The microRNA-212/132 cluster regulates hematopoietic stem cell maintenance and survival with age by buffering FOXO3 expression

MicroRNAs are critical post-transcriptional regulators of hematopoietic cell-fate decisions, though little remains known about their role in aging hematopoietic stem cells (HSCs). The microRNA-212/132 cluster (miR-212/132) is enriched in HSCs and is up-regulated during hematopoietic aging. Both over-expression and deletion of microRNAs in this cluster leads to inappropriate hematopoiesis with age. Enforced expression of miR-132 in the bone marrow compartment of mice led to rapid HSC cycling followed by their depletion. A genetic deletion of the miR-212/132 cluster in mice resulted in HSCs that had altered cycling, function, and survival in response to growth factor starvation. We found that miR-212/132 exerts its effect on aging HSCs by targeting the transcription factor FOXO3, a known aging associated gene. Our data demonstrates that miR-212/132 plays a role in maintaining balanced hematopoietic output by buffering FOXO3 expression. We have thus identified a novel target that may play a role in age-related hematopoietic defects. RNA-seq (SMART-Seq2 protocol) for LT-HSCs (LSK CD150+ CD48-), ST-HSCs (LSK CD150- CD48-) and MPPs (LSK CD150- CD48+) from WT and miR-212/132-/- mice