Abstract
Heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNPA2/B1) plays an important role in RNA processing via in m6A modification of pre-mRNA or pre-miRNA. However, the functional role of and relationship between m6A and hnRNPA2/B1 in early embryonic development are unclear. Here, we found that hnRNPA2/B1 is crucial for early embryonic development by virtue of regulating specific gene transcripts. HnRNPA2/B1 was localized to the nucleus and cytoplasm during subsequent embryonic development, starting at fertilization. Knockdown of hnRNPA2/B1 delayed embryonic development after the 4-cell stage and blocked further development. RNA-Seq analysis revealed changes in the global expression patterns of genes involved in transcription, translation, cell cycle, embryonic stem cell differentiation, and RNA methylation in hnRNPA2/B1 KD blastocysts. The levels of the inner cell mass markers OCT4 and SOX2 were decreased in hnRNPA2/B1 KD blastocysts, whereas that of the differentiation marker GATA4 was decreased. N6-Adenosine methyltransferase METTL3 knock-down caused embryonic developmental defects similar to those in hnRNPA2/B1 KD embryos. Moreover, METTL3 KD blastocysts showed increased mis-localization of hnRNPA2/B1 and decreased m6A RNA methylation. Taken together, our results suggest that hnRNPA2/B1 is essential for early embryogenesis through the regulation of transcription-related factors and determination of cell fate transition. Moreover, hnRNPA2/B1 is regulated by METTL3-dependent m6A RNA methylation.
Highlights
During the initial few rounds of mitotic cell division, gene expression in mammalian zygote is repressed, and the embryos rely on maternally accumulated mRNAs for their initial development
These results show that hnRNPA2/B1 transcription begins after zygotic genome activation (ZGA) and is localized in the nuclei and cytoplasm during early embryo development in mouse
The ZGA process is important during early embryonic development; RNA synthesis is involved in differentiation into inner cell mass (ICM)/TE and formation of the blastocyst. hnRNPA2/B1 is an RNA-binding protein and a member of the hnRNP family, and contains several RNA recognition motif (RRM) sites that can bind to mRNAs and regulate various mRNA processes such as mRNA transport, alternative splicing, and maintenance of mRNA stability[22,23,40]
Summary
During the initial few rounds of mitotic cell division, gene expression in mammalian zygote is repressed, and the embryos rely on maternally accumulated mRNAs for their initial development. In zygotic gene transcription and initial cell fate determinations, dynamic changes in epigenetic states occur. Several epigenetic changes related to transcriptional reprogramming, including DNA demethylation and histone modification involved in ZGA and pluripotency have been extensively studied[5,6,7,8]. MRNA in mammalian embryos undergo several post-transcriptional modifications during early embryogenesis. The length of the polyadenylated tail (poly(A) tail) of mRNA in many embryos is dynamically changed during oocyte maturation and early embryogenesis, controlling the translational efficiency of mRNAs. Recently, uridylation at the 3′ end of mRNAs has been found to play a role as a signal for mRNA degradation[9]. Heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNPA2/B1) has been found to mediate nuclear miRNA biogenesis, identifying N6-methyladenosine (m6A)[20]
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