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New Model System Describes the Importance of Smarca5 to Hematopoiesis

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Review of “The ISWI ATPase Smarca5 (Snf2h) is required for proliferation and differentiation of hematopoietic stem and progenitor cells” from STEM CELLS by Stuart P. Atkinson

The assembly and remodeling of chromatin aided by imitation switch (ISWI) proteins facilitate essential cellular tasks such as DNA replication, DNA repair, and transcription. Of the two vertebrate ISWIs (Smarca1 and Smarca5), studies indicate that the general function of the hematopoietic system requires Smarca5 activity [1, 2] with an added importance to erythroid cells.

As conventional knockout (KO) of murine Smarca5 is lethal early in embryonic development [2], the laboratories of Tomas Stopka (Charles University, Vestec, Czech Republic) and Arthur I. Skoultchi (Albert Einstein College of Medicine, New York, USA) have developed a new conditional KO mouse model to study the role of Smarca5 in hematopoiesis. Their findings, reported in STEM CELLS, now suggest that Smarca5 loss interferes with the proliferation and differentiation of hematopoietic stem cells (HSCs) and multipotent progenitors (MPPs) and modulates the proliferation and survival of fully committed erythroid progenitors (EPs) [3].

The engineered mouse employed in the study permitted the KO of Smarca5 expression at the earliest stages of definitive hematopoiesis (embryonic day 10.5) [4]. The conditional KO allowed embryos to develop past implantation, although Smarca5 loss abrogated definitive hematopoiesis within the fetal liver (FL) leading to anemia and embryo death at embryonic day 18.5 (See Figure). Further studies of stem and progenitor cells suggested that while Smarca5 loss promoted excessive cycling of HSCs and an increase in their number, the MPPs derived from HSCs remained in an immature state. Moreover, MPPs did not progress to terminal erythroid/myeloid differentiation.

Mechanistically, the KO of Smarca5 prompted the induction of p53 target gene expression via the activation p53 at residues associated with DNA damage and the action of the CBP/p300 acetylases. The modifications perturbed the MPP cell cycle and led to G2/M phase cell cycle blockade, the accumulation of cells with abnormal ploidy, and an increase in the proportion of apoptotic and necrotic cells. Smarca5 loss at later stages of erythroid development, assessed using a different conditional KO strategy, led to deficits in the proliferation and survival of committed erythroid progenitors (EPs).

While we now understand more about the normal role of Smarca5 in hematopoiesis, the authors note that this information could also assist in the construction of enhanced treatment strategies in acute myeloid leukemia and aggressive solid tumors that overexpress this chromatin-remodeling factor.

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References

  1. Bultman SJ, Gebuhr TC, and Magnuson T. A Brg1 mutation that uncouples ATPase activity from chromatin remodeling reveals an essential role for SWI/SNF-related complexes in beta-globin expression and erythroid development. Genes Dev 2005;19:2849-2861.
  2. Stopka T and Skoultchi AI. The ISWI ATPase Snf2h is required for early mouse development. Proc Natl Acad Sci U S A 2003;100:14097-14102.
  3. Kokavec J, Zikmund T, Savvulidi F, et al. The ISWI ATPase Smarca5 (Snf2h) Is Required for Proliferation and Differentiation of Hematopoietic Stem and Progenitor Cells. Stem Cells 2017;35:1614-1623.
  4. de Boer J, Williams A, Skavdis G, et al. Transgenic mice with hematopoietic and lymphoid specific expression of Cre. Eur J Immunol 2003;33:314-325.