Science1 publisher2 min readPublished
EMBL Rome's timed IVF shows look-alike mouse embryos carry very different RNA
EMBL Rome researchers timed mouse fertilization exactly and read single embryos over nine hours, finding that look-alike embryos hold very different RNA. With every embryo's age known, other labs gain a way to measure how far a treatment shifts genome activation in a mammal.
The Scientist · Science desk
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What happened
- As the embryo's own genome came on, RNA inherited from the mother drained away and genes for RNA production, protein synthesis and ribosome building grew more active.
- Earlier work had tied inherited H3K4me3 histone marks to keeping genes off, and the timed series showed the mark is removed at the same moment the genome activates.
- Boosting an enzyme that strips H3K4me3 removed the mark early, but it changed gene activity only modestly and did not switch the genome on any sooner.
- Embryos stripped of the mark early still went through genome activation and reached the blastocyst stage at rates comparable to untreated controls.
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Why it matters
- decision Mouse RNA studies that stage embryos by appearance alone risk pooling samples from different points in activation, a source of noise that timed fertilization removes.
- constraint The search for what keeps the mouse genome silent before activation loses a candidate that earlier research had proposed, and this study does not offer a replacement.
- precedent The team's catalogue of gradual expression changes gives later mouse studies a timed baseline to set their own embryos against.
Genome activation, the embryo's switch from molecules supplied by the mother to its own genome [2], has been followed closely in fruit flies and zebrafish. Mammalian data are thinner, according to EMBL Rome's account of the work, because the embryos are hard to reach and hard to sample at regular intervals [3]. The study, in Science Advances [1], gets around the sampling problem with timing: Ana Boskovic's group fixed the moment of fertilization in mouse IVF, then read gene activity in individual embryos at several time points [4].
Timing is the control in this design. The differences between look-alike embryos tracked small gaps in time since fertilization [5], a variable a microscope cannot see and the protocol sets for every embryo [4]. With age known, a change in RNA can be assigned either to the embryo's stage or to whatever was done to it.
The epigenome made a second test necessary. In the same window the embryo resets chemical tags on histones and strips and rebuilds DNA methylation, so several candidate drivers change together and none can be singled out by watching [8]. "We were particularly interested in a chemical modification of histone proteins called H3K4me3," said Jasmina Al-Mousawi, the lead author and a former PhD student in the group [9]. A shared timeline is still a correlation [10]. "We were therefore interested in whether these processes are causally linked," she said [11].
Removing the mark ahead of schedule is the right experiment for that question. If the mark's presence were holding the genome silent, taking it away early should have moved activation earlier. It did not [12], and the team concludes that the presence of H3K4me3 is not the feature keeping the genome quiet [14]. "One of the most important findings is how resilient to perturbations the early embryo appears to be," Boskovic said [15]. "Even when an abundant chromatin modification was removed prematurely, the embryos were still able to progress through this critical developmental transition without major adverse outcomes" [15].
The thing this doesn't tell you is what does keep the mouse genome silent before activation. The experiment removes one candidate and leaves the other simultaneous epigenetic changes untested [8]. The published summary does not give embryo counts, the number of time points, or how large the "modest" change in gene activity was [12]. All of it comes from mouse embryos made by IVF [4].
What to watch
- Whether the full Science Advances paper's embryo counts and effect sizes support calling the H3K4me3 effect on gene activity modest.
- Whether other groups use the timed-IVF protocol to test the other marks that reset during activation, such as DNA methylation, for a causal role in silencing.