Maternal LSD1/KDM1A is an essential regulator of chromatin and transcription landscapes during zygotic genome activation.
Bottom Line: Upon fertilization, the highly specialised sperm and oocyte genomes are remodelled to confer totipotency.The mechanisms of the dramatic reprogramming events that occur have remained unknown, and presumed roles of histone modifying enzymes are just starting to be elucidated.At the transcriptional level, the switch of the maternal-to-zygotic transition fails to be induced properly and LINE-1 retrotransposons are not properly silenced.
Affiliation: Institut Curie, Paris, France.
Upon fertilization, the highly specialised sperm and oocyte genomes are remodelled to confer totipotency. The mechanisms of the dramatic reprogramming events that occur have remained unknown, and presumed roles of histone modifying enzymes are just starting to be elucidated. Here, we explore the function of the oocyte-inherited pool of a histone H3K4 and K9 demethylase, LSD1/KDM1A during early mouse development. KDM1A deficiency results in developmental arrest by the two-cell stage, accompanied by dramatic and stepwise alterations in H3K9 and H3K4 methylation patterns. At the transcriptional level, the switch of the maternal-to-zygotic transition fails to be induced properly and LINE-1 retrotransposons are not properly silenced. We propose that KDM1A plays critical roles in establishing the correct epigenetic landscape of the zygote upon fertilization, in preserving genome integrity and in initiating new patterns of genome expression that drive early mouse development.
No MeSH data available.
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Mentions: Numerous Kdm1af/f::Zp3cre females were housed with wild-type males for several months, however no progeny was ever obtained, in contrast to Kdm1af/f or f/wt females that produced the expected range of pup number (4 to 7; data not shown). This indicated that Kdm1af/f::Zp3cre females are sterile. To determine the possible causes of sterility, control Kdm1af/f and mutant Kdm1af/f::Zp3cre females were mated with wild-type males and embryos were recovered on embryonic day 2 (E2) (Figure 1D and E). The total number of oocytes or embryos scored per female was on average 17 for the mutant background (206 oocytes or embryos obtained for 12 females studied) and 25 for the control (226 oocytes or embryos obtained for 9 females studied) (see Figure 1D). We found that the proportion of △m/wt two-cell stage embryos recovered (19%, n = 39/206) was far lower than that obtained with f/wt embryos (75% n = 170/226) (Figure 1D). Using Kdm1af/f::Zp3cre females, we also noted a high percentage of fertilized and unfertilized oocytes blocked at meiosis II (MII) (n = 95; 46%) compared to those recovered from control females (n = 34; 15%). Inspection of control (n = 75) and mutant (n = 55) MII oocytes revealed a high proportion of misaligned chromosomes on the metaphase spindle (Figure 1—figure supplement 1B and C) in mutants (41%) compared to controls (17%), suggesting that a lack of maternal KDM1A can lead to chromosome segregation defects. Furthermore, upon fertilization, transmission of inherited chromosomal abnormalities was clearly evident, with the frequent presence of micronuclei in KDM1A maternally depleted two-cell embryos (n = 40; 63%) (Figure 1—figure supplement 1D). Lastly, 19% (n = 39) of mutant embryos were still at the zygote stage compared to 0% in controls (Figure 1D). These results indicate that many MII oocytes lacking germline KDM1A are not competent at ovulation and that when fertilized their first cell cycle is delayed. Similar results were obtained when using females not subjected to superovulation for mating (Fig1—figure supplement 2).
No MeSH data available.