ZCCHC8 safeguards hematopoietic stem cell self-renewal and prevents bone marrow failure during stress hematopoiesis

The nuclear exosome targeting (NEXT) complex targets aberrant non-coding RNAs (ncRNAs) to degradation, maintaining ncRNAs quality and abundance. However, its physiological and pathological functions in hematopoiesis remain largely unknown. ZCCHC8, a core subunit of NEXT, is highly expressed in hemopoietic system and frequently mutated in bone marrow failure patients. Here, using a Zcchc8 conditional knockout mouse model, we explored the role of NEXT in hematopoiesis. Loss of Zcchc8 led to a reduction of hematopoietic stem cells (HSCs) in the steady state. While ZCCHC8 was dispensable for differentiation, Zcchc8-deficient HSCs exhibited compromised self-renewal capacity in response to transplantation, myeloablation and sublethal irradiation. Meanwhile, Zcchc8-deficient mice developed bone marrow failure after sublethal irradiation and myeloablation treatment. Transcriptome analysis revealed an accelerated proliferation of Zcchc8-deficient HSCs, which may be a cause of their impaired self-renewal. Mechanistically, ZCCHC8 was shown to regulate HSC function by degrading ncRNA Halr1 and guaranteeing Hoxa cluster expression. Together, our findings not only identified the essential function of ZCCHC8 in preserving HSC self-renewal, but also position it as a suppressor of bone marrow failure during stress hematopoiesis.