Abstract
Ageing-associated impairments in haemato-lymphopoiesis are associated with DNA damage accumulation and reduced maintenance of lymphoid-biased (Ly-biased) compared with myeloid-biased (My-biased) haematopoietic stem cells (HSCs). Here, in vivo RNAi screening identifies period circadian clock 2 (Per2) as a critical factor limiting the maintenance of HSCs in response to DNA damage and ageing. Under these conditions, Per2 is activated predominantly in Ly-biased HSCs and stimulates DNA damage signalling and p53-dependent apoptosis in haematopoietic cells. Per2 deletion ameliorates replication stress and DNA damage responses in haematopoietic cells, thereby improving the maintenance of Ly-biased HSCs, lymphopoiesis, and immune function in ageing mice without increasing the accumulation of DNA damage. Per2-deficient mice retain Batf/p53-dependent induction of differentiation of HSCs in response to DNA damage and exhibit an elongated lifespan. Together, these results identify Per2 as a negative regulator of Ly-biased HSCs and immune functions in response to DNA damage and ageing.