DescriptionThe SET domain protein methyltransferases play a critical role in histone modifications and global epigenetic regulations. Recent evidence suggests that some SET domain proteins may have the ability to modify non-histone proteins. The SET domain containing protein 4 (SETD4) was believed to be a non-histone methyltransferase, but no physiological substrate or biological functions of SETD4 has been identified. In this study, we constructed an inducible Setd4 knockout model and investigated the role of Setd4 in radiation sensitivity and tumorigenesis. We found that Setd4 deficient mice were significantly more resistant to radiation-induced hematopoietic syndrome than littermate wild type mice. Using several long-term bone marrow transplantation assays, we found that Setd4 deficient hematopoietic stem cells (HSCs) and progenitor cells (HPCs) have a slight in vivo growth advantage than the wild type cells, but are more sensitive to radiation. We also found that the Setd4 deficient recipient mice have an enhanced ability to engraft transplanted HSCs, suggesting an improved bone marrow niche for the Setd4 deficient animals. Using a radiation-induced thymic lymphoma model, we also found that Setd4 deletion delayed radiation-induced tumorigenesis. Collectively, our study suggests that Setd4 defect can enhance the recovery of radiation-induced bone marrow damage and suppress radiation-induced thymic lymphoma, and that Setd4 is a new gene involved in regulating bone marrow and hematopoietic functions in mice.