New mechanism of pluripotency exit in porcine embryonic stem cells for breeding and regenerative medicine
image: Figure 1. The schematic illustrates the mechanisms governing pluripotency exit, highlighting the pivotal role of PIAS4. By stabilizing KDM5B through SUMOylation, PIAS4 cooperatively modulates H3K4me3 levels at the promoters of pluripotency-associated genes (such as LEFTY2 and GNL3L), thereby driving pluripotency exit and cell fate determination.
Credit: Qin W, Wang Y, Duan H F, et al.
Embryonic stem cells (ESCs) are valued for their ability to self-renew indefinitely while retaining the potential to generate all somatic cell types. For pigs—a key biomedical and agricultural model—understanding how stem cells transition from pluripotency to differentiation has major implications for both regenerative medicine and genetic breeding. Yet, the precise molecular drivers of this transition have remained elusive.
In a new study published in Fundamental Research, a team led by Yi-Liang Miao, a professor at Huazhong Agricultural University, has pinpointed PIAS4, an E3 ubiquitin ligase, as a pivotal regulator of pluripotency exit in porcine embryonic stem cells.
“Exiting pluripotency is a decisive moment for stem cells, marking the point at which they embark on a path toward specialized fates,” explains Miao. “Our work shows that PIAS4 is a master switch in this process.”
The team's approach combined high-throughput genetics with chromatin profiling:
- CRISPR-based genome-wide screen: Using the CRISPR/Cas9 library screening of all E3 ubiquitin enzymes in pigs, the researchers identified PIAS4 as a top candidate essential for pluripotency exit. Cells lacking PIAS4 failed to downregulate pluripotency markers and remained trapped in an undifferentiated state.
- Epigenetic mechanism: Further analyses revealed that PIAS4 interacts with the histone demethylase KDM5B, enhancing its stability through SUMOylation. This cooperation enables fine-tuned control of H3K4me3, a histone mark critical for activating lineage-specific genes.
- LEFTY2–SMAD axis: The study also uncovered a downstream pathway in which PIAS4 suppresses LEFTY2 expression, thereby promoting SMAD2/3 phosphorylation and guiding mesendoderm specification.
“Our results highlight PIAS4 as a gatekeeper of pluripotency exit,” adds Prof. Miao. “Harnessing this knowledge could accelerate advances in both regenerative therapies and animal biotechnology.”
Beyond basic science, the implications are wide ranging. Porcine ESCs hold promise for xenotransplantation, disease modeling, precision breeding, and even cultured meat production.
###
Contact the author: Yi-Liang Miao, Institute of Stem Cell and Regenerative Biology, College of Animal Science and Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070, China, miaoyl@mail.hzau.edu.cn; Jilong Zhou, Institute of Stem Cell and Regenerative Biology, College of Animal Science and Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070, China, zhoujilong@mail.hzau.edu.cn
The publisher KeAi was established by Elsevier and China Science Publishing & Media Ltd to unfold quality research globally. In 2013, our focus shifted to open access publishing. We now proudly publish more than 200 world-class, open access, English language journals, spanning all scientific disciplines. Many of these are titles we publish in partnership with prestigious societies and academic institutions, such as the National Natural Science Foundation of China (NSFC).