Translatome and transcriptome co-profiling reveals a role of TPRXs in human zygotic genome activation

Abstract

Translational regulation plays a critical role during the oocyte-to-embryo transition (OET) and zygotic genome activation (ZGA). Here, we integrated ultra-low-input Ribo-seq with mRNA-seq to co-profile the translatome and transcriptome in human oocytes and early embryos. Comparison with mouse counterparts identified widespread differentially translated genes functioning in epigenetic reprogramming, transposon defense, and small RNA biogenesis, in part driven by species-specific regulatory elements in 3′ untranslated regions. Moreover, PRD-like homeobox transcription factors, including TPRXL, TPRX1, and TPRX2, are highly translated around ZGA. TPRX1/2/L knockdown leads to defective ZGA and preimplantation development. Ectopically expressed TPRXs bind and activate key ZGA genes in human embryonic stem cells. These data reveal the conservation and divergence of translation landscapes during OET and identify critical regulators of human ZGA.

Zygotic genome activation by the totipotency pioneer factor Nr5a2

“…The classification of Nr5a2 and Esrrb as pioneer factors suggests that the mechanism of multiple pioneer factors triggering ZGA is evolutionarily conserved from fly to mouse and possibly to human, despite differences in transcription factor identities. The species-specific regulation of some ZGA genes is supported by the recent finding that human-specific TPRXs contribute to ZGA ( 49 ). However, ZGA is a fundamental process that initiates control of the zygotic genome for all multicellular organisms.…”

NR5A2 connects genome activation to the first lineage segregation in early mouse development

“…The TF-regulome maps presented here also pave the ways for future studies to decode transcription circuitry underlying early development and cell fate decisions when life begins. Finally, given Nr5a2 expression is quite low in human embryos unlike its counterpart in mouse 50, 51 (Fig. S6a), it would be highly interesting to investigate whether other nuclear receptor TFs may execute similar functions in human early development.…”

“… a , Bar charts showing NR5A2/Nr5a2 mRNA levels from RNA-seq and ribosome-protected fragment (RPF, reflecting translation) levels from Ribo-seq in human (left) and mouse (right) early embryos. 13, 14 …”

Obox4promotes zygotic genome activation upon loss ofDux

“…Unlike Dux , which is structurally and functionally conserved throughout placentalia 47 , the ancestral locus of the Obox family appears to have undergone mouse-specific duplication and generated a gene cluster that is collectively syntenic to the Tprx2 locus in other mammals 48 . Despite the distal homology between Obox4 and Tprx2 , it has been recently reported that human TPRX2 is expressed in 8-cell embryos 14 Interestingly, while our work was being reviewed, TPRX2 was shown to cause defective ZGA upon embryonic depletion and bind critical ZGA genes in hESCs 49 , suggesting that the Tprx2 locus has undergone functionally convergent evolution despite its divergent genetic context. However, whether TPRX2 plays a similar role in humans to Obox4 in mice regarding the redundancy to Dux ( DUX4 in humans) remains to be elucidated.…”

“…Despite the distal homology between Obox4 and Tprx2, it has been recently reported that human TPRX2 is expressed in 8-cell embryos 14 . Interestingly, while our work was being reviewed, TPRX2 was shown to cause defective ZGA upon embryonic depletion and bind critical ZGA genes in hESCs 49 , suggesting that the Tprx2 locus has undergone functionally convergent evolution despite its divergent genetic context. However, whether TPRX2 plays a similar role in humans to Obox4 in mice regarding the redundancy to Dux (DUX4 in humans) remains to be elucidated.…”