The earliest stages of mammalian development involve the epigenetic reprogramming of both parental gametes to a state of totipotency. During this process the embryonic genome is transcriptionally silent and is regulated by factors deposited in the oocyte prior to fertilisation. Early embryonic transcription is characterised by widespread expression of retro-elements (LINE, SINE and ERV), usually silenced in the soma, but robustly expressed in the pre-implantation embryo, and essential for normal embryonic development. It is well established that retroelement reactivation interferes with DNA replication causing a stalling of the replication machinery and, if left unresolved, DNA damage. Given that such stresses would be catastrophic for the embryo at this stage, we hypothesised that cells must exploit novel mechanisms to maintain genomic stability in the founder cells of the entire organism.
Here we present unpublished data showing that mRNA export plays a crucial role in mitigating conflicts between the transcription and replication machinery. Specifically, we identify a novel cluster of paralogs of the main adapter protein for the TRanscription-Export (TREX) complex, ALY/REF, which are exclusively expressed during zygotic genome activation. Using an in vitro model for this stage of development, and a combination of CRISPR-activation, CRISPR-inhibition and degron-mediated protein tuning, we show that expression of this cluster of export adapter proteins is essential for cell viability. Surprisingly, when ALY/REF-TREX activity is inhibited, there is minimal impact on gene expression, however cells collapse out of S-phase of the cell cycle within 8 hours exhibiting signs of replication stress.
Collectively, our results show a strong requirement for mRNA export in safeguarding the embryonic genome and indicate an important role for this process outside of canonical gene expression.