title: Disparity between microRNA levels and promoter strength is associated with initiation rate and Pol II pausing.
abstract: MicroRNAs are transcribed by RNA polymerase II but the transcriptional features influencing their synthesis are poorly defined. Here we report that a TATA box in microRNA and protein-coding genes is associated with increased sensitivity to slow RNA polymerase II. Promoters driven by TATA box or NF-κB elicit high re-initiation rates, but paradoxically lower microRNA levels. MicroRNA synthesis becomes more productive by decreasing the initiation rate, but less productive when the re-initiation rate increases. This phenomenon is associated with a delay in miR-146a induction by NF-κB. Finally, we demonstrate that microRNAs are remarkably strong pause sites. Our findings suggest that lower efficiency of microRNA synthesis directed by TATA box or NF-κB is a consequence of frequent transcription initiations that lead to RNA polymerase II crowding at pause sites, thereby increasing the chance of collision and premature termination. These findings highlight the importance of the transcription initiation mechanism for microRNA synthesis, and have implications for TATA-box promoters in general.
authors.affiliation: Department of Biological Chemistry, The Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Nadav
authors.initials: N
authors.lastname: Marbach-Bar
authors.forename: Amitai
authors.initials: A
authors.lastname: Ben-Noon
authors.forename: Shaked
authors.initials: S
authors.lastname: Ashkenazi
authors.forename: Ana
authors.initials: A
authors.lastname: Tamarkin-Ben Harush
authors.forename: Tali
authors.initials: T
authors.lastname: Avnit-Sagi
authors.forename: Michael D
authors.initials: MD
authors.lastname: Walker
authors.forename: Rivka
authors.initials: R
authors.lastname: Dikstein
mesh_terms: D000818:Animals; D006224:Cricetinae; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012319:RNA Polymerase II / Q000235:genetics* / Q000378:metabolism; D061785:Transcription Initiation, Genetic; D014162:Transfection
chemical_list: D035683:MicroRNAs; D016328:NF-kappa B; D012319:RNA Polymerase II