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Chtop (Chromatin target of Prmt1) auto-regulates its expression level via intron retention and nonsense-mediated decay of its own mRNA

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posted on 2022-12-15, 04:04 authored by K Izumikawa, H Yoshikawa, H Ishikawa, Y Nobe, Y Yamauchi, S Philipsen, Richard SimpsonRichard Simpson, T Isobe, N Takahashi
Chtop (chromatin target of Prmt1) regulates various aspects of gene expression including transcription and mRNA export. Despite these important functions, the regulatory mechanism underlying Chtop expression remains undetermined. Using Chtop-expressing human cell lines, we demonstrate that Chtop expression is controlled via an autoregulatory negative feedback loop whereby Chtop binds its own mRNA to retain intron 2 during splicing; a premature termination codon present at the 5' end of intron 2 leads to nonsense-mediated decay of the mRNA. We also show that Chtop interacts with exon 2 of Chtop mRNA via its arginine-glycine-rich (RG) domain, and with intron 2 via its N-terminal (N1) domain; both are required for retention of intron 2. In addition, we show that hnRNP H accelerates intron 2 splicing of Chtop mRNA in a manner dependent on Chtop expression level, suggesting that Chtop and hnRNP H regulate intron 2 retention of Chtop mRNA antagonistically. Thus, the present study provides a novel molecular mechanism by which mRNA and protein levels are constitutively regulated by intron retention.

Funding

Core Research for Evolutional Science and Technology (CREST) from the Japan Science and Technology Agency (JST) [No. 13415564]; Grant-in-Aid for Scientific Research, Ministry of Education, Culture, Sports, Science & Technology of Japan (MEXT) [No. 24241075]; Global Innovation Research Organization of Tokyo University of Agriculture & Technology. Funding for open access charge: CREST/JST; Landsteiner Foundation for Blood Transfusion Research [LSBR 1040 to S.P.]; Netherlands Organization for Scientific Research [NWO/ZonMw TOP 40-00812-98-12128]; EU fp7 Specific Cooperation Research Project THALAMOSS [306201]. Some of the authors filed a patent application related to this work.

History

Publication Date

2016-11-16

Journal

Nucleic Acids Research

Volume

44

Issue

20

Pagination

13p. (p. 9847-9859)

Publisher

Oxford University Press

ISSN

1362-4962

Rights Statement

© The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

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