RACK1 maintains mouse hematopoietic stem cell quiescence

Hematopoietic stem cells (HSCs), with the capability of self-renewal and all blood lineages reconstruction, serve a crucial role in maintaining steady-state hematopoiesis within bone marrow during adulthood. The adaptor protein receptor for activated C kinase 1 (RACK1) has been implicated in the regulation of various transcription factors and signaling pathways by modulating their activation and/or stability. However, the specific role of RACK1 in the transcriptional control of HSC fates has not been previously elucidated. Here, we reported that RACK1 is enriched in hematopoietic progenitors. And its absence leads to BM failure with rapid loss of HSCs and downstream progenitors. Such phenotypes result from cell-intrinsic defects with enhanced proliferation and apoptosis of HSCs. scRNA-seq indicates Rack1 deletion leads to aberrant lineage molecular character of transcriptional HSCs and the emergence of HSK-like cells. At the molecular level, RACK1 directly binds to TAL1 core complex components and facilitates the assembly of the complex. Thus, RACK1 maintains mouse hematopoietic stem cell quiescence through, at least partially, promoting the assembly of TAL1 core complex. Single cell profiling from bone marrow Lin-cKit+ hematopoietic cells derived from RACK1 knockdown mice or control mice at 8 ~ 12-week-age respectively.