deletions and mutations into Proxl, we show that the repression of IFN-γ promoter by Proxl is largely dependent upon the physical interaction between Proxl and PPARγ. Furthermore, PPARγ antagonist treatment removes Proxl from IFN-γ promoter and attenuates repression of IFN-γ expression by Proxl. These findings establish Proxl as a new negative regulator of IFN-γ expression in T cells and will aid in the understanding of IFN-γ transcription regulation mechanisms.
文摘Long non-coding RNA (lncRNA) refers to an over 200 nt functional RNA molecule that will not be translated into protein. Previously thought to be dark matters of the genome, lncRNAs have been gradually recognized as crucial gene regulators. Although tremendous progress has been made in animals and human, the study of lncRNAs in plant is still in its infancy. Here, we reviewed the biogenesis and regulation mechanisms of lncRNAs and summarized the achievements that have been made in plant lncRNA identification and functional characterization. Genome-wide identification has uncovered large amount of lncRNAs in Arabidopsis, Rice, Maize and Wheat, and more information from other plant species will be expected with the aid of deep sequencing technologies. Similar to other species, LncRNA-mediated gene regulation also widely exists in plants, even though only a few functionally characterized examples are available. Up to now, at least four divergent lncRNA-mediated regulation mechanisms have been unraveled, including target mimicry, transcription interference, PRC2 associated histone methylation and DNA methylation. lncRNAs may be involved in the regulation of flowering, male sterility, nutrition metabolism, biotic and abiotic stress response in plants.
基金supported by the National Natural Science Foundation of China (Nos. 51808367 and 51878430)
文摘In this study,a modified continuous-flow nitrifying reactor was successfully operated for rapid cultivation of micro-granules and achieving robust nitritation.Results showed that sludge granulation with mean size of ca.100μm was achieved within three weeks by gradually increasing settling velocity-based selection pressure from 0.48 to 0.9 m/hr.Though Nitrospira like nitrite-oxidizing bacteria(NOB)were enriched in the micro-granules with a ratio between ammonia-oxidizing bacteria(AOB)and NOB of 5.7%/6.5% on day 21,fast nitritation was achieved within one-week by gradually increasing of influent ammonium concentration(from 50 to 200 mg/L).Maintaining ammonium in-excess was the key for repressing NOB in the micro-granules.Interestingly,when the influent ammonium concentration switched back to 50 mg/L still with the residual ammonium of 15–25 mg/L,the nitrite accumulation efficiency increased from 90%to 98%.Experimental results suggested that the NOB repression was intensified by both oxygen and nitrite unavailability in the inner layers of micro-granules.Unexpectedly,continuous operation with ammonium in excess resulted in overproduction of extracellular polysaccharides and overgrowth of some bacteria(e.g.,Nitrosomonas,Arenimonas,and Flavobacterium),which deteriorated the micro-granule stability and drove the micro-granules aggregation into larger ones with irregular morphology.However,efficient nitritation was stably maintained with extremely high ammonium oxidation potential(>50 mg/g VSS/hr)and nearly complete washout of NOB was obtained.This suggested that smooth and spherical granule was not a prerequisite for achieving NOB wash-out and maintaining effective nitritation in the granular reactor.Overall,the microgranules exhibited a great practical potential for high-rate nitritation.
基金Supported by the National Natural Science Foundation of China (No. 29976038).
文摘In order to understand the behavior of ligninolytic enzyme production by white rot fungi Phanerochaete chrysosporium, study on time courses and a mathematical model for the production of lignin peroxidase (LiP) and manganese peroxidase (MnP) of the fungi was undertaken. Based on the Monod-Jacob operon model, the ligninolytic enzyme would be synthesized in the absence of a related repressor. The repressor is assumed to be active in the presence of ammonia nitrogen, and as combined as co-repressor, it causes the inhibition of enzyme synthesis. The model can explain the mechanism of extracellular ligninolytic enzyme production by white rot fungi. The results,as predicted by the model, correspond closely to those observed in experimental studies. In addition, some light is also shed on unmeasured variables, such as the concentrations of repressor and mRNA that are related to the enzyme synthesis.
基金supported by the grants from the National Key Research and Development Program of China (2016YFD0100406)the Rice Molecular Design Breeding (2016YFD0101801)+1 种基金the National Natural Science Foundation of China (91535102 and 31771760)the Open Research Fund of State Key Laboratory of Hybrid Rice (Hunan Hybrid Rice Research Center) (2016KF09)
文摘Rice grain size is an important trait that affects rice yield and quality, and thus the identification of genes related to grain size is of great significance for improving rice yield and quality. Many genes related to grain size, such as DEP1(Huang et al., 2009),GW5(Liu et al., 2017).
