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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

Hypomorphic phenotype in Kdm1aVasa progeny.(A–D) Brightfield images of M+Z+. (A) and M-Z+ (B–D) embryos derived from Kdm1aVasa control and mutant mothers at embryonic day 3.5 (e3.5). Panels show blastocysts (A,B), a multicellular embryo (C) and a fragmented embryo (D). (E) Percentage of fragmented (purple), 1-cell (green), multi-cellular (blue) and blastocyst (yellow) embryos from Kdm1aVasa control and mutant mothers at e3.5. n = 58 for Kdm1aVasa M+Z+ embryos from 7 litters. n = 79 for Kdm1aVasa M-Z+ embryos from 10 litters. (F) Litter sizes of Kdm1aVasa control and mutant mothers. Average litter size for each indicated by red line. Each circle indicates one litter and n=number of litters analyzed. p-values calculated using an unpaired t-test with **** = p<0.0001 indicating statistical significance. (G) Percentage of newborn pups from Kdm1aVasa heterozygous control and mutant mothers that died perinatally. n = number of litters analyzed. p-values calculated using an unpaired t-test with **** = p<0.0001 indicating statistical significance.DOI:http://dx.doi.org/10.7554/eLife.08848.018
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fig4: Hypomorphic phenotype in Kdm1aVasa progeny.(A–D) Brightfield images of M+Z+. (A) and M-Z+ (B–D) embryos derived from Kdm1aVasa control and mutant mothers at embryonic day 3.5 (e3.5). Panels show blastocysts (A,B), a multicellular embryo (C) and a fragmented embryo (D). (E) Percentage of fragmented (purple), 1-cell (green), multi-cellular (blue) and blastocyst (yellow) embryos from Kdm1aVasa control and mutant mothers at e3.5. n = 58 for Kdm1aVasa M+Z+ embryos from 7 litters. n = 79 for Kdm1aVasa M-Z+ embryos from 10 litters. (F) Litter sizes of Kdm1aVasa control and mutant mothers. Average litter size for each indicated by red line. Each circle indicates one litter and n=number of litters analyzed. p-values calculated using an unpaired t-test with **** = p<0.0001 indicating statistical significance. (G) Percentage of newborn pups from Kdm1aVasa heterozygous control and mutant mothers that died perinatally. n = number of litters analyzed. p-values calculated using an unpaired t-test with **** = p<0.0001 indicating statistical significance.DOI:http://dx.doi.org/10.7554/eLife.08848.018

Mentions: Similar to Kdm1aGdf9and Kdm1aZp3 M-Z+ embryos, the majority of Kdm1aVasaM-Z+ embryos arrest prior to the blastocyst stage (Figure 4A–E). In control Kdm1aVasaM+Z+ embryos at e3.5, 55% of embryos have reached the blastocyst stage, 35% are multicellular (>2C) and 10% are fragmented/degraded (n=37, Figure 4E). In contrast, at e3.5 85% of the Kdm1aVasaM-Z+ embryos have fragmented/degraded (n=35, Figure 4E). However, unlike Kdm1aGdf9and Kdm1aZp3 M-Z+ embryos, which undergo complete embryonic arrest at the 1-2C stage, by e3.5 6% of Kdm1aVasaM-Z+ embryos have reached the multicellular stage (>2C) and 5% are blastocysts (n=35, Figure 4E). Remarkably, some of these Kdm1aVasaM-Z+ embryos survive to birth. The average litter size born from Kdm1aVasamutant mothers is 2.3 (n=20), versus 6.2 (n=32) born from littermate control mothers (Figure 4F). However, the vast majority of time vaginal plugged Kdm1aVasamutant mothers give rise to no viable progeny. Thus, this average litter size is undoubtedly a vast overestimate of the survival of Kdm1aVasaM-Z+ embryos overall.10.7554/eLife.08848.018Figure 4.Hypomorphic phenotype in Kdm1aVasa progeny.


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)

Hypomorphic phenotype in Kdm1aVasa progeny.(A–D) Brightfield images of M+Z+. (A) and M-Z+ (B–D) embryos derived from Kdm1aVasa control and mutant mothers at embryonic day 3.5 (e3.5). Panels show blastocysts (A,B), a multicellular embryo (C) and a fragmented embryo (D). (E) Percentage of fragmented (purple), 1-cell (green), multi-cellular (blue) and blastocyst (yellow) embryos from Kdm1aVasa control and mutant mothers at e3.5. n = 58 for Kdm1aVasa M+Z+ embryos from 7 litters. n = 79 for Kdm1aVasa M-Z+ embryos from 10 litters. (F) Litter sizes of Kdm1aVasa control and mutant mothers. Average litter size for each indicated by red line. Each circle indicates one litter and n=number of litters analyzed. p-values calculated using an unpaired t-test with **** = p<0.0001 indicating statistical significance. (G) Percentage of newborn pups from Kdm1aVasa heterozygous control and mutant mothers that died perinatally. n = number of litters analyzed. p-values calculated using an unpaired t-test with **** = p<0.0001 indicating statistical significance.DOI:http://dx.doi.org/10.7554/eLife.08848.018
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Related In: Results  -  Collection

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fig4: Hypomorphic phenotype in Kdm1aVasa progeny.(A–D) Brightfield images of M+Z+. (A) and M-Z+ (B–D) embryos derived from Kdm1aVasa control and mutant mothers at embryonic day 3.5 (e3.5). Panels show blastocysts (A,B), a multicellular embryo (C) and a fragmented embryo (D). (E) Percentage of fragmented (purple), 1-cell (green), multi-cellular (blue) and blastocyst (yellow) embryos from Kdm1aVasa control and mutant mothers at e3.5. n = 58 for Kdm1aVasa M+Z+ embryos from 7 litters. n = 79 for Kdm1aVasa M-Z+ embryos from 10 litters. (F) Litter sizes of Kdm1aVasa control and mutant mothers. Average litter size for each indicated by red line. Each circle indicates one litter and n=number of litters analyzed. p-values calculated using an unpaired t-test with **** = p<0.0001 indicating statistical significance. (G) Percentage of newborn pups from Kdm1aVasa heterozygous control and mutant mothers that died perinatally. n = number of litters analyzed. p-values calculated using an unpaired t-test with **** = p<0.0001 indicating statistical significance.DOI:http://dx.doi.org/10.7554/eLife.08848.018
Mentions: Similar to Kdm1aGdf9and Kdm1aZp3 M-Z+ embryos, the majority of Kdm1aVasaM-Z+ embryos arrest prior to the blastocyst stage (Figure 4A–E). In control Kdm1aVasaM+Z+ embryos at e3.5, 55% of embryos have reached the blastocyst stage, 35% are multicellular (>2C) and 10% are fragmented/degraded (n=37, Figure 4E). In contrast, at e3.5 85% of the Kdm1aVasaM-Z+ embryos have fragmented/degraded (n=35, Figure 4E). However, unlike Kdm1aGdf9and Kdm1aZp3 M-Z+ embryos, which undergo complete embryonic arrest at the 1-2C stage, by e3.5 6% of Kdm1aVasaM-Z+ embryos have reached the multicellular stage (>2C) and 5% are blastocysts (n=35, Figure 4E). Remarkably, some of these Kdm1aVasaM-Z+ embryos survive to birth. The average litter size born from Kdm1aVasamutant mothers is 2.3 (n=20), versus 6.2 (n=32) born from littermate control mothers (Figure 4F). However, the vast majority of time vaginal plugged Kdm1aVasamutant mothers give rise to no viable progeny. Thus, this average litter size is undoubtedly a vast overestimate of the survival of Kdm1aVasaM-Z+ embryos overall.10.7554/eLife.08848.018Figure 4.Hypomorphic phenotype in Kdm1aVasa progeny.

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