A Biogenesis Step Upstream of Microprocessor Controls miR-17∼92 Expression

The precise control of miR-17 similar to 92 microRNA (miRNA) is essential for normal development, and overexpression of certain miRNAs from this cluster is oncogenic. Here, we find that the relative expression of the six miRNAs processed from the primary (pri-miR-17 similar to 92) transcript is dynamically regulated during embryonic stem cell (ESC) differentiation. Pri-miR-17 similar to 92 is processed to a biogenesis intermediate, termed progenitor-miRNA'' (pro-miRNA). Pro-miRNA is an efficient substrate for Microprocessor and is required to selectively license production of pre-miR-17, pre-miR-18a, pre-miR-19a, pre-miR- 20a, and pre-miR-19b from this cluster. Two complementary cis-regulatory repression domains within pri-miR-17 similar to 92 are required for the blockade of miRNA processing through the formation of an autoinhibitory RNA conformation. The endonuclease CPSF3 (CPSF73) and the spliceosome-associated ISY1 are responsible for pro-miRNA biogenesis and expression of all miRNAs within the cluster except miR-92. Thus, developmentally regulated pro-miRNA processing is a key step controlling miRNA expression and explains the posttranscriptional control of miR-17 similar to 92 expression in development.