Essential role for de novo DNA methyltransferase Dnmt3a in paternal and maternal imprinting

Kaneda, Masahiro; Okano, Masaki; Hata, Kenichiro; Sado, Takashi; Tsujimoto, Naomi; Li, En; Sasaki, Hidetada

doi:10.1038/nature02633

Cited by 1,246 publications

(1,026 citation statements)

References 24 publications

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“…This raises a logical question, whether the DNA damage observed at the end of 36 days could be interpreted as a primary effect of STZ as this agent is known to induce oxidative stress, DNA damage and apoptosis [20]. The DNA methylation events during spermatogenesis have important implications for gamete integrity and transmission of epigenetic information to the next generation [21]. The hyperglycemic state did not show any significant difference in methylation pattern of germ cells after one or two spermatogenesis cycle except in preleptotene/zygotene cell population where labeling index was higher than control at 72 days suggesting hypermethyation.…”

Section: Discussionmentioning

confidence: 99%

Germ cell abnormalities in streptozotocin induced diabetic mice do not correlate with blood glucose level

Bose

Adiga

D’Souza

et al. 2012

J Assist Reprod Genet

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Purpose To assess the effect of streptozotocin induced hyperglycemia on germ cell integrity, DNA ploidy and methylation status for a period of two spermatogenesis cycles in adult male Swiss albino mice. Methods Streptozotocin injected mice were monitored for hyperglycemia at a regular interval for a period of 36 and 72 days. The DNA integrity in epididymal spermatozoa was determined by the comet assay. Flow cytometric analysis was done in germ cells to assess the DNA ploidy. The global methylation analysis in germ cells was done by 5-methyl cytosine immunostaining.Results Streptozotocin administration successfully resulted in hyperglycemic response which significantly affected serum testosterone level, sperm DNA integrity and DNA ploidy at the end of 36 days. However, no changes were observed in either epididymal sperm concentration or germ cell methylation status. In contrast, at the end of 76 days, although serum testosterone level, sperm DNA integrity and DNA ploidy status were unperturbed significantly in hyperglycemic group, the epididymal sperm concentration and methylation status of preleptotene/zygotene cells were significantly altered. Importantly, an attempt to find out the association between the blood glucose levels and the abnormalities in hyperglycemic group failed to demonstrate any correlation. Conclusions The germ cell abnormalities observed in hyperglycemic group could be interpreted as a primary effect of streptozotocin and not due to hyperglycemia. Our results call for further evaluation of streptozotocin before its application to study the hyperglycemic responses on male germ cells.

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Section: Discussionmentioning

confidence: 99%

Germ cell abnormalities in streptozotocin induced diabetic mice do not correlate with blood glucose level

Bose

Adiga

D’Souza

et al. 2012

J Assist Reprod Genet

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“…Naïve antigen-specific cells obtained from transgenic P14 mice 30 were used as an antigen-specific naïve control. Dnmt3a conditional knockout mice were generated by breeding previously characterized floxed Dnmt3a mice with mice that contain a granzyme b driven recombinase transgene 17,31 . Genotyping and recombination of the Dnmt3a locus was performed using primers listed in Supplemental Table 1.…”

Section: Methodsmentioning

confidence: 99%

Effector CD8 T cells dedifferentiate into long-lived memory cells

Youngblood

Hale

Kissick

et al. 2017

Nature

392

359

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Memory CD8 T cells that circulate in the blood and are present in lymphoid organs are an essential component of long-lived T cell immunity. These resting memory CD8 T cells remain poised to rapidly elaborate effector functions upon re-exposure to pathogen, but also have many properties in common with naïve cells, including the ability to migrate to lymph nodes and spleen, and their pluri-potency. Thus, memory cells embody features of both naïve and effector cells, fueling a long-standing debate centered on whether memory T cells develop from effector cells or directly from naïve cells1–4. To better define the developmental path of memory CD8 T cells we investigated changes in DNA methylation programming at naïve and effector genes in virus specific CD8 T cells during acute LCMV infection of mice. Methylation profiling of effector CD8 T cell subsets at day 4 and 8 after infection showed that, rather than retaining a naïve epigenetic state, the subset of cells that gives rise to memory cells acquired de novo DNA methylation programs at naïve-associated genes and became demethylated at loci of classically defined effector molecules. Conditional deletion of the de novo methyltransferase, Dnmt3a, at an early stage of effector differentiation strikingly reduced methylation of naïve-associated genes and resulted in faster re-expression of these naïve genes, accelerating memory cell development. Longitudinal phenotypic and epigenetic characterization of virus-specific memory-precursor CD8 T cells transferred into antigen-free mice revealed that their differentiation into memory cells was coupled to cell-division independent erasure of de novo methylation programs and re-expression of naïve-associated genes. These data provide evidence that epigenetic repression of naïve-associated genes in effector CD8 T cells can be reversed in cells that develop into long-lived memory CD8 T cells supporting a differentiation model where memory T cells arise from a subset of fate-permissive effector T cells.

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“…As mentioned above, imprinting marks are established in either the male or the female germline. Although the DNA methyltransferase DNMT3A is essential for putting methylation imprints onto the ICRs, (36) the question remains as to how the sex-specific establishment of imprints is regulated. How, for instance, does the H19 ICR become methylated only in the male germline, and conversely, that the KvDMR1 ICR becomes methylated exclusively in growing oocytes?…”

Section: Introductionmentioning

confidence: 99%