What’s New in Biology: Viral Elements and Embryonic Development

Topics: Embryonic development, retrotransposons, zygotic genome activation, regulation of gene expression

Original Publication: “Endogenous retroviruses synthesize heterologous chimeric RNAs to reinforce human early embryo development” — Yangquan Xiang, et al., 2026. Science.

Artistic depiction of some of the complexity inside a cell. (Image from Digizyme)

Biological Problem:

Embryos rely on maternally deposited mRNAs (messenger RNAs that are already inside the egg before fertilization), which can be quickly translated into proteins during early development. However, the embryo must soon begin to transcribe (or produce) its own RNAs, and this shift is called zygotic genome activation (ZGA).

Failure to activate the zygotic genome results in developmental arrest, meaning that the cells of the embryo no longer grow or divide, which can be one explanation of infertility.

zygotic genome activation (ZGA): the process by which an early embryo begins to transcribe its genome.

Methods:

The authors used RNA sequencing to compare the transposable elements (TEs) between healthy and arrested embryos. This technique allows them to compare the sequences themselves, in addition to the relative abundance of each RNA transcript.

Transposable elements (TEs), transposons: DNA sequences that are capable of changing their position within the genome. TEs originated from ancient viruses that became incorporated into other genomes, and over evolutionary time, host cells developed mechanisms to “silence” these TEs to prevent hopping which could disrupt normal gene sequences.

To examine what happens in the absence of a particular transcript, the authors used antisense oligos (ASOs), which are small non-coding RNAs that have the complimentary sequence to a “target” RNA. Recognition of the target RNA by the ASO prevents the target from functioning properly (if the target is an mRNA, ASO binding prevents translation into a protein). This targeted attenuation is also referred to as “knockdown.”

Schematic to depict an antisense oligo targeting an mRNA. (Image from National Ataxia Foundation)

Oligo (short for oligonucleotide): a short combination of nucleotides (e.g. molecules found in nucleic acids, abbreviated A, C, T, G, and U)

Findings:

The authors found one particular transposable element family, called MLT2A1, was much less abundant in embryos that had arrested compared to healthy embryos.

Intentionally depleting MLT2A1 subfamily TEs by using antisense oligos resulted in a higher number of arrested embryos, suggesting that proper expression of these TEs is required for zygotic genome activation.

Surprisingly, transcripts from the MLT2A1 TEs were chimeric, having fusions of different genes. These transcripts sometimes including both coding and non-coding sequences, or could also include sequences from other TE subfamilies.

These MLT2A1 transcripts were found to bind to a protein that recruits the enzyme RNA polymerase II, which is required to facilitate zygotic genome transcription.

From the paper, Fig. 1C. Embryos with a control knockdown (KD, top row) or with knockdown of MLT2A1 (bottom row). Scale bars = 50µm.

Future Directions and Potential Applications:

This surprising demonstration that an ancient viral sequence is required to be expressed for zygotic genome activation opens explains one facet of embryonic arrest. These findings also suggest that other TE transcripts may have functional roles in embryonic development or in other gene regulatory contexts that can be explored.

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