Human stem cells can differentiate into any human cell. However, the process of dedifferentiation, essentially reverse differentiation, has been implicated in several diseases. Researchers have now uncovered the key mechanisms of the stem cell dedifferentiation process, opening the door to the development of new disease treatments.
Human pluripotent stem cells (hPSCs) self-renew, differentiate and develop into specialized higher cell types in a unidirectional process. Despite previous studies examining signaling molecules and genes that influence this process, the underlying mechanisms remain unclear.
However, there is another process called dedifferentiation that is seen in tissue regeneration and diseases such as cancer. In dedifferentiation, stem cells essentially develop in reverse, transitioning from a more differentiated to a less differentiated state. It is unclear how dedifferentiation is blocked once stem cells begin to differentiate.
A team of researchers at POSTECH and UCSB are now investigating the dedifferentiation process and its driving forces. They started by mapping gene transcription start sites, which provide important information about gene expression.
Researchers have discovered that a transcription factor called ZBTB12 is involved in hPSC differentiation. This is the first time ZBTB12 has been reported to be involved in the differentiation process. Transcription factors (TFs) are involved in the conversion of DNA into RNA (transcription) and are essential for the regulation of gene expression.
Performing single-cell RNA sequencing, they found that ZBTB12 inhibited dedifferentiation. ZBTB12-deficient hPSCs dedifferentiated into more primitive stem cells. They were prevented from differentiating into higher morphologies, confirming that the ZBTB12 gene is essential for stem cell differentiation.
Armed with this information, researchers discovered that ZBTB12 is the key to inhibiting the expression of human endogenous retrovirus H (HERVH). Human endogenous retroviruses, which make up about 8% of the human genome, are ‘fossil viruses’ found on DNA and are relics of ancient infections transmitted over millions of years along the primate germline.
In particular, HERVHs are retrotransposons, 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, which then jumps to another location on the genome and is copied into DNA by an enzyme called reverse transcriptase. Retrotransposons are silenced in healthy tissues but found to be upregulated in cancer.
The implication is that ZBTB12 acts as a molecular barrier to prevent hPSC dedifferentiation and may guide future disease therapy.
“Our study identifies a molecular barrier that prevents stem cell dedifferentiation and provides insight into the core mechanisms of unidirectional stem cell differentiation that have long remained enigmatic,” said the study’s corresponding author. “This discovery of this mechanism holds great promise in enhancing our understanding and management of age-related and cancerous diseases, where cellular dedifferentiation is frequent,” said Jiwon Jang.
The study was published in a journal Nature Communications.
Source: POSTECH! via EurekAlert
