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Summary Pluripotency, the ability of cells to self-renew and differentiate into all the cell types in an animal’s body, is vital for mammalian early development. This study presented a comprehensive comparative transcriptomic analysis of embryonic stem cells across multiple mammalian species, defining their progression through expanded/extended, naïve, formative, and primed pluripotency states. Our findings revealed both conserved and species-specific mechanisms underlying pluripotency regulation. We also emphasized the limitations of existing state-specific markers and their limited cross-species applicability, while identifyingde novopluripotency markers that can inform future research. Despite variability in gene expression dynamics, gene co-expression networks showed remarkable conservation across species. Among pluripotency states, the primed state demonstrated the highest conservation, evidenced by shared markers, preserved gene networks, and stronger selective pressures acting on its genes. These findings provide critical insights into the evolution and regulation of pluripotency, laying a foundation for refining stem cell models to enhance their translational potential in regenerative medicine, agriculture, and conservation biology.
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BENDing with Polycomb in pluripotency and cancer
Abstract Three recent publications on BEND3 firmly establish its role as a novel sequence‐specific transcription factor that is essential for PRC2 recruitment and maintenance of pluripotency. Here, we briefly review our current understanding of the BEND3‐PRC2 axis in the regulation of pluripotency and also explore the possibility of a similar connection in cancer.
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- PAR ID:
- 10414155
- Publisher / Repository:
- Wiley Blackwell (John Wiley & Sons)
- Date Published:
- Journal Name:
- BioEssays
- Volume:
- 45
- Issue:
- 8
- ISSN:
- 0265-9247
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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Abstract Insight into the molecular mechanisms governing the development and maintenance of pluripotency is important for understanding early development and the use of stem cells in regenerative medicine. We demonstrate the selective inhibition of mTORC1 signaling is important for developing the inner cell mass (ICM) and the self-renewal of human embryonic stem cells. S6K suppressed the expression and function of pluripotency-related transcription factors (PTFs) OCT4, SOX2, and KLF4 through phosphorylation and ubiquitin proteasome-mediated protein degradation, indicating that S6K inhibition is required for pluripotency. PTFs inhibited mTOR signaling. The phosphorylation of S6 was decreased in PTF-positive cells of the ICM in embryos. Activation of mTORC1 signaling blocked ICM formation and the selective inhibition of S6K by rapamycin increased the ICM size in mouse blastocysts. Thus, selective inhibition of mTORC1 signaling supports the development and maintenance of pluripotency.more » « less
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Abstract Polycomb repressive complex 2 (PRC2) is a histone methyltransferase that methylates histone H3 at Lysine 27. PRC2 is critical for epigenetic gene silencing, cellular differentiation and the formation of facultative heterochromatin. It can also promote or inhibit oncogenesis. Despite this importance, the molecular mechanisms by which PRC2 compacts chromatin are relatively understudied. Here, we visualized the binding of PRC2 to naked DNA in liquid at the single-molecule level using atomic force microscopy. Analysis of the resulting images showed PRC2, consisting of five subunits (EZH2, EED, SUZ12, AEBP2 and RBBP4), bound to a 2.5-kb DNA with an apparent dissociation constant ($$K_{\rm{D}}^{{\rm{app}}}$$) of 150 ± 12 nM. PRC2 did not show sequence-specific binding to a region of high GC content (76%) derived from a CpG island embedded in such a long DNA substrate. At higher concentrations, PRC2 compacted DNA by forming DNA loops typically anchored by two or more PRC2 molecules. Additionally, PRC2 binding led to a 3-fold increase in the local bending of DNA’s helical backbone without evidence of DNA wrapping around the protein. We suggest that the bending and looping of DNA by PRC2, independent of PRC2’s methylation activity, may contribute to heterochromatin formation and therefore epigenetic gene silencing.more » « less
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