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

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^*

^*Corresponding author for this work

Molecular Biosciences

Research output: Contribution to journal › Article › peer-review

11 Scopus citations

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.

Original language	English (US)
Article number	110673
Journal	Cell reports
Volume	39
Issue number	2
DOIs	https://doi.org/10.1016/j.celrep.2022.110673
State	Published - Apr 12 2022

Funding

We thank the members of our laboratory, Yoshihiro Sambu, Risa Yumino, Koutaro Asada, Yoshitaka Naito, and Masashi Murata for discussion of the manuscript. We thank Dr. Yasuhiro Murakawa for helpful comments on the analysis of the RIKEN FANTOM5 database. This work was supported by JSPS KAKENHI grant numbers 15K08410 , 17K15671 , 18K07048 , 17H04067 , 21H02706 , and 21K06953 ; the Strategic Research Foundation Grant-aided Project ( S1511011 ) for Private Universities from the Ministry of Education, Culture, Sports, Science and Technology of Japan ( MEXT ); and a research grant from the Takeda Science Foundation .

Keywords

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

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.celrep.2022.110673

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title = "Nuclear microRNAs release paused Pol II via the DDX21-CDK9 complex",

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.",

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AU - Ohno, Shin ichiro

AU - Oikawa, Keiki

AU - Tsurui, Toshiaki

AU - Harada, Yuichirou

AU - Ono, Kana

AU - Tateishi, Mizumo

AU - Mirza, Aashiq

AU - Takanashi, Masakatsu

AU - Kanekura, Kosuke

AU - Nagase, Kumiko

AU - Shimada, Yoshihisa

AU - Kudo, Yujin

AU - Ikeda, Norihiko

AU - Ochiya, Takahiro

AU - Wang, Xiaozhong

AU - Kuroda, Masahiko

PY - 2022/4/12

Y1 - 2022/4/12

N2 - 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.

AB - 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.

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KW - promoter-associated noncoding RNA

KW - small activating RNA

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

Abstract

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Keywords

ASJC Scopus subject areas

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