The term epigenetics refers to heritable changes not encoded by DNA. The organization of DNA into chromatin fibers affects gene expression in a heritable manner and is therefore one mechanism of epigenetic inheritance...The term epigenetics refers to heritable changes not encoded by DNA. The organization of DNA into chromatin fibers affects gene expression in a heritable manner and is therefore one mechanism of epigenetic inheritance. Large parts of eukaryotic genomes consist of constitutively highly condensed heterochromatin, important for maintaining genome integrity but also for silencing of genes within. Small RNA, together with factors typically associated with RNA interference （RNAi） targets homologous DNA sequences and recruits factors that modify the chromatin, com- monly resulting in formation of heterochromatin and silencing of target genes. The scope of this review is to provide an overview of the roles of small RNA and the RNAi components, Dicer, Argonaute and RNA dependent polymerases in epigenetic inheritance via heterochromatin formation, exemplified with pathways from unicellular eukaryotes, plants and animals.展开更多
Wheat-rye addition and substitution lines and their self progenies revealed variations in telomeric heterochromatin and centromeres, Furthermore, a mitotically unstable dicentric chromosome and stable multicentric chr...Wheat-rye addition and substitution lines and their self progenies revealed variations in telomeric heterochromatin and centromeres, Furthermore, a mitotically unstable dicentric chromosome and stable multicentric chromosomes were observed in the progeny of a Chinese Spring-lmperial rye 3R addition line. An unstable multicentric chromosome was found in the progeny of a 6R/6D substitution line. Drastic variation of terminal heterochromatin including movement and disappearance of terminal heterochromatin occurred in the progeny of wheat- rye addition line 3R, and the 5RS ditelosomic addition line. Highly stable minichromosomes were observed in the progeny ofa monosomic 4R addition line, a ditelosomic 5RS addition line and a 6R/6D substitution line. Minichromosomes, with and without the FISH signals for telomeric DNA （TTTAGGG）n, derived from a monosomic 4R addition line are stable and transmissible to the next generation. The results indicated that centromeres and terminal heterochromatin can be profoundly altered in wheat-rye hybrid derivatives.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
In the budding yeast Saccharomyces cerevisiae, heterochromatin structure is found at three chromosome regions, which are homothallic mating-type loci, rDNA regions and telomeres. To address how telomere heterochromati...In the budding yeast Saccharomyces cerevisiae, heterochromatin structure is found at three chromosome regions, which are homothallic mating-type loci, rDNA regions and telomeres. To address how telomere heterochromatin is assembled under physiological conditions, we employed a de novo telomere addition system, and analyzed the dynamic chromatin changes of the TRPI reporter gene during telomere elongation. We found that integrating a 255-bp, but not an 81-bp telomeric sequence near the TRP1 promoter could trigger Sir2 recruitment, active chromatin mark（s）＇ removal, chromatin compaction and TRP1 gene silencing, indicating that the length of the telomeric sequence inserted in the internal region of a chromosome is critical for determining the chromatin state at the proximal region. Interestingly, Rill but not Rif2 or yKu is indispensable for the formation of intra-chromosomal silent chromatin initiated by telomeric sequence. When an internal short telomeric sequence （e.g., 81 bp） gets exposed to become a de novo telomere, the herterochromatin features, such as Sir recruitment, active chromatin mark（s）＇ removal and chromatin compaction, are detected within a few hours before the de novo telomere reaches a stable length. Our results recapitulate the molecular dynamics and reveal a coherent picture of telomere het- erochromatin formation.展开更多
In a recent study published in Science,Tiebang Kang and his colleagues1 identify ASB7 as a key negative regulator of heterochromatin maintenance through targeted degradation of the H3K9me3 methyltransferase SUV39H1.Th...In a recent study published in Science,Tiebang Kang and his colleagues1 identify ASB7 as a key negative regulator of heterochromatin maintenance through targeted degradation of the H3K9me3 methyltransferase SUV39H1.The work uncovers a cell cycle-regulated chromatin-associated ubiquitin ligase circuit that maintains epigenetic homeostasis and reveals a novel vulnerability in cancer that may be exploited therapeutically.展开更多
In Arabidopsis, pericentromeric repeats, retroelements, and silenced rRNA genes are assembled into heterochromatin within nuclear structures known as chromocenters. The mechanisms governing higher-order heterochromati...In Arabidopsis, pericentromeric repeats, retroelements, and silenced rRNA genes are assembled into heterochromatin within nuclear structures known as chromocenters. The mechanisms governing higher-order heterochromatin organization are poorly understood but 24-nt small interfering RNAs （siRNAs） are known to play key roles in heterochromatin formation. Nuclear RNA polymerase IV （Pol IV）, RNA-DEPENDENT RNA POLYMERASE 2 （RDR2）, and DICER-LIKE 3 （DCL3） are required for biogenesis of 24-nt siRNAs that associate with ARGONAUTE 4 （AGO4）. Nuclear RNA polymerase V （Pol V） collaborates with DRD1 （DEFICIENT IN RNA-DEPENDENT DNA METHYLATION 1） to generate transcripts at heterochromatic loci that are hypothesized to bind to siRNA-AGO4 complexes and subsequently recruit the de-novo DNA methylation and/or histone modifying machinery. Here, we report that decondensation of the major pericentromeric repeats and depletion of the heterochromatic mark histone H3 lysine 9 dimethylation at chromocenters occurs specifically in pol V and drdl mutants. Disruption of pericentromeric repeats condensation is coincident with transcriptional reactivation of specific classes of pericentromeric 180-bp repeats. We further demonstrate that Pol V functions independently of Pol IV, RDR2, and DCL3-mediated siRNA production to affect interphase heterochromatin organization, possibly by involving RNAs that recruit structural or chromatin-modifying proteins.展开更多
Plants encode a diverse repertoire of DNA methyltransferases that have specialized to target cytosines for methylation in specific sequence contexts. These include the de novo methyltransferase, DOMAINS REARRANGED MET...Plants encode a diverse repertoire of DNA methyltransferases that have specialized to target cytosines for methylation in specific sequence contexts. These include the de novo methyltransferase, DOMAINS REARRANGED METHYLTRANSFERASE 2 （DRM2）, which methylates cytosines in all sequence contexts through an RNA-guided process, the CHROMOMETHYLASES （CMTs）, which methylate CHH and CHG cytosines （where H is A, T, or C）, and METHYLTRANSFERASE 1 （MET1）, which maintains methylation of symmetrical CG contexts. In this review, we discuss the sequence specificities and targeting of each of these pathways. In particular, we highlight recent studies that indicate CMTs preferentially target CWG or CWA/CAW motifs （where W is A or T）, and discuss how self-reinforcing feedback loops between DNA methyltransferases and histone modifications characteristic of heterochromatin specify targeting. Finally, the initiating events that lead to gene body methylation are discussed as a model illustrating how interde- pendent targeting of different silencing pathways can potentiate the establishment of off-target epialleles.展开更多
Di-and tri-methylation of lysine 36 on histone H3(H3K36me2/3)is catalysed by histone methyltransferase Set2,which plays an essential role in transcriptional regulation.Although there is a single H3K36 methyltransferas...Di-and tri-methylation of lysine 36 on histone H3(H3K36me2/3)is catalysed by histone methyltransferase Set2,which plays an essential role in transcriptional regulation.Although there is a single H3K36 methyltransferase in yeast and higher eukaryotes,two H3K36 methyltransferases,Ash1 and Set2,were present in many filamentous fungi.However,their roles in H3K36 methylation and transcriptional regulation remained unclear.Combined with methods of RNA-seq and ChIP-seq,we revealed that both Ash1 and Set2 are redundantly required for the full H3K36me2/3 activity in Magnaporthe oryzae,which causes the devastating worldwide rice blast disease.Ash1 and Set2 distinguish genomic H3K36me2/3-marked regions and are differentially associated with repressed and activated transcription,respectively.Furthermore,Ash1-catalysed H3K36me2 was co-localized with H3K27me3 at the chromatin,and Ash1 was required for the enrichment and transcriptional silencing of H3K27me3-occupied genes.With the different roles of Ash1 and Set2,in H3K36me2/3 enrichment and transcriptional regulation on the stress-responsive genes,they differentially respond to various stresses in M.oryzae.Overall,we reveal a novel mechanism by which two H3K36 methyltransferases catalyze H3K36me2/3 that differentially associate with transcriptional activities and contribute to enrichment of facultative heterochromatin in eukaryotes.展开更多
Heterochromatin is characteristically more compact than chromatin is mediated by special histone modifications, euchromatin in the eukaryotic genome. The establishment of hetero- recruitment and propagation of heteroc...Heterochromatin is characteristically more compact than chromatin is mediated by special histone modifications, euchromatin in the eukaryotic genome. The establishment of hetero- recruitment and propagation of heterochromatin specific proteins, as well as formation of special primary and high order structures of chromatin. Chromatin remodeling factors are ATPases that can alter the conformation and/or positioning of nucleosomes along DNA in an ATP-dependent manner. There is increasing evidence implicating chromatin remodeling activities in heterochromatin in various organisms ranging from yeasts to humans. Chromatin remodeling factors play roles in the establishment, maintenance and epigenetic inheritance of heterochromatin, but the underlying molecular mechanisms have just begun to be investigated.展开更多
Heterochromatin,being transcriptionally inactive,is the highly condensed form of chromatin that is associated with Histone H3 lysine 9 methylation (H3K9me)and DNA methylation in eukaryotic cells.In fission yeast and a...Heterochromatin,being transcriptionally inactive,is the highly condensed form of chromatin that is associated with Histone H3 lysine 9 methylation (H3K9me)and DNA methylation in eukaryotic cells.In fission yeast and animals,Heterochromatin Protein 1 (HP1)plays a major role in forming and maintaining heterochromatin.展开更多
Objective:To investigate the impact of SWI/SNF complex on heterochromatin DNA damage repair after exposure to X-ray irradiation,in order to explore the underlying mechanism.Methods:NIH3T3 and MRC5 cells were treated w...Objective:To investigate the impact of SWI/SNF complex on heterochromatin DNA damage repair after exposure to X-ray irradiation,in order to explore the underlying mechanism.Methods:NIH3T3 and MRC5 cells were treated with 50 nmol/L siRNA targeting SWI/SNF complex subunits(BRM,ARID1A,BRG1 and SNF5),and YAP/TAZ.At 24 h after transfection,the cells were irradiated with 0.5 and 1 Gy of X-rays.At 20,60 and 240 min post-irradiation,γH2AX assay was performed to evaluate the radiation response in total or heterochromatin.Comet assay was used to determine the role of YAP/TAZ in DNA damage when the cells were irradiated with 4 Gy of X-rays.NIH3T3 were treated with 50 nmol/L siRNA targeting BRM/BRG1 and YAP/TAZ to determine their relationship on heterochromatin DNA damage repair.Results:In NIH3T3,SWI/SNF complex subunits(BRM,ARID1A and BRG1)knock-down increasedγH2AX in total and heterochromatin at 1 Gy 60 min post-irradiation(P<0.05),while SNF5 knock-down decreased heterochromatinγH2AX at 1 Gy 20 min post-irradiation(P<0.05).In MRC5,BRM and BRG1 knock-down increasedγH2AX in total and heterochromatin at 1 Gy 60 min post-irradiation(P<0.05).Inconsistently,ARID1A knockdown did not affect it,and SNF5 knock-down increased heterochromatinγH2AX at 1 Gy 60 min post-irradiation(P<0.05).Moreover,YAP/TAZ knock-down decreased heterochromatinγH2AX in NIH3T3 and MRC5(P<0.05).Meanwhile,YAP/TAZ knock-down decreased Tail Moment in comet assay at 4 Gy 60 min post-irradiation(P<0.05).BRM/BRG1 combining with YAP/TAZ knock-down significantly decreased heterochromatinγH2AX compared with single BRM/BRG1 knock-down at 0.5 Gy 60 min post-irradiation(P<0.05).Conclusions:The SWI/SNF complex subunits exhibited varying effects on DNA damage repair.BRM/BRG1 knockdown promotedγH2AX accumulation in heterochromatin through YAP/TAZ.This study provides a novel direction for DNA damage repair and sheds light on the role of SWI/SNF complex in response to DNA damage repair in heterochromatin.展开更多
In a recent study published in Nature,Huang,Wong and their colleagues identified G2E3 as the major histone H3 lysine 14 mono-ubiquitin(H3K14ub)ligase in mammalian cells.1 By coupling G2E3-dependent H3K14 ubiquitinatio...In a recent study published in Nature,Huang,Wong and their colleagues identified G2E3 as the major histone H3 lysine 14 mono-ubiquitin(H3K14ub)ligase in mammalian cells.1 By coupling G2E3-dependent H3K14 ubiquitination to the recruitment of SUV39H at pericentromeric chromatin,the authors define a conserved pathway that guides the reassembly of H3K9me3 domains after mitosis and secures the proper compartmentalization of chromatin.展开更多
The conserved histone variant H3.3 plays pivotal roles in heterochromatin formation and retrotransposon silencing.However,the molecular mechanism underlying H3.3-primed heterochromatin regulation remains elusive.Here,...The conserved histone variant H3.3 plays pivotal roles in heterochromatin formation and retrotransposon silencing.However,the molecular mechanism underlying H3.3-primed heterochromatin regulation remains elusive.Here,we demonstrate that H3.3-specific Ser31 phosphorylation and Lys27 trimethylation synergistically promote H3K9me3-heterochromatin formation.Mechanistically,polycomb protein chromobox homolog 7(CBX7)preferentially binds Ser31-phosphorylated H3.3K27me3 nucleosomes and then recruits KRAB-associated protein 1(KAP1),which may further engage the histone lysine 9 methyltransferase to establish H3K9me3-associated heterochromatin.Remarkably,H3K9me3 is significantly impaired when the H3.3–CBX7 interaction is disrupted,accompanied by the activation of retrotransposons.Moreover,during X-chromosome inactivation(XCI),H3K9me2/3 fails to accumulate at the inactive X(Xi)when blocking the H3.3–CBX7–KAP1 axis.Taken together,our results reveal a novel molecular mechanism by which H3.3 Ser31 phosphorylation(H3.3Ser31p)facilitates H3K9me3-heterochromatin formation during retrotransposon silencing and XCI via the H3.3K27me3–CBX7–KAP1 axis.展开更多
The basic unit of chromatin is the nucleosomal core particle, containing 147 bp of DNA that wraps twice around an octamer of core histones. The core histones bear a highly dynamic N-terminal amino acid tail around 20-...The basic unit of chromatin is the nucleosomal core particle, containing 147 bp of DNA that wraps twice around an octamer of core histones. The core histones bear a highly dynamic N-terminal amino acid tail around 20-35 residues in length and rich in basic amino acids. These tails extending from the surface of nucleosome play an important role in folding of nucleosomal arrays into higher order chromatin structure, which plays an important role in eukaryotic gene regulation. The amino terminal tails protruding from the nuclesomes get modified by the addition of small groups such as methyl, acetyl and phosphoryl groups. In this review, we focus on these complex modi- fication patterns and their biological functions. Moreover, these modifications seem to be part of a complex scheme where distinct histone modifications act in a sequential manner or in combination to form a ＂histone code＂ read by other proteins to control the structure and/or function of the chromatin fiber. Errors in this histone code may be involved in many human diseases especially cancer, the nature of which could be therapeutically exploited. Increasing evidence suggests that many proteins bear multiple, distinct modifications, and the ability of one modification to antagonize or synergize the deposition of another can have significant biological consequences.展开更多
文摘The term epigenetics refers to heritable changes not encoded by DNA. The organization of DNA into chromatin fibers affects gene expression in a heritable manner and is therefore one mechanism of epigenetic inheritance. Large parts of eukaryotic genomes consist of constitutively highly condensed heterochromatin, important for maintaining genome integrity but also for silencing of genes within. Small RNA, together with factors typically associated with RNA interference （RNAi） targets homologous DNA sequences and recruits factors that modify the chromatin, com- monly resulting in formation of heterochromatin and silencing of target genes. The scope of this review is to provide an overview of the roles of small RNA and the RNAi components, Dicer, Argonaute and RNA dependent polymerases in epigenetic inheritance via heterochromatin formation, exemplified with pathways from unicellular eukaryotes, plants and animals.
基金supported by the grants of the National High Technology Research and Development Program("863"Program) of China(No.2011AA100101)the Special Financial Grant from the China Postdoctoral Science Foundation (No.2012T50157),and 2011 Collaborative Innovation Plan of the Ministry Of Education of China
文摘Wheat-rye addition and substitution lines and their self progenies revealed variations in telomeric heterochromatin and centromeres, Furthermore, a mitotically unstable dicentric chromosome and stable multicentric chromosomes were observed in the progeny of a Chinese Spring-lmperial rye 3R addition line. An unstable multicentric chromosome was found in the progeny of a 6R/6D substitution line. Drastic variation of terminal heterochromatin including movement and disappearance of terminal heterochromatin occurred in the progeny of wheat- rye addition line 3R, and the 5RS ditelosomic addition line. Highly stable minichromosomes were observed in the progeny ofa monosomic 4R addition line, a ditelosomic 5RS addition line and a 6R/6D substitution line. Minichromosomes, with and without the FISH signals for telomeric DNA （TTTAGGG）n, derived from a monosomic 4R addition line are stable and transmissible to the next generation. The results indicated that centromeres and terminal heterochromatin can be profoundly altered in wheat-rye hybrid derivatives.
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.
基金supported by the National Natural Science Foundation of China (Nos.31230040,31461143003 and 31521061 to J.Q.Z.)Ministry of Science and Technology of the People's Republic of China(No. 2013CB910403 toJ.Q.Z.)
文摘In the budding yeast Saccharomyces cerevisiae, heterochromatin structure is found at three chromosome regions, which are homothallic mating-type loci, rDNA regions and telomeres. To address how telomere heterochromatin is assembled under physiological conditions, we employed a de novo telomere addition system, and analyzed the dynamic chromatin changes of the TRPI reporter gene during telomere elongation. We found that integrating a 255-bp, but not an 81-bp telomeric sequence near the TRP1 promoter could trigger Sir2 recruitment, active chromatin mark（s）＇ removal, chromatin compaction and TRP1 gene silencing, indicating that the length of the telomeric sequence inserted in the internal region of a chromosome is critical for determining the chromatin state at the proximal region. Interestingly, Rill but not Rif2 or yKu is indispensable for the formation of intra-chromosomal silent chromatin initiated by telomeric sequence. When an internal short telomeric sequence （e.g., 81 bp） gets exposed to become a de novo telomere, the herterochromatin features, such as Sir recruitment, active chromatin mark（s）＇ removal and chromatin compaction, are detected within a few hours before the de novo telomere reaches a stable length. Our results recapitulate the molecular dynamics and reveal a coherent picture of telomere het- erochromatin formation.
基金supported by the ERC award(Project-ID:ChOReS,#10107875)to N.T.
文摘In a recent study published in Science,Tiebang Kang and his colleagues1 identify ASB7 as a key negative regulator of heterochromatin maintenance through targeted degradation of the H3K9me3 methyltransferase SUV39H1.The work uncovers a cell cycle-regulated chromatin-associated ubiquitin ligase circuit that maintains epigenetic homeostasis and reveals a novel vulnerability in cancer that may be exploited therapeutically.
文摘In Arabidopsis, pericentromeric repeats, retroelements, and silenced rRNA genes are assembled into heterochromatin within nuclear structures known as chromocenters. The mechanisms governing higher-order heterochromatin organization are poorly understood but 24-nt small interfering RNAs （siRNAs） are known to play key roles in heterochromatin formation. Nuclear RNA polymerase IV （Pol IV）, RNA-DEPENDENT RNA POLYMERASE 2 （RDR2）, and DICER-LIKE 3 （DCL3） are required for biogenesis of 24-nt siRNAs that associate with ARGONAUTE 4 （AGO4）. Nuclear RNA polymerase V （Pol V） collaborates with DRD1 （DEFICIENT IN RNA-DEPENDENT DNA METHYLATION 1） to generate transcripts at heterochromatic loci that are hypothesized to bind to siRNA-AGO4 complexes and subsequently recruit the de-novo DNA methylation and/or histone modifying machinery. Here, we report that decondensation of the major pericentromeric repeats and depletion of the heterochromatic mark histone H3 lysine 9 dimethylation at chromocenters occurs specifically in pol V and drdl mutants. Disruption of pericentromeric repeats condensation is coincident with transcriptional reactivation of specific classes of pericentromeric 180-bp repeats. We further demonstrate that Pol V functions independently of Pol IV, RDR2, and DCL3-mediated siRNA production to affect interphase heterochromatin organization, possibly by involving RNAs that recruit structural or chromatin-modifying proteins.
文摘Plants encode a diverse repertoire of DNA methyltransferases that have specialized to target cytosines for methylation in specific sequence contexts. These include the de novo methyltransferase, DOMAINS REARRANGED METHYLTRANSFERASE 2 （DRM2）, which methylates cytosines in all sequence contexts through an RNA-guided process, the CHROMOMETHYLASES （CMTs）, which methylate CHH and CHG cytosines （where H is A, T, or C）, and METHYLTRANSFERASE 1 （MET1）, which maintains methylation of symmetrical CG contexts. In this review, we discuss the sequence specificities and targeting of each of these pathways. In particular, we highlight recent studies that indicate CMTs preferentially target CWG or CWA/CAW motifs （where W is A or T）, and discuss how self-reinforcing feedback loops between DNA methyltransferases and histone modifications characteristic of heterochromatin specify targeting. Finally, the initiating events that lead to gene body methylation are discussed as a model illustrating how interde- pendent targeting of different silencing pathways can potentiate the establishment of off-target epialleles.
基金supported by the National Natural Science Foundation of China (32170192 and 32370200 to Z.T)National Youth Talent Support Program.
文摘Di-and tri-methylation of lysine 36 on histone H3(H3K36me2/3)is catalysed by histone methyltransferase Set2,which plays an essential role in transcriptional regulation.Although there is a single H3K36 methyltransferase in yeast and higher eukaryotes,two H3K36 methyltransferases,Ash1 and Set2,were present in many filamentous fungi.However,their roles in H3K36 methylation and transcriptional regulation remained unclear.Combined with methods of RNA-seq and ChIP-seq,we revealed that both Ash1 and Set2 are redundantly required for the full H3K36me2/3 activity in Magnaporthe oryzae,which causes the devastating worldwide rice blast disease.Ash1 and Set2 distinguish genomic H3K36me2/3-marked regions and are differentially associated with repressed and activated transcription,respectively.Furthermore,Ash1-catalysed H3K36me2 was co-localized with H3K27me3 at the chromatin,and Ash1 was required for the enrichment and transcriptional silencing of H3K27me3-occupied genes.With the different roles of Ash1 and Set2,in H3K36me2/3 enrichment and transcriptional regulation on the stress-responsive genes,they differentially respond to various stresses in M.oryzae.Overall,we reveal a novel mechanism by which two H3K36 methyltransferases catalyze H3K36me2/3 that differentially associate with transcriptional activities and contribute to enrichment of facultative heterochromatin in eukaryotes.
基金supported by U.S. National Institutes of Health (Grant No. GM62484)
文摘Heterochromatin is characteristically more compact than chromatin is mediated by special histone modifications, euchromatin in the eukaryotic genome. The establishment of hetero- recruitment and propagation of heterochromatin specific proteins, as well as formation of special primary and high order structures of chromatin. Chromatin remodeling factors are ATPases that can alter the conformation and/or positioning of nucleosomes along DNA in an ATP-dependent manner. There is increasing evidence implicating chromatin remodeling activities in heterochromatin in various organisms ranging from yeasts to humans. Chromatin remodeling factors play roles in the establishment, maintenance and epigenetic inheritance of heterochromatin, but the underlying molecular mechanisms have just begun to be investigated.
文摘Heterochromatin,being transcriptionally inactive,is the highly condensed form of chromatin that is associated with Histone H3 lysine 9 methylation (H3K9me)and DNA methylation in eukaryotic cells.In fission yeast and animals,Heterochromatin Protein 1 (HP1)plays a major role in forming and maintaining heterochromatin.
基金supported by grants from National Natural Science Foundation of China(31971165 and 82173465)Leading Talents Program of Gusu District(ZXL2022454)Jiangsu Provincial Outstanding Postdoctoral Program(2023ZB254),China.
文摘Objective:To investigate the impact of SWI/SNF complex on heterochromatin DNA damage repair after exposure to X-ray irradiation,in order to explore the underlying mechanism.Methods:NIH3T3 and MRC5 cells were treated with 50 nmol/L siRNA targeting SWI/SNF complex subunits(BRM,ARID1A,BRG1 and SNF5),and YAP/TAZ.At 24 h after transfection,the cells were irradiated with 0.5 and 1 Gy of X-rays.At 20,60 and 240 min post-irradiation,γH2AX assay was performed to evaluate the radiation response in total or heterochromatin.Comet assay was used to determine the role of YAP/TAZ in DNA damage when the cells were irradiated with 4 Gy of X-rays.NIH3T3 were treated with 50 nmol/L siRNA targeting BRM/BRG1 and YAP/TAZ to determine their relationship on heterochromatin DNA damage repair.Results:In NIH3T3,SWI/SNF complex subunits(BRM,ARID1A and BRG1)knock-down increasedγH2AX in total and heterochromatin at 1 Gy 60 min post-irradiation(P<0.05),while SNF5 knock-down decreased heterochromatinγH2AX at 1 Gy 20 min post-irradiation(P<0.05).In MRC5,BRM and BRG1 knock-down increasedγH2AX in total and heterochromatin at 1 Gy 60 min post-irradiation(P<0.05).Inconsistently,ARID1A knockdown did not affect it,and SNF5 knock-down increased heterochromatinγH2AX at 1 Gy 60 min post-irradiation(P<0.05).Moreover,YAP/TAZ knock-down decreased heterochromatinγH2AX in NIH3T3 and MRC5(P<0.05).Meanwhile,YAP/TAZ knock-down decreased Tail Moment in comet assay at 4 Gy 60 min post-irradiation(P<0.05).BRM/BRG1 combining with YAP/TAZ knock-down significantly decreased heterochromatinγH2AX compared with single BRM/BRG1 knock-down at 0.5 Gy 60 min post-irradiation(P<0.05).Conclusions:The SWI/SNF complex subunits exhibited varying effects on DNA damage repair.BRM/BRG1 knockdown promotedγH2AX accumulation in heterochromatin through YAP/TAZ.This study provides a novel direction for DNA damage repair and sheds light on the role of SWI/SNF complex in response to DNA damage repair in heterochromatin.
基金Grants supporting this project are from the National Key Research and Development Program of China(2021YFA1300601)National Natural Science Foundation of China grants(82273048 and 82341015).
文摘In a recent study published in Nature,Huang,Wong and their colleagues identified G2E3 as the major histone H3 lysine 14 mono-ubiquitin(H3K14ub)ligase in mammalian cells.1 By coupling G2E3-dependent H3K14 ubiquitination to the recruitment of SUV39H at pericentromeric chromatin,the authors define a conserved pathway that guides the reassembly of H3K9me3 domains after mitosis and secures the proper compartmentalization of chromatin.
基金supported by the Ministry of Science and Technology of China(2023YFA0913402)the National Natural Science Foundation of China(32230020,32571493,32171186,32270614,32270581,and 32370645)+3 种基金Basic Research Program Based on Major Scientific Infrastructures,CAS(JZHKYPT-2021-05)supported by the Beijing Municipal Science and Technology Committee(Z221100007022001)the Fundamental Research Funds for the Central Universities(2042022dx0003)supported by the New Cornerstone Science Foundation.
文摘The conserved histone variant H3.3 plays pivotal roles in heterochromatin formation and retrotransposon silencing.However,the molecular mechanism underlying H3.3-primed heterochromatin regulation remains elusive.Here,we demonstrate that H3.3-specific Ser31 phosphorylation and Lys27 trimethylation synergistically promote H3K9me3-heterochromatin formation.Mechanistically,polycomb protein chromobox homolog 7(CBX7)preferentially binds Ser31-phosphorylated H3.3K27me3 nucleosomes and then recruits KRAB-associated protein 1(KAP1),which may further engage the histone lysine 9 methyltransferase to establish H3K9me3-associated heterochromatin.Remarkably,H3K9me3 is significantly impaired when the H3.3–CBX7 interaction is disrupted,accompanied by the activation of retrotransposons.Moreover,during X-chromosome inactivation(XCI),H3K9me2/3 fails to accumulate at the inactive X(Xi)when blocking the H3.3–CBX7–KAP1 axis.Taken together,our results reveal a novel molecular mechanism by which H3.3 Ser31 phosphorylation(H3.3Ser31p)facilitates H3K9me3-heterochromatin formation during retrotransposon silencing and XCI via the H3.3K27me3–CBX7–KAP1 axis.
文摘The basic unit of chromatin is the nucleosomal core particle, containing 147 bp of DNA that wraps twice around an octamer of core histones. The core histones bear a highly dynamic N-terminal amino acid tail around 20-35 residues in length and rich in basic amino acids. These tails extending from the surface of nucleosome play an important role in folding of nucleosomal arrays into higher order chromatin structure, which plays an important role in eukaryotic gene regulation. The amino terminal tails protruding from the nuclesomes get modified by the addition of small groups such as methyl, acetyl and phosphoryl groups. In this review, we focus on these complex modi- fication patterns and their biological functions. Moreover, these modifications seem to be part of a complex scheme where distinct histone modifications act in a sequential manner or in combination to form a ＂histone code＂ read by other proteins to control the structure and/or function of the chromatin fiber. Errors in this histone code may be involved in many human diseases especially cancer, the nature of which could be therapeutically exploited. Increasing evidence suggests that many proteins bear multiple, distinct modifications, and the ability of one modification to antagonize or synergize the deposition of another can have significant biological consequences.
