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SOX15 - A Crucial Factor in the Generation of Human Primordial Germ Cell-Like Cells

Review of “The chromatin accessibility landscape reveals distinct transcriptional regulation in the induction of human primordial germ cell-like cells from pluripotent stem cells” from Stem Cell Reports by Stuart P. Atkinson

The in-vitro differentiation of human pluripotent stem cells into human primordial germ cell-like cells (PGCLCs) [1] has provided a relatively straightforward and ethical means of studying the regulatory networks controlling the development and maintenance of their in vivo counterparts, primordial germ cells (PGCs). A recent study led by Zhaoting Liu, Xiao-Yang Zhao (Southern Medical University, Guangzhou), and Gang Chang (Shenzhen University Health Science Center, Shenzhen, Guangdong, China) recently monitored chromatin accessibility and transcriptome dynamics during the in-vitro differentiation of human embryonic stem cells (ESCs) into PGCLCs to better understand this process, and now report the importance of a SOX15-mediated regulatory network underly this process [2].

In summary, Wang, Veerapandian, Yang, and Song et al. demonstrated a crucial role for the SOX15 transcription factor (previously reported as a critical human PGCLC maintenance factor [3]) in suppressing somatic gene expression profiles associated while supporting those gene expression profiles that preserve latent pluripotency during the generation of PGCLCs. Human PGCs express high levels of SOX15 [4], and the loss of SOX15 expression in differentiating ESCs prompted early gene expression alterations compared to wild-type cells and a reduction in PGCLC number at late stages of differentiation; furthermore, the study also identified ETV5 (ETS Variant Transcription Factor 5) as a downstream regulator of SOX15 essential for PGCLC maintenance.

The subsequent analysis of chromatin dynamics during PGCLC generation revealed several transcription factor binding motifs as potential “accelerators” (AP2, OCT4:SOX17, and SOX15) or “suppressors” (GATA, AP1, and TEAD) of PGCLC induction. Furthermore, the authors propose the existence of a stepwise switch of OCT/SOX heterodimerization preferences [5] during the differentiation of ESCs into PGCLCs – while OCT4/SOX2 heterodimer binding predominates in pluripotent ESCs, early PGCLCs employed an OCT4/SOX17 heterodimer [6], with a putative OCT4/SOX15 binding module active in later stage PGCLCs.

Overall, the authors of this highly detailed study underscore the general importance of SOX15 in the establishment of the regulatory networks underpinning the establishment of PGCLCs/PGCs and the determination of the germ cell line.

For more on the role of SOX15 in the differentiation of human primordial germ cell-like cells, stay tuned to the Stem Cells Portal!


References

  1. Mitsunaga S, Odajima J, Yawata S, et al., Relevance of iPSC-derived human PGC-like cells at the surface of embryoid bodies to prechemotaxis migrating PGCs. Proceedings of the National Academy of Sciences 2017;114:E9913.
  2. Wang X, Veerapandian V, Yang X, et al., The chromatin accessibility landscape reveals distinct transcriptional regulation in the induction of human primordial germ cell-like cells from pluripotent stem cells. Stem Cell Reports 2021;16:1245-1261.
  3. Pierson Smela M, Sybirna A, Wong F, et al., Testing the role of SOX15 in human primordial germ cell fate [version 1; peer review: 2 approved]. Wellcome Open Research 2019;4.
  4. Guo F, Yan L, Guo H, et al., The Transcriptome and DNA Methylome Landscapes of Human Primordial Germ Cells. Cell 2015;161:1437-1452.
  5. Chang YK, Srivastava Y, Hu C, et al., Quantitative profiling of selective Sox/POU pairing on hundreds of sequences in parallel by Coop-seq. Nucleic Acids Research 2017;45:832-845.
  6. Jostes SV, Fellermeyer M, Arévalo L, et al., Unique and redundant roles of SOX2 and SOX17 in regulating the germ cell tumor fate. International Journal of Cancer 2020;146:1592-1605.