Dynamic regulation of miRNA expression in ordered stages of cellular development.

Short RNA expression in several distinct stages of T-lymphocyte development was comprehensively profiled. The total number of microRNAs (miRNAs) expressed per cell at different stages of development varies over nearly an order of magnitude in parallel with changes in total cellular RNA content, suggesting that global miRNA levels are coregulated with the translational capacity of the cell. However, individual miRNAs were dynamically regulated during T-cell development, with at least one miRNA or miRNA family overrepresented at each developmental stage. miRNA regulation in this developmental pathway is characterized by analog rather than switch-like behavior, with temporal enrichments at distinct stages of development observed against a background of constant, basal expression of the miRNA. Enrichments of these miRNAs are temporally correlated with depletions of the transcript levels of targets containing seed matches to the specific miRNAs, and may have specific functional consequences. miR-181a, which is specifically enriched at the CD4(+)CD8(+) (DP) stage of thymocyte development, can repress the expression of Bcl-2, CD69, and the T-cell receptor, all of which are coordinately involved in positive selection.