https://orcid.org/0000-0002-2149-835X
Abstract
Cohesin recently emerged as a new regulator of hematopoiesis and leukemia. In addition to cohesin, whether proteins that regulate cohesin’s function have any direct role in hematopoiesis and hematologic diseases has not been fully examined. Separase, encoded by the ESPL1 gene, is an important regulator of cohesin’s function. Canonically, protease activity of Separase resolves sister chromatid cohesion by cleaving cohesin subunit-Rad21 at the onset of anaphase. Using a Separase haploinsufficient mouse model, we have uncovered a novel role of Separase in hematopoiesis. We report that partial disruption of Separase distinctly alters the functional characteristics of hematopoietic stem/progenitor cells (HSPCs). Although analyses of peripheral blood and bone marrow of Espl1+/Hyp mice broadly displayed unperturbed hematopoietic parameters during normal hematopoiesis, further probing of the composition of early hematopoietic cells in Espl1+/Hyp bone marrow revealed a mild reduction in the frequencies of the Lin−Sca1+Kit− (LSK) or LSK CD48+CD150− multipotent hematopoietic progenitors population without a significant change in either long-term or short-term hematopoietic stem cells (HSCs) subsets at steady state. Surprisingly, however, we found that Separase haploinsufficiency promotes regeneration activity of HSCs in serial in vivo repopulation assays. In vitro colony formation assays also revealed an enhanced serial replating capacity of hematopoietic progenitors isolated from Espl1+/Hyp mice. Microarray analysis of differentially expressed genes showed that Separase haploinsufficiency in HSCs (SP-KSL) leads to enrichment of gene signatures that are upregulated in HSCs compared to committed progenitors and mature cells. Taken together, our findings demonstrate a key role of Separase in promoting hematopoietic regeneration of HSCs.
This study reveals a novel role of cohesin protease, Separase, in hematopoiesis and hematopoietic stem cell (HSC) function. In recent years, the cohesin complex has emerged as a key regulator of self-renewal and differentiation in HSCs, and cohesin genes have been reported to be one of the recurrently mutated gene categories in myeloid malignancies. There have been increasing efforts to decipher how cohesin proteins regulate clonal hematopoiesis and how perturbation of cohesin genes leads to hematologic malignancies. In this context, however, very little is known about the role of proteins that directly regulate cohesin functions on hematopoiesis. This study will not only bridge this knowledge gap but also will be of considerable general interest in advancing the field.
