Nuclear microRNAs release paused Pol II via the DDX21-CDK9 complex

Shin-Ichiro Ohno; Keiki Oikawa; Toshiaki Tsurui; Yuichirou Harada; Kana Ono; Mizumo Tateishi; Aashiq Mirza; Masakatsu Takanashi; Kosuke Kanekura; Kumiko Nagase; Yoshihisa Shimada; Yujin Kudo; Norihiko Ikeda; Takahiro Ochiya; Xiaozhong Wang; Masahiko Kuroda

doi:10.1016/j.celrep.2022.110673

Nuclear microRNAs release paused Pol II via the DDX21-CDK9 complex

Cell Rep. 2022 Apr 12;39(2):110673. doi: 10.1016/j.celrep.2022.110673.

Authors

Affiliations

¹ Department of Molecular Pathology, Tokyo Medical University, 6-1-1, Shinjuku, Shinjuku-ku, Tokyo, 160-8402, Japan.
² Department of Pharmacology, Weill Cornell Medicine, New York, NY 10065, USA.
³ Department of Respiratory Surgery, Tokyo Medical University, Tokyo, 160-8402, Japan.
⁴ Department of Molecular and Cellular Medicine, Tokyo Medical University, Tokyo, 160-8402, Japan.
⁵ Department of Molecular Biosciences, Northwestern University, Evanston, IL 60208, USA.
⁶ Department of Molecular Pathology, Tokyo Medical University, 6-1-1, Shinjuku, Shinjuku-ku, Tokyo, 160-8402, Japan. Electronic address: kuroda@tokyo-med.ac.jp.

PMID: 35417682
DOI: 10.1016/j.celrep.2022.110673

Abstract

RNA activation (RNAa) is an uncharacterized mechanism of transcriptional activation mediated by small RNAs, such as microRNAs (miRNAs). A critical issue in RNAa research is that it is difficult to distinguish between changes in gene expression caused indirectly by post-transcriptional regulation and direct induction of gene expression by RNAa. Therefore, in this study, we seek to identify a key factor involved in RNAa, using the induction of ZMYND10 by miR-34a as a system to evaluate RNAa. We identify the positive transcription elongation factors CDK9 and DDX21, which form a complex with nuclear AGO and TNRC6A, as important transcriptional activators of RNAa. In addition, we find that inhibition of DDX21 suppresses RNAa by miR-34a and other miRNAs without inhibiting post-transcriptional regulation. Our findings reveal a strong connection between RNAa and release of paused Pol II, facilitating RNAa research by making it possible to separately analyze post-transcriptional regulation and RNAa.

Keywords: CDK9; CP: Molecular biology; DDX21; RNA activation; ZMYND10; divergent transcription; miR-34; microRNA; promoter-associated noncoding RNA; small activating RNA.

MeSH terms

Cell Nucleus / metabolism
Cyclin-Dependent Kinase 9* / metabolism
DEAD-box RNA Helicases* / metabolism
Gene Expression Regulation
MicroRNAs* / genetics
RNA Polymerase II* / metabolism
Transcriptional Activation

Substances

MicroRNAs
Cyclin-Dependent Kinase 9
RNA Polymerase II
DEAD-box RNA Helicases