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bioRxiv · 10.1101/860239

Deletion of mouse Setd4 promotes the recovery of hematopoietic failure.

Feng, X.·Lu, H.·Yue, J.·Shettigar, M.·Liu, J.·Denzin, L. K.·Shen, Z.
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Abstract

Acquired hematopoietic failure is commonly caused by therapeutic and accidental exposure to toxic agents to the bone marrow (BM). Efficient recovery from the BM failure is not only dictated by the intrinsic sensitivity and proliferation capacity of the hematopoietic stem and progenitor cells, but also nourished by the BM environment niche. Identification of genetic factors that improve the recovery from hematopoietic failure is essential. Vertebrate SETD4 is a poorly characterized, putative non-histone methyl-transferase whose physiological substrates have not yet been fully identified. By inducing Setd4 deletion in adult mice, we found that loss of Setd4 improved the survival of whole body irradiation induced BM failure. This was associated with improved recoveries of long-term and short-term hematopoietic stem cells (HSC), and early progenitor cells. BM transplantation analyses surprisingly showed that the improved recovery was not due to a radiation resistance of the Setd4 deficient HSC, but that Setd4 deficient HSC were actually more sensitive to radiation. However, the Setd4 deficient mice were better recipients for allogeneic HSC transplantation. Furthermore, there was an enhanced splenic erythropoiesis in Setd4 deficient mice. These findings not only revealed a previously unrecognized role of the Setd4 as a unique modulator of hematopoiesis, but also underscored the critical role of the BM niche in the recovery of hematopoietic failure. These studies also implicated Setd4 as a potential target for therapeutic inhibition to improve the conditioning of the BM niche prior to allogeneic transplantation. Key pointsO_LIDeletion of Setd4 in adult mice improved the survival from hematopoietic failure. C_LIO_LISetd4 deficiency sensitized HSCs to radiation, but improved bone marrow environment niche. C_LIO_LIThe study suggests that SETD4 as a potential inhibitory target to improve bone marrow niche function for recovery of bone marrow failure. C_LI

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Feng, X., Lu, H., Yue, J., Shettigar, M., Liu, J., Denzin, L. K., Shen, Z.. 2019-11-29. Deletion of mouse Setd4 promotes the recovery of hematopoietic failure.. https://doi.org/10.1101/860239

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