Impaired Repopulating Ability of Uhrf2−/− Hematopoietic Progenitor Cells in Mice

Abstract

UHRF proteins catalyze the ubiquitination of target proteins and are involved in regulating gene expression. Some studies reported a reduced expression of UHRF2 in acute leukemia cells, but the role of UHRF2 in hematopoiesis remains unknown. Here, we generated Uhrf2−/− mice to clarify the role of UHRF2 deletion in hematopoiesis. Compared to Uhrf2+/+ mice, Uhrf2−/− mice showed no differences in complete blood counts, as well as bone marrow (BM) findings and spleen weights. Proportions of cells in progenitor fractions in BM were comparable between Uhrf2+/+ mice and Uhrf2−/− mice. However, in competitive repopulation assays with BM transplants (BMT), the proportions of Uhrf2−/− cells were decreased relative to Uhrf2+/+ cells in all lineages. After the second BMT, Uhrf2−/− neutrophils were few, while 20–30% of Uhrf2−/− T cells and B cells were still detected. RNA sequencing showed downregulation of some genes associated with stem-cell function in Uhrf2−/− hematopoietic stem/progenitor cells (HSPCs). Interestingly, trimethylated histone H3 lysine 9 was increased in Uhrf2−/− HSPCs in a cleavage under targets and tagmentation assay. While UHRF2 deletion did not cause hematologic malignancy or confer a growth advantage of HSPCs, our results suggest that UHRF2 may play a role in the regulation of hematopoiesis.

E3 Ubiquitin Ligase Uhrf2 Knockout Reveals a Critical Role in Social Behavior and Synaptic Plasticity in the Hippocampus

“…Increased trimethylation of histone H3 lysine 9 in hematopoietic stem/progenitor cells in Uhrf2 −/− mice has been reported, indicating impaired repopulating ability and functioning of hematopoietic progenitors [69]. Additionally, Uhrf2 accumulation has been observed in retinal progenitor cells (RPCs), and its conditional deletion resulted in reduced 5hmC levels, altered gene expressions, and disruption of retinal cell proliferation and differentiation [70].…”