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Deciphering the Role of Separase in HSCs and Hematopoiesis

Review of "Haploinsufficiency of Cohesin Protease, Separase, Promotes Regeneration of Hematopoietic Stem Cells in Mice" from STEM CELLS by Stuart P. Atkinson

Cohesin, the protein complex that mediates sister chromatid cohesion, has described roles in regulating the self‐renewal and differentiation of hematopoietic stem (HSC) and progenitor cells. Separase, an endopeptidase that resolves the cohesion of sister chromatids by cleaving cohesin subunit Rad21 during mitosis [1], represents just one of the many factors that modulate the stability of the cohesin complex and its association with DNA elements. While studies have linked dysregulated Separase expression and bone marrow deficits and leukemia development [2-4], we currently lack studies of Separase function during normal hematopoiesis.

Now, researchers led by Debananda Pati (Baylor College of Medicine, Houston, TX, USA) have employed a mouse model that possesses one disrupted allele of the gene encoding Separase (Espl1), which exhibits accelerated lymphoma and leukemia when crossed to a p53 null background [5], to fully explore the role of Separase in hematopoiesis and the function of HSCs. 

Reporting in STEM CELLS [6], Kumar et al. uncovered a novel role of Separase in hematopoiesis through their studies in the Separase-haploinsufficient mouse model, which partially disrupts Separase function. Interestingly, their initial evaluations of peripheral blood and bone marrow failed to discover perturbed hematopoietic parameters during normal hematopoiesis; however, a more in-depth analysis of early hematopoietic cells in the bone marrow revealed an increase in the numbers of multipotent hematopoietic progenitor cells in the absence of significant changes in long‐term or short‐term HSCs under steady-state conditions.

Serial in vivo repopulation assays subsequently discovered that Separase haploinsufficiency promoted the regenerative activity of HSCs, while in vitro colony formation assays revealed that Separase haploinsufficiency enhanced the serial replating ability of hematopoietic progenitor cells. Microarray analysis finally suggested that the prodegenerative activity observed in HSCs with Separase haploinsufficiency derives from the specific upregulation of HSC-specific genes, which included Runx1, Hoxa9, and Pbx1, perhaps due to an impact on cohesin‐mediated gene expression.

Taken together, these findings provide evidence for a previously unknown function of Separase in hematopoiesis; specifically, they suggest that Separase regulates the function and differentiation of HSCs. The authors suggest that the pharmacologic inhibition of Separase activity may help to further our understanding of normal and malignant hematopoiesis and perhaps even form part of strategies that modulate HSC functions ex vivo to improve their regenerative potential.

For more on HSCs, hematopoiesis, and Separase's function, stay tuned to the Stem Cells Portal!

References

  1. Zhang N and Pati D, Biology and insights into the role of cohesin protease separase in human malignancies. Biological Reviews 2017;92:2070-2083.
  2. Patel H and Gordon MY, Abnormal centrosome-centriole cycle in chronic myeloid leukaemia? British Journal of Haematology 2009;146:408-417.
  3. Wirth KG, Wutz G, Kudo NR, et al., Separase: a universal trigger for sister chromatid disjunction but not chromosome cycle progression. Journal of Cell Biology 2006;172:847-860.
  4. Basu D, Zhang N, Panigrahi AK, et al., Development and validation of a fluorogenic assay to measure separase enzyme activity. Analytical Biochemistry 2009;392:133-138.
  5. Mukherjee M, Ge G, Zhang N, et al., Separase Loss of Function Cooperates with the Loss of p53 in the Initiation and Progression of T- and B-Cell Lymphoma, Leukemia and Aneuploidy in Mice. PLOS ONE 2011;6:e22167.
  6. Kumar P, Cheng H, Paudyal S, et al., Haploinsufficiency of cohesin protease, Separase, promotes regeneration of hematopoietic stem cells in mice. STEM CELLS 2020;38:1624-1636.