While lingering memories can represent unwelcome guests, destroying them with the power of dynamite may seem like overkill! However, a volatile new study now describes TNT or transient-naïve-treatment as a simple means of ridding human induced pluripotent stem cells (hiPSC) of their epigenetic memories and improving their therapeutic potential.
An explosive epigenetic team headed by Jose M. Polo (Monash University) and Ryan Lister (University of Western Australia) knew that the epigenetic memories of cell-of-origin distinguished reprogrammed hiPSCs from human embryonic stem cells (hESCs) and negatively impacted their function and therapeutic use. Their new study, which began by characterizing epigenetic profiles during the generation of “primed” (resembling post-implantation epiblast) and “naïve” (resembling pre-implantation epiblast) hiPSCs, now describes a reprogramming strategy – TNT – that emulates the epigenetic reset occurring during embryogenesis and generates hiPSCs with greater similarity to hESCs and hence improved therapeutic potential.
Let’s hear from Buckberry, Liu, Poppe, and Colleagues on how TNT can destroy epigenetic memories in hiPSCs:
- Epigenetic memory in hiPSCs concentrates in cell-of-origin-dependent repressive chromatin domains marked by H3K9me3, lamin B1, and aberrant CpH methylation (where H represents A, C, or T)
- TNT reprogramming – seven days of fibroblast medium culture, transient naive culture treatment for five days, and finally primed medium culture – simply and effectively erases epigenetic memories by reconfiguring hiPSC-associated repressive chromatin domains to an hESC-like state
- The remodeling of H3K9me3 heterochromatin domains and transient genome-wide DNA demethylation associated with the TNT strategy occurs in a process that does not disrupt genomic imprinting
- The removal of epigenetic memories by TNT reprogramming in an isogenic system corrects the transposable element overexpression and differential gene expression usually present in hiPSCs
- TNT reprogramming endows hiPSCs with an enhanced and more homogeneous differentiation potential than primed hiPSCs with TNT-reprogrammed hiPSCs and hESCs possessing similar differentiation efficiencies
These findings suggest that the practical and scalable TNT reprogramming approach has the explosive power to destroy epigenetic memories and produce hiPSCs similar to hESCs; therefore, this dynamite approach may become the standard for biomedical/therapeutic applications and also provide a means to study epigenetic memory.
“It solves problems associated with conventionally generated iPS cells that if not addressed could have severely detrimental consequences for cell therapies in the long run,” notes co-first author Jia Tan, while study co-leader Ryan Lister states, “We predict that TNT reprogramming will establish a new benchmark for cell therapies and biomedical research, and substantially advance their progress.” For more on how TNT can destroy epigenetic memories and generate hiPSCs with improved function, see Nature, August 2023.