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Forget your Past for Enhanced Reprogramming!

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Review of “Reprogramming by De-bookmarking the Somatic Transcriptional Program through Targeting of BET Bromodomains” from Cell Reports by Stuart P. Atkinson

While the attainment of the pluripotent state is key for the production of induced pluripotent stem cells (iPSCs), the erasure of the transcriptional program or “memory” of the donor cell state is equally important. Knowing this, researchers from the laboratory of Kejin Hu (University of Alabama at Birmingham, USA) hoped to get somatic cells to forget their past and lose their cellular memory by interfering with the chromatin modifications which regulate transcriptional programs [1]. Will this lead to enhanced reprogramming?

To compel cells to forget their past, Shao et al inhibited the function of BET (bromodomain and extra-terminal domain) proteins that bind to acetylated histones and positively regulate gene expression. Studies have suggested that BET proteins remain stuck on mitotic chromatin throughout the cell division cycle and “bookmark” active genes. This forms a transcriptional memory that allows the cells to reinitiate the previous transcriptional state and maintain their cellular identity [2, 3].

The study tested three different BET inhibitors (JQ1, CPI203, I-BET151), employing an intermittent- and low-dose treatment schedule during early stages of reprogramming of human fibroblasts. This strategy permitted cell survival, a 22-fold average increase in reprogramming independent of the small molecule, and the production of genomically stable iPSCs.

But was the enhanced reprogramming down to the removal of the fibroblastic transcriptional program? To test this, the authors conducted deep sequencing of RNA and ascertained that BET inhibitor treatment of fibroblasts mediated a decrease in the expression of a large number of fibroblast-specific genes and the loss of fibroblastic morphology. Interestingly, the addition of the reprogramming factors into the mix led to a potent synergism with BET inhibition leading to the downregulation or total repression of the expression of an extended list of fibroblast-specific genes.

A loss of memory never tends to be a good thing, but iPSC researchers couldn’t be happier for fibroblasts to forget their past! But is there more to come? Can we pharmacologically manipulate cell memory to enhance small molecule-only reprogramming or direct reprogramming of somatic cells types (transdifferentiation)? Keep your eyes on the Stem Cell portal to find out!

References

  1. Shao Z, Yao C, Khodadadi-Jamayran A, et al. Reprogramming by De-bookmarking the Somatic Transcriptional Program through Targeting of BET Bromodomains. Cell Reports 16:3138-3145.
  2. Kanno T, Kanno Y, Siegel RM, et al. Selective recognition of acetylated histones by bromodomain proteins visualized in living cells. Mol Cell 2004;13:33-43.
  3. Zhao R, Nakamura T, Fu Y, et al. Gene bookmarking accelerates the kinetics of post-mitotic transcriptional re-activation. Nat Cell Biol 2011;13:1295-1304.