Under chronic metabolic/inflammatory stress relevant to atherosclerosis, bone-marrow progenitors and HSCs undergo durable reprogramming: Western diet in Ldlr−/− mice elicits NLRP3-dependent epigenomic/transcriptomic remodeling of myeloid progenitors with heightened innate responses; peripheral ischemia in Apoe−/− mice imposes epigenetic imprints in HSCs that propagate inflammation and accelerate atherosclerosis; conversely, enhancing cholesterol efflux (rHDL/LXR) or exercise restores HSPC quiescence and reduces inflammatory leukocyte output and plaque inflammation (37, 90–92). The gene discussed is LDLR; the disease is atherosclerosis.