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Breaking down Epigenetic Barriers to iPSC Reprogramming

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Review of “TRIM28 is an Epigenetic Barrier to Induced Pluripotent Stem Cell Reprogramming” from Stem Cells by Stuart P. Atkinson

Change is always a difficult proposition; even unstoppable forces and immovable objects come up against problematic barriers and obstacles! For the process of induced pluripotent stem cell (iPSC) reprogramming, changing from a somatic cell type to a pluripotent cell type comes up against epigenetic barriers; the need to alter genome-wide epigenetic profiles which mediate gene expression.

Researchers from the laboratories of Denise Miles (Walter and Eliza Hall Institute, Parkville, Australia) and Maarten van Lohuizen (Netherlands Cancer Institute, Amsterdam, The Netherlands) sought to better understand the iPSC reprogramming process, identify and understand any potential epigenetic barriers, and then using this knowledge, improve reprogramming efficiency.

In their new Stem Cells study, Mile et al have employed a large-scale short hairpin (sh)RNA screen to identify the epigenetic modifier Tripartite motif-containing 28 (Trim28) as one of the major epigenetic barriers to iPSC reprogramming [1].

The initial screen assessed the effects of shRNAs for 670 unique genes during inducible reprogramming of immortalized Oct4-reporter mouse embryonic fibroblasts (MEFs). Trim28 and Setdb1, which normally interact to establish the repressive H3K9me3 histone mark, came out as the top hits, with Setdb1 loss already known to enhance reprogramming [2]. 

Concentrating on Trim28, the authors demonstrated that the knockdown of Trim28 enhanced reprogramming by 17- to 21-fold without having any effect on cell proliferation. Interestingly, the genes upregulated after loss of Trim28 during reprogramming did not belong to a specific pathway but instead tended to be genes situated in repressed chromatin regions associated with high levels of H3K9me3. Furthermore, the relaxation of the chromatin state following Trim28 loss permitted the expression of endogenous retroviruses (ERVs), suggesting that Trim28 knockdown may require tight control to limit any deleterious “side-effects” of enhanced reprogramming.

Another great Stem Cells study, one more of the barriers to iPSC reprogramming overcome! The authors suggest that their findings herald the H3K9me3 barrier as the most important epigenetic barrier to iPSC reprogramming and note an interest in uncovering roles for Trim28 in other in vitro reprogramming methods. One thing is for sure, this paper brings us one step closer to the full realization of the role epigenetic has in the maintenance of both the somatic and pluripotent cell states.

References

  1. Miles DC, de Vries NA, Gisler S, et al. TRIM28 is an Epigenetic Barrier to Induced Pluripotent Stem Cell Reprogramming. STEM CELLS 2017;35:147-157.
  2. Chen J, Liu H, Liu J, et al. H3K9 methylation is a barrier during somatic cell reprogramming into iPSCs. Nat Genet 2013;45:34-42.