We seek to learn both how cells control the activity of transposable elements (TEs) and how the activity of TEs regulates cells.
One of the most striking aspects of mammalian genomes is the extraordinary abundance of TEs. Their ability to mobilize and insert anywhere in the genome can cause mutations that are generally detrimental to the host. However, TEs might also have played a major role in mammalian biology by forming gene regulatory networks as part of the ‘self.’
Recently, much of our work focuses on systematically understanding the role of TEs in early embryos. During early embryogenesis, a TE burst occurs, which accompanies a burst of an abundant set of clustered genes/multi-copy genes (e.g., Dux, Zscan4, Obox). We are particularly interested in the role of TEs in zygotic genome activation (ZGA), cell potency, and normal embryonic development. To this end, we use mouse and hamster embryos and embryonic stem cells (mESCs) as models to reveal how TEs and clustered genes regulate host gene networks to ensure ZGA and normal embryonic development. We are currently engaged in generating mice and mESCs with genome-edited TEs and clustered gene loci.
TEs have been studied en masse but not as individual entities within their genomic ecosystem. The most challenging part of our research is, therefore, to elucidate how each TE element behaves differently during ZGA and embryonic development and how such behaviors affect gene regulatory networks of the totipotent state and the transition from totipotency to pluripotency. To reveal the role of individual TEs and facilitate the experiments described above, we are currently engaged in developing state-of-the art bioinformatic platforms to analyze individual TEs and clustered genes.
With the information we obtain, we try to develop cell culture systems that induce mESCs into blastocyst-like structures with totipotency. Together, our work will attempt to reveal how the functions of TEs and each clustered gene are integrated to give rise to emergent properties that regulate development. Conceptual advances in these model animals will strongly impact our understanding of this fascinating regulatory pathway in humans.
Related Reviews:
Siomi H, Siomi MC.
On the road to reading the RNA-interference code
Nature 2009. 457: 396-404.
Iwasaki YW, Siomi MC, Siomi H.
PIWI-Interacting RNA: Its Biogenesis and Functions
Annu Rev Biochem. 2015. 84: 405-433
Guo Y, Li TD, Modzelewski AJ, Siomi H.
Retrotransposon renaissance in early embryos
Trends in Genetics 2023. 40: 39-51
Solberg T, Kobayashi-Ishihara M, Siomi H.
The impact of retrotransposons on the chromatin landscape of early embryos
Ann N Y Acad Sci 2024. 1542: 11-24