| 1. |
- Broeske, Ann-Marie, et al.
(author)
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DNA methylation protects hematopoietic stem cell multipotency from myeloerythroid restriction
- 2009
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 41:11, s. 69-1207
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Journal article (peer-reviewed)abstract
- DNA methylation is a dynamic epigenetic mark that undergoes extensive changes during differentiation of self-renewing stem cells. However, whether these changes are the cause or consequence of stem cell fate remains unknown. Here, we show that alternative functional programs of hematopoietic stem cells (HSCs) are governed by gradual differences in methylation levels. Constitutive methylation is essential for HSC self-renewal but dispensable for homing, cell cycle control and suppression of apoptosis. Notably, HSCs from mice with reduced DNA methyltransferase 1 activity cannot suppress key myeloerythroid regulators and thus can differentiate into myeloerythroid, but not lymphoid, progeny. A similar methylation dosage effect controls stem cell function in leukemia. These data identify DNA methylation as an essential epigenetic mechanism to protect stem cells from premature activation of predominant differentiation programs and suggest that methylation dynamics determine stem cell functions in tissue homeostasis and cancer.
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| 2. |
- Chen, Richard Z, et al.
(author)
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DNA hypomethylation leads to elevated mutation rates
- 1998
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 395:6697, s. 89-93
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Journal article (peer-reviewed)abstract
- Genome-wide demethylation has been suggested to be a step in carcinogenesis. Evidence for this notion comes from the frequently observed global DNA hypomethylation in tumour cells, and from a recent study suggesting that defects in DNA methylation might contribute to the genomic instability of some colorectal tumour cell lines. DNA hypomethylation has also been associated with abnormal chromosomal structures, as observed in cells from patients with ICF (Immunodeficiency, Centromeric instability and Facial abnormalities) syndrome and in cells treated with the demethylating agent 5-azadeoxycytidine. Here we report that murine embryonic stem cells nullizygous for the major DNA methyltransferase (Dnmt1) gene exhibited significantly elevated mutation rates at both the endogenous hypoxanthine phosphoribosyltransferase (Hprt) gene and an integrated viral thymidine kinase (tk) transgene. Gene deletions were the predominant mutations at both loci. The major cause of the observed tk deletions was either mitotic recombination or chromosomal loss accompanied by duplication of the remaining chromosome. Our results imply an important role for mammalian DNA methylation in maintaining genome stability.
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| 3. |
- Hansson, Mats G., et al.
(author)
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Commentary: Isolated Stem Cells - Patentable as Cultural Artifacts?
- 2007
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In: Stem Cells. - : Oxford University Press (OUP). - 1066-5099 .- 1549-4918. ; 25:6, s. 1507-1510
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Journal article (peer-reviewed)abstract
- This article argues that an isolated embryonic stem cell basically represents a cultural artifact that has no equivalent to cells of the embryo, and that it is likely that the isolation of adult stem cells has a similar consequence. An isolated stem cell could thus be distinguished as something other than the stem cell existing as part of a human body. Since isolation of stem cells implies modification, product patents should, where the results carry enough novelty, inventive step, and potential for industrial application, as a matter of principle be a viable option for patent authorities. Questions of morality, which may affect the patentability, should also be viewed in light of the distinction between isolated result and body part. At the same time, it is essential that patent authorities do not accept broad patent claims that will be detrimental to research. Disclosure of potential conflicts of interest is found at the end of this article.
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| 4. |
- Kokaia, Merab, et al.
(author)
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Suppressed epileptogenesis in BDNF mutant mice
- 1995
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In: Experimental Neurology. - : Elsevier BV. - 0014-4886. ; 133:2, s. 215-224
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Journal article (peer-reviewed)abstract
- Kindling is an animal model of epilepsy in which repeated electrical stimulations lead to progressive and permanent amplification of seizure activity, culminating in generalized convulsions. Each brief period of seizure activity during kindling epileptogenesis causes a marked, transient increase of the synthesis of brain-derived neurotrophic factor (BDNF) in cortical and hippocampal neurons. We find that the development of kindling is markedly suppressed in mice heterozygous for a deletion of the BDNF gene. In contrast, the maintenance of kindling is unaffected. The mutant mice show lower levels of BDNF mRNA in cortical and hippocampal neurons after seizures than do wild-type mice. Hippocampal mossy fiber sprouting is augmented in BDNF mutants but there are no other morphological abnormalities. These results show that BDNF plays an important role in establishing hyperexcitability during epileptogenesis, probably by increasing efficacy in stimulated synapses.
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