ABSTRACT
The Ten-eleven translocation (TET) enzymes regulate gene expression by promoting DNA demethylation and partnering with chromatin modifiers. TET2, a member of this family, is frequently mutated in hematological disorders. The contributions of TET2 in hematopoiesis have been attributed to its DNA demethylase activity, and the significance of its nonenzymatic functions has remained undefined. To dissect the catalytic and non-catalytic requirements of Tet2, we engineered catalytically inactive Tet2 mutant mice and conducted comparative analyses of Tet2 mutant and Tet2 knockout animals. Tet2 knockout mice exhibited expansion of hematopoietic stem and progenitor cells (HSPCs) and developed myeloid and lymphoid disorders, while Tet2 mutant mice predominantly developed myeloid malignancies reminiscent of human myelodysplastic syndromes. HSPCs from Tet2 knockout mice exhibited distinct gene expression profiles, including downregulation of Gata2. Overexpression of Gata2 in Tet2 knockout bone marrow cells ameliorated disease phenotypes. Our results reveal the non-catalytic roles of TET2 in HSPC homeostasis.
Subject(s)
Biocatalysis , DNA-Binding Proteins/metabolism , Hematopoietic Stem Cells/metabolism , Homeostasis , Proto-Oncogene Proteins/metabolism , Animals , Bone Marrow/metabolism , DNA-Binding Proteins/deficiency , DNA-Binding Proteins/genetics , Dioxygenases , Gene Expression Regulation , Hematologic Neoplasms/genetics , Hematologic Neoplasms/pathology , Mice, Knockout , Mutation/genetics , Phenotype , Proto-Oncogene Proteins/deficiency , Proto-Oncogene Proteins/geneticsABSTRACT
BACKGROUND: Psychiatrists in clinical practice face a number of stressors related to patient care, such as overwork. On the other hand, they gain satisfaction from their work. We quantified and assessed the potential relationship between levels of occupational stress, satisfaction, and depressive symptoms among Japanese clinical psychiatrists. We surveyed 206 psychiatrists with up to 15 years of clinical experience who primarily worked in patient care. Levels of occupational stress and occupational satisfaction were measured using the Visual Analogue Scale and the level of depressive symptoms was measured by the Center for Epidemiologic Studies Depression Scale. Workplace stressors and satisfiers were also evaluated. RESULTS: Out of 206 psychiatrists, 154 (74.8%) responded to the survey. The respondents' mean (SD) age was 34.3 (5.2) years. The estimated prevalence of significant depressive symptoms was 34.4% (n = 53), and the experienced frequent violence was 14.9% (n = 23). The level of depressive symptoms was inversely correlated with the level of occupational satisfaction. In respondents who reported a moderate level of occupational stress, having fewer depressive symptoms was associated with higher occupational satisfaction, but this association was not significant in those who reported a high level of stress. In addition, high occupational satisfaction was associated with interest towards work content, ability to work at one's discretion, opportunities for growth and career development, and ease of communication with supervisors and colleagues. CONCLUSIONS: Nearly one-third of the psychiatrists screened positive for significant depressive symptoms. Having fewer depressive symptoms was associated with higher occupational satisfaction in those who reported a moderate level of stress. Implications from the present findings may be to enhance occupational satisfaction by discussing work interests with a supervisor, as well as increased opportunities for career development, which may prevent depression among psychiatrists.
