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Maternally provided LSD1/KDM1A enables the maternal-to-zygotic transition and prevents defects that manifest postnatally.

Wasson JA, Simon AK, Myrick DA, Wolf G, Driscoll S, Pfaff SL, Macfarlan TS, Katz DJ - Elife (2016)

Bottom Line: Moreover, partial loss of maternal LSD1/KDM1A results in striking phenotypes weeks after fertilization; including perinatal lethality and abnormal behavior in surviving adults.These maternal effect hypomorphic phenotypes are associated with alterations in DNA methylation and expression at imprinted genes.These results establish a novel mammalian paradigm where defects in early epigenetic reprogramming can lead to defects that manifest later in development.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell Biology, Emory University School of Medicine, Atlanta, United States.

ABSTRACT
Somatic cell nuclear transfer has established that the oocyte contains maternal factors with epigenetic reprogramming capacity. Yet the identity and function of these maternal factors during the gamete to embryo transition remains poorly understood. In C. elegans, LSD1/KDM1A enables this transition by removing H3K4me2 and preventing the transgenerational inheritance of transcription patterns. Here we show that loss of maternal LSD1/KDM1A in mice results in embryonic arrest at the 1-2 cell stage, with arrested embryos failing to undergo the maternal-to-zygotic transition. This suggests that LSD1/KDM1A maternal reprogramming is conserved. Moreover, partial loss of maternal LSD1/KDM1A results in striking phenotypes weeks after fertilization; including perinatal lethality and abnormal behavior in surviving adults. These maternal effect hypomorphic phenotypes are associated with alterations in DNA methylation and expression at imprinted genes. These results establish a novel mammalian paradigm where defects in early epigenetic reprogramming can lead to defects that manifest later in development.

No MeSH data available.


Related in: MedlinePlus

Imprinting analysis of Kdm1aVasa progeny.(A,C,E) Allele-specific bisulfite analysis of, Igf2r (A), Mest (C), and Snrpn (E). Each line represents the clone of an allele. Each circle represents a CpG dinucleotide where closed circles indicate methylation and open circles indicate no methylation. Maternal and paternal alleles are indicated. (B,D,F) Relative expression analysis of Igf2r (B), Mest (D), and Snrpn (F). Expression normalized to β-actin. Error bars indicate ± S.E.M. p-values calculated using an unpaired t-test with n.s. indicating p>0.05, * = p<0.05, ** = p<0.005, **** = p<0.0001. All asterisks indicate statistical significance. All analyses were performed on a stage matched B6/CAST hybrid control pup and 2 maternal effect progeny (MEP) exhibiting perinatal lethality.DOI:http://dx.doi.org/10.7554/eLife.08848.025
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fig6s1: Imprinting analysis of Kdm1aVasa progeny.(A,C,E) Allele-specific bisulfite analysis of, Igf2r (A), Mest (C), and Snrpn (E). Each line represents the clone of an allele. Each circle represents a CpG dinucleotide where closed circles indicate methylation and open circles indicate no methylation. Maternal and paternal alleles are indicated. (B,D,F) Relative expression analysis of Igf2r (B), Mest (D), and Snrpn (F). Expression normalized to β-actin. Error bars indicate ± S.E.M. p-values calculated using an unpaired t-test with n.s. indicating p>0.05, * = p<0.05, ** = p<0.005, **** = p<0.0001. All asterisks indicate statistical significance. All analyses were performed on a stage matched B6/CAST hybrid control pup and 2 maternal effect progeny (MEP) exhibiting perinatal lethality.DOI:http://dx.doi.org/10.7554/eLife.08848.025

Mentions: In addition to the altered imprinting at Zac1 and Impact, we observe a general disruption of several additional imprinted genes. At two of these additional imprinted loci (H19 and Igf2r), DNA methylation is altered (Figure 6G and Figure 6—figure supplement 1A). For example, at H19 DNA methylation is inappropriately lost on the paternal allele in MEP1 (Figure 6G). There is also a slight acquisition of inappropriate methylation on the maternal allele of both MEP (Figure 6G). At two additional imprinted genes (Mest and Snrpn), DNA methylation appears normal (Figure 6—figure supplement 1C,E). Furthermore, at three of the additional imprinted loci, we observe an overall decrease in gene expression. These include Igf2r, Mest, and Snrpn (Figure 6—figure supplement 1B,D,F), while at H19, expression levels are unaffected (Figure 6H). However, the allele-specific expression of all of these additional imprinted loci remains unaffected (data not shown). Taken together, the changes in DNA methylation and expression indicate a general disruption in the normal regulation of genomic imprinting.


Maternally provided LSD1/KDM1A enables the maternal-to-zygotic transition and prevents defects that manifest postnatally.

Wasson JA, Simon AK, Myrick DA, Wolf G, Driscoll S, Pfaff SL, Macfarlan TS, Katz DJ - Elife (2016)

Imprinting analysis of Kdm1aVasa progeny.(A,C,E) Allele-specific bisulfite analysis of, Igf2r (A), Mest (C), and Snrpn (E). Each line represents the clone of an allele. Each circle represents a CpG dinucleotide where closed circles indicate methylation and open circles indicate no methylation. Maternal and paternal alleles are indicated. (B,D,F) Relative expression analysis of Igf2r (B), Mest (D), and Snrpn (F). Expression normalized to β-actin. Error bars indicate ± S.E.M. p-values calculated using an unpaired t-test with n.s. indicating p>0.05, * = p<0.05, ** = p<0.005, **** = p<0.0001. All asterisks indicate statistical significance. All analyses were performed on a stage matched B6/CAST hybrid control pup and 2 maternal effect progeny (MEP) exhibiting perinatal lethality.DOI:http://dx.doi.org/10.7554/eLife.08848.025
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4829428&req=5

fig6s1: Imprinting analysis of Kdm1aVasa progeny.(A,C,E) Allele-specific bisulfite analysis of, Igf2r (A), Mest (C), and Snrpn (E). Each line represents the clone of an allele. Each circle represents a CpG dinucleotide where closed circles indicate methylation and open circles indicate no methylation. Maternal and paternal alleles are indicated. (B,D,F) Relative expression analysis of Igf2r (B), Mest (D), and Snrpn (F). Expression normalized to β-actin. Error bars indicate ± S.E.M. p-values calculated using an unpaired t-test with n.s. indicating p>0.05, * = p<0.05, ** = p<0.005, **** = p<0.0001. All asterisks indicate statistical significance. All analyses were performed on a stage matched B6/CAST hybrid control pup and 2 maternal effect progeny (MEP) exhibiting perinatal lethality.DOI:http://dx.doi.org/10.7554/eLife.08848.025
Mentions: In addition to the altered imprinting at Zac1 and Impact, we observe a general disruption of several additional imprinted genes. At two of these additional imprinted loci (H19 and Igf2r), DNA methylation is altered (Figure 6G and Figure 6—figure supplement 1A). For example, at H19 DNA methylation is inappropriately lost on the paternal allele in MEP1 (Figure 6G). There is also a slight acquisition of inappropriate methylation on the maternal allele of both MEP (Figure 6G). At two additional imprinted genes (Mest and Snrpn), DNA methylation appears normal (Figure 6—figure supplement 1C,E). Furthermore, at three of the additional imprinted loci, we observe an overall decrease in gene expression. These include Igf2r, Mest, and Snrpn (Figure 6—figure supplement 1B,D,F), while at H19, expression levels are unaffected (Figure 6H). However, the allele-specific expression of all of these additional imprinted loci remains unaffected (data not shown). Taken together, the changes in DNA methylation and expression indicate a general disruption in the normal regulation of genomic imprinting.

Bottom Line: Moreover, partial loss of maternal LSD1/KDM1A results in striking phenotypes weeks after fertilization; including perinatal lethality and abnormal behavior in surviving adults.These maternal effect hypomorphic phenotypes are associated with alterations in DNA methylation and expression at imprinted genes.These results establish a novel mammalian paradigm where defects in early epigenetic reprogramming can lead to defects that manifest later in development.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell Biology, Emory University School of Medicine, Atlanta, United States.

ABSTRACT
Somatic cell nuclear transfer has established that the oocyte contains maternal factors with epigenetic reprogramming capacity. Yet the identity and function of these maternal factors during the gamete to embryo transition remains poorly understood. In C. elegans, LSD1/KDM1A enables this transition by removing H3K4me2 and preventing the transgenerational inheritance of transcription patterns. Here we show that loss of maternal LSD1/KDM1A in mice results in embryonic arrest at the 1-2 cell stage, with arrested embryos failing to undergo the maternal-to-zygotic transition. This suggests that LSD1/KDM1A maternal reprogramming is conserved. Moreover, partial loss of maternal LSD1/KDM1A results in striking phenotypes weeks after fertilization; including perinatal lethality and abnormal behavior in surviving adults. These maternal effect hypomorphic phenotypes are associated with alterations in DNA methylation and expression at imprinted genes. These results establish a novel mammalian paradigm where defects in early epigenetic reprogramming can lead to defects that manifest later in development.

No MeSH data available.


Related in: MedlinePlus