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Reduced dosage of the modifiers of epigenetic reprogramming Dnmt1, Dnmt3L, SmcHD1 and Foxo3a has no detectable effect on mouse telomere length in vivo.

Roberts AR, Blewitt ME, Youngson NA, Whitelaw E, Chong S - Chromosoma (2011)

Bottom Line: Studies carried out in cultured cells have implicated modifiers of epigenetic reprogramming in the regulation of telomere length, reporting elongation in cells that were for DNA methyltransferase DNA methyltransferase 1 (Dnmt1), both de novo DNA methyltransferases, Dnmt3a and Dnmt3b or various histone methyltransferases.Terminal restriction fragment analysis was used to compare telomere length in homozygous mutants, heterozygous mutants and wild-type littermates.Contrary to expectation, we did not detect overall lengthening in the mutants, raising questions about the role of epigenetic processes in telomere length in vivo.

View Article: PubMed Central - PubMed

Affiliation: Epigenetics Laboratory, Queensland Institute of Medical Research, Herston, QLD, Australia.

ABSTRACT
Studies carried out in cultured cells have implicated modifiers of epigenetic reprogramming in the regulation of telomere length, reporting elongation in cells that were for DNA methyltransferase DNA methyltransferase 1 (Dnmt1), both de novo DNA methyltransferases, Dnmt3a and Dnmt3b or various histone methyltransferases. To investigate this further, we assayed telomere length in whole embryos or adult tissue from mice carrying mutations in four different modifiers of epigenetic reprogramming: Dnmt1, DNA methyltransferase 3-like, structural maintenance of chromosomes hinge domain containing 1, and forkhead box O3a. Terminal restriction fragment analysis was used to compare telomere length in homozygous mutants, heterozygous mutants and wild-type littermates. Contrary to expectation, we did not detect overall lengthening in the mutants, raising questions about the role of epigenetic processes in telomere length in vivo.

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Telomere length in cells deficient for SmcHD1. TRF results are shown for Smchd1+/+, Smchd1+/MD1 and Smchd1MD1/MD1 10.5-day p.c. female embryos (a) and 9-week-old male spleen (b). MD1 MommeD1
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Fig4: Telomere length in cells deficient for SmcHD1. TRF results are shown for Smchd1+/+, Smchd1+/MD1 and Smchd1MD1/MD1 10.5-day p.c. female embryos (a) and 9-week-old male spleen (b). MD1 MommeD1

Mentions: Smchd1MommeD1 is a mutant line that emerged from the ENU mutagenesis screen and was identified as a modifier of epigenetic gene silencing (Blewitt et al. 2008). The mutation was associated with an increase in the expression of the GFP reporter transgene. Females homozygous for the mutation die around mid-gestation from a defect in the maintenance of X chromosome inactivation, while males homozygous for the mutation can survive to adulthood (Blewitt et al. 2008). Smchd1MommeD1 is considered to be a mutation, as homozygous embryos exhibit 5-fold less mRNA than wild-type littermates at 10.5 days p.c. Homozygous mutant females have placental defects and display hypomethylation at X-linked genes that are normally subject to X-inactivation. The expression of some of these genes is upregulated as a result (Blewitt et al. 2008). To test whether telomere length is altered in SmcHD1-deficient cells, we performed TRF analysis on homozygous mutant female embryos at 10.5 days p.c. and on spleen from homozygous mutant adult males (Fig. 4a, b, respectively). These mice are on a FVB/NJ strain background so the normal range of TRF length is greater than that of the C57BL/6J strain, as mentioned previously. While we again observed inter-individual variation in TRFs, there was no apparent difference in the range of sizes in mutant compared to wild-type mice, indicating no detectable effect of SmcHD1 deficiency on overall telomere length.Fig. 4


Reduced dosage of the modifiers of epigenetic reprogramming Dnmt1, Dnmt3L, SmcHD1 and Foxo3a has no detectable effect on mouse telomere length in vivo.

Roberts AR, Blewitt ME, Youngson NA, Whitelaw E, Chong S - Chromosoma (2011)

Telomere length in cells deficient for SmcHD1. TRF results are shown for Smchd1+/+, Smchd1+/MD1 and Smchd1MD1/MD1 10.5-day p.c. female embryos (a) and 9-week-old male spleen (b). MD1 MommeD1
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3140923&req=5

Fig4: Telomere length in cells deficient for SmcHD1. TRF results are shown for Smchd1+/+, Smchd1+/MD1 and Smchd1MD1/MD1 10.5-day p.c. female embryos (a) and 9-week-old male spleen (b). MD1 MommeD1
Mentions: Smchd1MommeD1 is a mutant line that emerged from the ENU mutagenesis screen and was identified as a modifier of epigenetic gene silencing (Blewitt et al. 2008). The mutation was associated with an increase in the expression of the GFP reporter transgene. Females homozygous for the mutation die around mid-gestation from a defect in the maintenance of X chromosome inactivation, while males homozygous for the mutation can survive to adulthood (Blewitt et al. 2008). Smchd1MommeD1 is considered to be a mutation, as homozygous embryos exhibit 5-fold less mRNA than wild-type littermates at 10.5 days p.c. Homozygous mutant females have placental defects and display hypomethylation at X-linked genes that are normally subject to X-inactivation. The expression of some of these genes is upregulated as a result (Blewitt et al. 2008). To test whether telomere length is altered in SmcHD1-deficient cells, we performed TRF analysis on homozygous mutant female embryos at 10.5 days p.c. and on spleen from homozygous mutant adult males (Fig. 4a, b, respectively). These mice are on a FVB/NJ strain background so the normal range of TRF length is greater than that of the C57BL/6J strain, as mentioned previously. While we again observed inter-individual variation in TRFs, there was no apparent difference in the range of sizes in mutant compared to wild-type mice, indicating no detectable effect of SmcHD1 deficiency on overall telomere length.Fig. 4

Bottom Line: Studies carried out in cultured cells have implicated modifiers of epigenetic reprogramming in the regulation of telomere length, reporting elongation in cells that were for DNA methyltransferase DNA methyltransferase 1 (Dnmt1), both de novo DNA methyltransferases, Dnmt3a and Dnmt3b or various histone methyltransferases.Terminal restriction fragment analysis was used to compare telomere length in homozygous mutants, heterozygous mutants and wild-type littermates.Contrary to expectation, we did not detect overall lengthening in the mutants, raising questions about the role of epigenetic processes in telomere length in vivo.

View Article: PubMed Central - PubMed

Affiliation: Epigenetics Laboratory, Queensland Institute of Medical Research, Herston, QLD, Australia.

ABSTRACT
Studies carried out in cultured cells have implicated modifiers of epigenetic reprogramming in the regulation of telomere length, reporting elongation in cells that were for DNA methyltransferase DNA methyltransferase 1 (Dnmt1), both de novo DNA methyltransferases, Dnmt3a and Dnmt3b or various histone methyltransferases. To investigate this further, we assayed telomere length in whole embryos or adult tissue from mice carrying mutations in four different modifiers of epigenetic reprogramming: Dnmt1, DNA methyltransferase 3-like, structural maintenance of chromosomes hinge domain containing 1, and forkhead box O3a. Terminal restriction fragment analysis was used to compare telomere length in homozygous mutants, heterozygous mutants and wild-type littermates. Contrary to expectation, we did not detect overall lengthening in the mutants, raising questions about the role of epigenetic processes in telomere length in vivo.

Show MeSH