Targeted inhibition of V(D)J recombination by a histone methyltransferase

Osipovich, Oleg; Milley, Robin; Meade, Amber; Tachibana, Makoto; Shinkai, Yoichi; Krangel, Michael S.; Oltz, Eugene M.

doi:10.1038/ni1042

Cited by 95 publications

(72 citation statements)

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“…We have reported that a null G9a-mutation in embryonic stem (ES) cells led to a loss of H3-K9 dimethylation at the Mage-a promoter and reversed transcriptional repression of Mage-a genes (Tachibana et al 2002). Targeting of G9a and induction of H3-K9 methylation at antigen receptor gene segments suppressed their germline transcription and V(D)J recombination (Osipovich et al 2004). Furthermore, G9a-mediated H3-K9 methylation has been implicated in the silencing of developmentally regulated genes via interaction with CDP/cut (Nishio and Walsh 2004), the plasma cell transcription factor Blimp-1 (Gyory et al 2004), and the neuron-restrictive silencing factor NRSF/REST (Roopra et al 2004).…”

Section: ) G9amentioning

confidence: 99%

Histone methyltransferases G9a and GLP form heteromeric complexes and are both crucial for methylation of euchromatin at H3-K9

Tachibana¹,

Ueda²,

Fukuda³

et al. 2005

Genes Dev.

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Histone H3 Lys 9 (H3-K9) methylation is a crucial epigenetic mark for transcriptional silencing. G9a is the major mammalian H3-K9 methyltransferase that targets euchromatic regions and is essential for murine embryogenesis. There is a single G9a-related methyltransferase in mammals, called GLP/Eu-HMTase1. Here we show that GLP is also important for H3-K9 methylation of mouse euchromatin. GLP-deficiency led to embryonic lethality, a severe reduction of H3-K9 mono-and dimethylation, the induction of Mage-a gene expression, and HP1 relocalization in embryonic stem cells, all of which were phenotypes of G9a-deficiency. Furthermore, we show that G9a and GLP formed a stoichiometric heteromeric complex in a wide variety of cell types. Biochemical analyses revealed that formation of the G9a/GLP complex was dependent on their enzymatic SET domains. Taken together, our new findings revealed that G9a and GLP cooperatively exert H3-K9 methyltransferase function in vivo, likely through the formation of higher-order heteromeric complexes.[Keywords: Histone; methylation; G9a; GLP] Supplemental material is available at http://www.genesdev.org.

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Section: ) G9amentioning

confidence: 99%

Histone methyltransferases G9a and GLP form heteromeric complexes and are both crucial for methylation of euchromatin at H3-K9

Tachibana¹,

Ueda²,

Fukuda³

et al. 2005

Genes Dev.

Self Cite

717

760

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“…Apart from cis-elements in the immune receptor loci, including recombination signal sequence, enhancers and promoters [48,65], some trans-elements have been shown to play an important part in the regulation of V(D)J recombination [66][67][68]. Moreover, accumulating evidence has demonstrated the role of epigenetic factors in the regulation of V(D)J recombination, probably by altering the chromatin accessibility at the immune receptor loci [66,[69][70][71][72][73][74][75]. Future investigations into the upstream signals that regulate those known downstream regulators of V(D)J recombination should be able to provide insights into how the V(D)J recombination process can be manipulated.…”

Section: Future Challengesmentioning

confidence: 99%

Determinants of public T cell responses

et al. 2012

Cell Res

113

112

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Historically, sharing T cell receptors (TCRs) between individuals has been speculated to be impossible, considering the dramatic discrepancy between the potential enormity of the TCR repertoire and the limited number of T cells generated in each individual. However, public T cell response, in which multiple individuals share identical TCRs in responding to a same antigenic epitope, has been extensively observed in a variety of immune responses across many species. Public T cell responses enable individuals within a population to generate similar antigen-specific TCRs against certain ubiquitous pathogens, leading to favorable biological outcomes. However, the relatively concentrated feature of TCR repertoire may limit T cell response in a population to some other pathogens. It could be a great benefit for human health if public T cell responses can be manipulated. Therefore, the mechanistic insight of public TCR generation is important to know. Recently, high-throughput DNA sequencing has revolutionized the study of immune receptor repertoires, which allows a much better understanding of the factors that determine the overlap of TCR repertoire among individuals. Here, we summarize the current knowledge on public T-cell response and discuss future challenges in this field.

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“…Some combinations of Su(var) mutations increase meiotic recombination in Drosophila heterochromatin42, and loss of gene-silencing components in budding and fission yeasts increases both meiotic and somatic recombination in the rDNA33 ,43 . Similarly, the G9a H3K9 methyltransferase regulates accessibility of the V(D)J recombination machinery during mouse lymphocyte development 44 . Here, we expand on previous studies by demonstrating the impact of these mechanisms on nucleolar organization and the spatial arrangement of repeated sequences in the nucleus of a developing animal.…”

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H3K9 methylation and RNA interference regulate nucleolar organization and repeated DNA stability

2006

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Investigations aimed at identifying regulators of nuclear architecture in Drosophila demonstrated that cells lacking H3K9 methylation and RNA interference (RNAi) pathway components displayed disorganized nucleoli, ribosomal DNA (rDNA) and satellite DNAs. The levels of H3K9 dimethylation (H3K9me2) in chromatin associated with repeated DNAs decreased dramatically in Su(var)3-9 and dcr-2 (dicer-2) mutant tissues compared with wild type. We also observed a substantial increase in extrachromosomal circular (ecc) repeated DNAs in mutant tissues. The disorganized nucleolus phenotype depends on the presence of Ligase 4 and ecc DNA formation is not induced by removal of cohesin. We conclude that the structural integrity and organization of repeated DNAs and nucleoli are regulated by the H3K9 methylation and RNAi pathways, and other regulators of heterochromatin-mediated silencing. In addition, repeated DNA stability involves suppression of non-homologous end joining (NHEJ) or other recombination pathways. These results suggest a mechanism for how local chromatin structure can regulate genome stability, and the organization of chromosomal elements and nuclear organelles.Nuclei and chromosomes maintain specific and dynamic architectures that are required for many essential functions 1 . Nuclear bodies are involved in diverse biological processes and exhibit dynamic mobility, and individual chromosomes occupy distinct domains within interphase nuclei2. Chromosomes in the metazoan interphase nucleus are comprised of two types of cytologically and functionally distinct chromatin, euchromatin and heterochromatin3. Patterns of posttranslational histone modifications associated with these domains are strongly correlated with functions such as gene regulation, chromosome inheritance and replication timing4. For example, regions that display heterochromatinmediated gene silencing are rich in histone H3K9 methylation and lack many histone acetylations, whereas histones in transcriptionally active euchromatic regions are highly acetylated and methylated at H3K4 (ref. 5).The first indication that chromosome organization can affect gene expression stems from the discovery of position effect variegation (PEV) in Drosophila 6 . PEV describes the epigenetic inactivation or silencing of a euchromatic gene that has been positioned close to or within ©2007 Nature Publishing Group 3 Correspondence should be addressed to G.H.K. (karpen@fruitfly.org). AUTHOR CONTRIBUTIONS I.P. performed all the experiments, and J.P. and G.K. collaborated on data analysis and project planning.Note: Supplementary Information is available on the Nature Cell Biology website. COMPETING FINANCIAL INTERESTSThe authors declare that they have no competing financial interests. The nucleolus, the site of ribosome assembly, is an example of an essential nuclear organelle. The nucleolus organizer region (NOR) contains tandemly repeated ribosomal DNAs (rDNAs), and is embedded in heterochromatin in most eukaryotes. Single rDNA genes inserted into euchromatin are able...

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Targeted inhibition of V(D)J recombination by a histone methyltransferase

Cited by 95 publications

References 50 publications

Histone methyltransferases G9a and GLP form heteromeric complexes and are both crucial for methylation of euchromatin at H3-K9

Histone methyltransferases G9a and GLP form heteromeric complexes and are both crucial for methylation of euchromatin at H3-K9

Determinants of public T cell responses

H3K9 methylation and RNA interference regulate nucleolar organization and repeated DNA stability

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