Revealing the main mechanism of differentiation of human pluripotent stem cells

The process of cellular differentiation, in which human pluripotent stem cells (hPCSs) develop from primitive to developed states, is an essential aspect of life. Understanding this process not only sheds light on basic principles of life, but also holds great promise for developing treatments for diverse diseases. The underlying differentiation mechanism was recently identified by researchers from POSTECH and the University of California, Santa Barbara (UCSB).

The POSTECH team led by Prof. Jiwon Jang and Yujeong Oh (Department of Life Sciences) collaborated with the UCSB research team (Dasol Han, Kenneth S., and Papp) on the domain containing the zinc finger protein. The researchers found that ZBTB12 acts as a molecular barrier to prevent dedifferentiation of hPSCs. Their findings have been published in Nature Communications.

In their embryonic development, stem cells progress unidirectionally from a primitive (less differentiated) state to a more advanced (more differentiated) state. This process is known as cellular differentiation, but the reasons behind its one-way movement have remained unclear. Studies of signaling molecules and genes to induce stem cell differentiation have been performed, but the underlying mechanism regulating differentiation has remained unclear.

Meanwhile, dedifferentiation, a phenomenon in which cells revert to an earlier, less specialized state, is also seen in tissue regeneration and diseases such as cancer. Reverse translocations, which make up more than 40% of the human genome, have been found to be silent in healthy tissues but upregulated in cancer, making research on their cellular functions and dedifferentiation mechanisms crucial in understanding the origins of various diseases.

The research team discovered a transcription factor called ZBTB12, which has not been reported before in the differentiation process of hPSCs. They also analyzed the RNA-sequencing of single cells to demonstrate that ZBTB12 suppresses dedifferentiation. When ZBTB12 was deficient in hPSCs, they differentiated into more primitive stem cells, preventing them from differentiating. This confirms that the ZBTB12 gene is an essential factor in stem cell differentiation.

These results enabled the researchers to report that ZBTB12 is a key factor that suppresses the expression of human endogenous retrovirus H (HERVH), a primate-specific retroviral transduction, and acts as a molecular barrier to prevent hPSC reductase.

POSTECH Professor Jiwon Jang explained, “Our study has identified the molecular barrier preventing dedifferentiation in stem cells, providing insights into the underlying mechanism of unidirectional stem cell differentiation, which has long been a mystery. The discovery of this mechanism holds great promise for advancing our understanding and treatment of cancerous and related diseases. age at which cellular differentiation occurs most frequently.