Human stem cells can differentiate into any human cell. But the process of dedifferentiation, essentially differentiation in reverse, is implicated in several diseases. Now researchers have uncovered a mechanism that is key to the process of stem cell dedifferentiation, opening the door to the development of new disease treatments.
Human pluripotent stem cells (hPSCs) self-renew, differentiating and developing into specialized, more advanced cell types in a one-way process. Despite previous studies examining the signaling molecules and genes that influence this process, the underlying mechanisms remain unclear.
However, there’s another process called dedifferentiation that’s seen in tissue regeneration and diseases like cancer. In dedifferentiation, stem cells essentially develop in reverse, moving from a more to a less differentiated state. How dedifferentiation is blocked once stem cells begin to differentiate is unknown.
Now, a team of researchers from POSTECH and UCSB have looked at the dedifferentiation process and what drives it. They began by mapping gene transcription start sites, which provide key information about gene expression.
The researchers discovered that a transcription factor called ZBTB12 was involved in hPSC differentiation, the first time that ZBTB12 had been reported as being involved in the differentiation process. Transcription factors (TFs) are involved in the conversion (transcription) of DNA into RNA and are vital to controlling gene expression.
Undertaking single-cell RNA sequencing, they found that ZBTB12 inhibits dedifferentiation. hPSCs with a deficiency of ZBTB12 dedifferentiated into more primitive stem cells. They were prevented from differentiating into a more advanced form, confirming that the ZBTB12 gene is essential to stem cell differentiation.
Armed with this information, the researchers found that ZBTB12 is key in inhibiting the expression of human endogenous retrovirus H (HERVH). Comprising about 8% of the human genome, human endogenous retroviruses are “fossil viruses” found on DNA, relics of ancient infections transmitted along primates’ germlines over millions of years.
HERVH, in particular, is a retrotransposon, a highly unique group of transposable elements that make up more than 40% of the human genome. Retrotransposons use a “copy and paste” mechanism to copy DNA into RNA before the RNA jumps to another location on the genome and is copied back into DNA by an enzyme called reverse transcriptase. Retrotransposons have been found to be silenced in healthy tissue but upregulated in cancer.
What this means, the researchers say, is that ZBTB12 acts as a molecular barrier, preventing the dedifferentiation of hPSCs, something that has the potential to guide future disease treatments.
“Our study has identified the molecular barrier that prevents dedifferentiation in stem cells, providing insight into the core mechanism of unidirectional stem cell differentiation, which has long remained a mystery,” said Jiwon Jang, corresponding author of the study. “This discovery of this mechanism holds significant promise for enhancing our comprehension and management of age-related and cancerous ailments where cellular dedifferentiation frequently occurs.”