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DPPA4 Function in Pluripotent Stem Cells: EBP1 Lends a Hand

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Review of “ERBB3-binding protein (EBP1) is a novel DPPA4 cofactor in human pluripotent cells” from STEM CELLS by Stuart P. Atkinson

The expression of Developmental Pluripotency-Associated 4 (DPPA4) represents a common trait of pluripotent stem cells and cancer cells; however, we know frustratingly little about the function of this highly conserved protein in either context. To solve this vexing problem, researchers from the laboratory of Paul S. Knoepfler (University of California, Davis, USA) set out to study human DPPA4 protein function via the identification of putative protein cofactors. Their excellent new study, published recently in STEM CELLS, now reports the identification of the ERBB3 Binding Protein 1 (EBP1) [1, 2] as a major cofactor that impacts the transcriptional activity of DPPA4 in pluripotent cells [3]. 

Somanath et al. first employed a proteomic screen of human embryonic stem cell (hESC) nuclear extracts to identify potential binding factors for DPPA4. These assays revealed the ubiquitous EBP1 protein as the strongest binding partner - an unexpected finding given the lack of previous studies detailing EBP1 expression or function in pluripotent cells. 

Of the two EBP1 isoforms, which display largely opposing functions, the authors discovered that the EBP1-p48 isoform bound to DPPA4 in hESCs, induced pluripotent stem cells (iPSCs), and in DPPA4- and EBP1-expressing pluripotent NTERA-2 (NT2) embryonic carcinoma cells [4] through a highly conserved SAF-A/B, Acinus and PIAS (SAP) domain. However, DPPA4-EBP1 binding levels generally reduced during hESC/iPSC/ECC differentiation, leading to very weak or no interaction in non-pluripotent cells. 

On the functional level, the authors uncovered evidence that EBP1-p48 binding either supported transcriptional activation or inhibited transcriptional repression of target genes by DPPA4, although they did not discount the existence of additional functions.

Overall, this exciting new study suggests that EBP1 “lends a hand” in pluripotent and cancer cells and modulates the transcriptional function of DPPA4, a finding that the authors hope will play a major role in the development of safer and more effective translatable stem cell therapeutics [5].

For more on DPPA4, binding partners and their role in pluripotent cells, stay tuned to the Stem Cells Portal!

References

  1. Xia X, Lessor TJ, Zhang Y, et al., Analysis of the Expression Pattern of Ebp1, an ErbB-3-Binding Protein. Biochemical and Biophysical Research Communications 2001;289:240-244.
  2. Liu Z, Ahn J-Y, Liu X, et al., Ebp1 isoforms distinctively regulate cell survival and differentiation. Proceedings of the National Academy of Sciences 2006;103:10917-10922.
  3. Priyanka S, M. BK, and S. KP, ERBB3‐Binding Protein 1 (EBP1) Is a Novel Developmental Pluripotency‐Associated‐4 (DPPA4) Cofactor in Human Pluripotent Cells. STEM CELLS 2018;36:671-682.
  4. Chaerkady R, Kerr CL, Kandasamy K, et al., Comparative proteomics of human embryonic stem cells and embryonal carcinoma cells. PROTEOMICS 2010;10:1359-1373.
  5. Barrilleaux B and Knoepfler Paul S, Inducing iPSCs to Escape the Dish. Cell Stem Cell 2011;9:103-111.