Deletion of mouseSetd4promotes the recovery of hematopoietic failure

Abstract

Key points:• Deletion of Setd4 in adult mice improved the survival from hematopoietic failure.• Setd4 deficiency sensitized HSCs to radiation, but improved bone marrow environment niche.• The study suggests that SETD4 as a potential inhibitory target to improve bone marrow niche function for recovery of bone marrow failure.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. Authorship Contributions: XF and ZS: designed the experiments, performed data analysis, and drafted the initial versions of manuscript. XF: performed most of the experiments; HL, JL, and MS: performed and assisted with some of the experiments. HL, and JY: performed some of the early studies led to the construction of the mouse models; LD, and SD: provided resources for some experiments, computational analysis, and edited the manuscript. ZS: directed and oversaw the project, secured funding for the study, completed the final version of the manuscript. Conflict of Interest statement:The authors declare that there were no competing interests.

The Mammalian KU70 C-terminus SAP Domain Is Required to Repair Exogenous DNA Damage

“…This impairment leads to BM failure and often results in animal death, typically occurring within 1-3 weeks post-TBI. To test whether the SAP deletion confers a sensitization of the BM to radiation damage, we exposed sex-matched littermates to an 8 Gy TBI, a dosage known to cause mouse lethality due to BM failure (25). We observed that the KU70-ΔSAP mice were hypersensitive to IR.…”