It’s been a while now since Yamanaka and his team discovered the recipe of everlasting youth, for cells at least. Yet, the road leading from differentiated cell to pluripotency passes through largely uncharted territory. Now, Yamanaka and colleagues show that the activation of human endogenous retroviruses is a key landmark on the induced pluripotency highway.
This story begins last year with the discovery that not all iPSCs are created equal. Although some human iPSCs appear pluripotent, they fail to differentiate normally. Yamanaka called these cells ‘differentiation defective’ iPSCs (DD-iPSCs).
These ‘imposter’ iPSCs are distinguishable from ‘true’ iPSCs because they express high levels of several genes controlled by type 7 long terminal repeats (LTR7) of type H human endogenous retroviruses (HERV-H).
In their latest study, Yamanaka and colleagues explore the significance of the expression of HERV-Hs. They compared global gene expression in DD-iPSCs and normal iPSCs, looked at expression changes during the reprogramming process and examined how these elements are regulated.
Here’s what they found:
- Over 20% of genes more strongly expressed in DD-iPSCs than in normal iPSCs were located within 30 kb of a LTR7 element, confirming their previous finding that DD-iPSCs have a specific LTR7 signature.
- DD-iPSC markers and more than 40% of LTR7 elements in the human genome are transiently activated during reprogramming.
- The key pluripotency factors OCT3/4, SOX2, and KLF4 regulate LTR7-driven genes.
KLF4 is the most important factor in this story. KLF4 is transiently active during reprogramming in normal iPSCs, but in DD-iPSCs its expression remains high, where it activates LTR7 elements. What’s more, shRNA targeting KLF4 or conserved LTR7 sequences effectively reversed the DD-iPSC phenotype.
Therefore, these retroviral elements block differentiation in DD-iPSCs, but their activation is also necessary for reprogramming, because the knock-down of LTR7 transcripts impairs the generation of iPSCs. Thus, the dynamic regulation of LTR7 elements is essential for reprogramming and the subsequent normal differentiation of iPSCs.
One idea is that retroviral elements direct pluripotency factors to specific gene networks during reprogramming.
Check out PNAS August 2014 for the precise directions.