The Roles of RNA Epigenetics & RNA Processing in Embryonic Development
July 26, 2019
One of the first events in embryonic development is a process called zygotic genome activation (ZGA). It’s during ZGA that any epigenetic modifications from the maternal or paternal genomes are removed and the zygote begins a new transcriptional profile and adopts a pluripotent state.
ZGA is a critical process in development and there are many different mechanisms and layers of regulation involved, including epigenetic changes and post-transcriptional activities such as mRNA processing and modifications.
A recent paper published in the journal Scientific Reports investigated the role of the RNA epigenetic modification N6-methyladenosine (m6A) and the RNA-binding protein hnRNPA2/B1 in embryonic development.
A Role for RNA Processing in Embryonic Development
Gene regulation is an extremely complex process that involves regulation at many different steps, both at the level of transcription and post-transcriptionally. One of the major types of post-transcriptional regulation of gene expression is RNA processing, which includes mRNA splicing, polyadenylation, and RNA modification.
A major protein family involved in RNA processing is the heterogeneous nuclear ribonucleoproteins (hnRNPs). hnRNPs are nuclear RNA-binding proteins and they have been reported to play roles in RNA splicing, mRNA stability, polyadenylation, and mRNA localization. In particular, the protein hnRNPA2/B1 has been shown to play an important role in the processing of mRNA and miRNAs, likely through a mechanism involving m6A modifications in these RNAs.
A team of researchers in South Korea recently investigated the role of hnRNPA2/B1 during embryonic development and the involvement of the RNA modification m6A in the regulation of this process.
They found that hnRNPA2/B1 was expressed very early in development, and its levels drastically increased at the 4-cell stage of embryogenesis. These results confirmed that hnRNPA2/B1 is expressed after ZGA and suggest that it may play an important role in embryonic development.
The researchers next used RNAi to knock down the levels of hnRNPA2/B1 and observed delays in development, which is consistent with this factor contributing to the early developmental process.
Furthermore, the team of scientists also reported that the levels of the pluripotency factors OCT4 and SOX2 were reduced when hnRNPA2/B1 was knocked down, further supporting it plays a role in regulating the expression of genes involved in pluripotency and cellular differentiation.
Additional RNA-Seq experiments demonstrated that the global transcription patterns were altered at the blastocyst stage of development when hnRNPA2/B1 was knocked down. In particular, the m6A demethylase ALKBH5 was down-regulated when hnRNPA2/B1 was knocked down, suggesting that hnRNPA2/B1 normally positively regulates its expression and therefore plays a role in regulating the epigenetic modification of RNA.
What is the m6A Modification in RNA?
The m6A modification has been found in many different types of RNAs, including mRNAs, tRNAs, snRNAs, and other types of non-coding RNAs. This epigenetic modification to RNA is catalyzed by the METTL3-14 complex and is removed by the enzyme FTO and the previously mentioned ALKBH5.
It is hypothesized that m6A acts as a beacon for RNA-binding proteins that recognize, or “read,” this modification and then carry out their biological activities, such as RNA processing, at these modified sites.
The YTH domain family of RNA-binding proteins (YTHDF1, YTHDF2, YTHDF3, and YTHDC1) are the best-characterized factors that read the m6A modification, but there are other proteins being identified that can recognize and bind m6A in RNA. In particular, hnRNPA2/B1 binds to m6A in certain miRNAs, suggesting that it might regulate the processing of these non-coding RNAs.
Link Between m6A in RNA and RNA Processing During Embryo Development
Researchers recently investigated the involvement of the m6A epigenetic modification in RNA and the RNA-binding protein hnRNPA2/B1 in embryonic development by performing experiments after knocking down the m6A RNA methyltransferase METTL3 using RNAi.
The levels of m6A were decreased in cells with METTL3 knocked down and the knockdown contributed to significant developmental defects. Furthermore, the levels of hnRNPA2/B1 were decreased and its localization was altered in the METTL3 knockdown cells, it accumulated more in the cytoplasm rather than in the nucleus where it normally localizes. These results suggested that m6A in RNA might be required for proper intracellular localization of hnRNPA2/B1.
The Rise of RNA Modifications and Epitranscriptomics
While DNA methylation is still the best-studied epigenetic modification of nucleic acids, it is clear that RNA modifications, including m6A, also deserve recognition because they are important players in many different biological processes.
There are currently almost 200 different RNA modifications known to exist. Several of these, including m6A and 5-mC, have been reported to have roles in the regulation of gene expression.
The field of RNA epigenetics, also known as epitranscriptomics, is young and there is still a lot to learn. Active Motif is committed to developing the antibodies, kits, services, and other tools that will facilitate discoveries that move RNA epigenetics research forward.
Reference: Kwon, J. et al. Functional roles of hnRNPA2/ B1 regulated by METTL3 in mammalian embryonic development. Scientific Reports 9:8640. (2019)
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