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Totipotency – Just an miRNA Away?



Review of “Deficiency of microRNA miR-34a expands cell fate potential in pluripotent stem cells” from Science by Stuart P. Atkinson

We often consider the pluripotent state of pluripotent stem cells (PSCs) as the top level of the cellular hierarchy, as they represent cells with the ability to generate all embryonic cell lineages. Yet, the totipotent cellular state, present in the cells of mouse zygotes and 2-cell stage (2C) blastomeres [1, 2] looms above the pluripotent state with the additional ability to generate extra-embryonic cell types.

Following reports of rare PSC populations with expanded cell fate potential (See original study for extensive references) researchers from the laboratory of Lin He (University of California, Berkeley, USA) proposed that the identification and removal of certain molecular barriers may “nudge” pluripotent ESCs/IPSCs into the higher, totipotent state.

Now, in a new Science study that could lead to the production of human totipotent stem cells, Choi, Lin, and Risso et al report that the loss of miR-34a microRNA (miRNA) expression in mouse (m)PSCs allows transit to the totipotent state [3]. Are we just an miRNA away from totipotency?

So why pick on miR-34a? A previous study indicated that miR-34 miRNAs represented a barrier to the induced pluripotent cell (iPSC) reprogramming process [4], and in agreement with this study, teratoma assays and differentiation soon demonstrated to the authors that miR-34a null mPSCs featured the ability to differentiate into cells of the three germ layers and extra-embryonic placental lineages, suggestive of totipotent differentiation capacity.  Furthermore, miR-34a null mPSCs also expressed MuERV-L (MERVL) endogenous retroviruses, similar to totipotent 2C blastomeres and ESCs with expanded cell fate potential. 

So what’s the link? It turns out that miR-34a is a potent and direct repressor of the GATA-binding protein 2 (Gata2) transcription factor. During early pre-implantation development, Gata2 exhibits an expression pattern similar to MERVL and the study soon discovered that MERVL transcriptional regulatory elements contain a confirmed Gata2 binding site. One possibility is that Gata2-mediated MERVL activation following miR-34a loss may activate nearby 2C blastomere-specific genes, such as Hnf4a and Usp17lc, and alter the molecular network of the cell towards a totipotent fate.

This all suggests that the understanding of the mouse totipotent state may just be an miRNA away, and given the fact that human embryonic stem cells (hESCs) express specific retrotransposon families during the transition to naive-state pluripotency [5, 6], we may also be a step closer to human totipotency. 

What other secrets do these evolutionary remnants of invading foreign DNA sequences hold in store? Keep tuned to the Stem Cells Portal to find out.


  1. Papaioannou VE, Mkandawire J, and Biggers JD. Development and phenotypic variability of genetically identical half mouse embryos. Development 1989;106:817-827.
  2. Tarkowski AK. Experiments on the development of isolated blastomers of mouse eggs. Nature 1959;184:1286-1287.
  3. Choi YJ, Lin CP, Risso D, et al. Deficiency of microRNA miR-34a expands cell fate potential in pluripotent stem cells. Science 2017;355:
  4. Choi YJ, Lin CP, Ho JJ, et al. miR-34 miRNAs provide a barrier for somatic cell reprogramming. Nat Cell Biol 2011;13:1353-1360.
  5. Wang J, Xie G, Singh M, et al. Primate-specific endogenous retrovirus-driven transcription defines naive-like stem cells. Nature 2014;516:405-409.
  6. Theunissen TW, Friedli M, He Y, et al. Molecular Criteria for Defining the Naive Human Pluripotent State. Cell Stem Cell 2016;19:502-515.