Role of the microRNA-290 Gene Cluster in Stem Cell and Organismal Aging

IL My lab mapped a quantitative trait locus (QTL) regulating two traits--natural variation between two strains of mice in (a) the rate of hematopoietic progenitor cycling and (b) their mean lifespan-to the same physical location on mouse chromosome 7. Reciprocal congenic mice fully recapitulated the progenitor cycling phenotype, depending on the genotype of donor alleles in this small interval (3.1cM) containing only 90 genes. Transcriptome analysis revealed no differentially expressed genes. However, microRNA (miR) microarrays demonstrated significant strain-dependent variation in expression of miR-290 family members. The primary transcript encoding all of the 290 family is located within the consensus congenic interval. Differential miR expression of all members was confirmed by quantitative RT-PCR. Moreover, in addition to the strain variation, expression of 290 miRs was strongly age-dependent and increased in both strains in old age. Our results therefore are notable in that this family of miRs usually associated with embryonic stem cells, may be a biomarker of aging by down-regulating a crucial set of proteins in stem and progenitor cells. 1. We will investigate the age-dependent expression of the miR-290 family in both mouse and human hematopoietic progenitor cells. 2. We will attempt to determine the functional intersection between the two phenotypes by which the QTL was originally mapped, and the miR-290 family. We will do so by investigating the potential proteins targeted by the the miRs. 3. We will over-express the mirR-290 cluster in stem and progenitor cells to determine the effects on aging phenotypes of these cells.