title: A Biogenesis Step Upstream of Microprocessor Controls miR-17∼92 Expression.
abstract: The precise control of miR-17∼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∼92) transcript is dynamically regulated during embryonic stem cell (ESC) differentiation. Pri-miR-17∼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∼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∼92 expression in development.
authors.affiliation: Stem Cell Program, Boston Children's Hospital, Boston, MA 02115, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Peng
authors.initials: P
authors.lastname: Du
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Longfei
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Piotr
authors.initials: P
authors.lastname: Sliz
authors.affiliation: Stem Cell Program, Boston Children's Hospital, Boston, MA 02115, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA; Harvard Stem Cell Institute, Boston, MA 02115, USA. Electronic address: rgregory@enders.tch.harvard.edu.
authors.forename: Richard I
authors.initials: RI
authors.lastname: Gregory
mesh_terms: D000818:Animals; D001483:Base Sequence; D002454:Cell Differentiation; D053595:Embryonic Stem Cells / Q000378:metabolism*; D004720:Endonucleases / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism*; D008969:Molecular Sequence Data; D009690:Nucleic Acid Conformation; D012323:RNA Processing, Post-Transcriptional; D043244:Ribonuclease III / Q000378:metabolism; D016415:Sequence Alignment; D017381:Spliceosomes / Q000378:metabolism
chemical_list: D035683:MicroRNAs; D004720:Endonucleases; D043244:Ribonuclease III