The mammalian nucleus is highly organized into chromosome territories and a number of distinct membrane-less nuclear bodies or sub-nuclear structures that can affect nuclear neighborhoods and gene regulation. Distinct nuclear bodies contain specific protein and RNA components that define particular nuclear processes. Paraspeckles, first identified in 2002, are composed of the long noncoding RNA (lncRNA) NEAT1 which confers structural integrity and multiple proteins, including PSP1α, p54nrb and PSF for its potential functions.
In many cells, mRNAs containing inverted Alu repeats (IRAlus) in their 3′-untranslated regions (3′-UTRs) are inefficiently exported to the cytoplasm. Such nuclear retention correlates with paraspeckle-associated protein complexes containing p54nrb. However, nuclear retention of mRNAs containing IRAlus is variable and how regulation of retention and export is achieved is poorly understood.
Here we show one mechanism of such regulation via the arginine methyltransferase CARM1. We demonstrate that disruption of CARM1 enhances the nuclear retention of mRNAs containing IRAlus. CARM1 regulates this nuclear retention pathway at two levels: CARM1 methylates the coiled-coil domain of p54nrb, resulting in reduced binding of p54nrb to mRNAs containing IRAlus; CARM1 also acts as a transcription regulator to suppress NEAT1 transcription, leading to reduced paraspeckle formation. These actions of CARM1 work together synergistically to regulate the export of transcripts containing IRAlus from paraspeckles under certain cellular stresses, such as poly(I:C) treatment. This work demonstrates how a post-translational modification of an RNA binding protein affects protein-RNA interaction and also uncovers a mechanism of transcriptional regulation of the long noncoding RNA NEAT1.
This work done by CHEN Lingling’s group from Shanghai Institute of Biochemistry and Cell Biology was published in Genes & Development on March 15th under the title “Protein arginine methyltransferase CARM1 attenuates the paraspeckle-mediated nuclear retention of mRNAs containing IRAlus” and further highlighted in Genes & Development on April 1st, 2015 (Elbarbary & Maquat. Genes Dev. 2015, 29:687–689). This study was supported by the grants from the Chinese Academy of Sciences (the Strategic Priority Research Program), the Ministry of Science and Technology, and National Natural Science Foundation of China.
AUTHOR CONTACT:
CHEN Lingling
Shanghai Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences
Shanghai,200031
E-mail: linglingchen@sibcb.ac.cn
Figure: A model of how the nuclear retention of IRAlus mRNAs at paraspeckles is regulated. Left, under normal conditions, CARM1 suppresses NEAT1 transcription and paraspeckle formation and also methylates p54nrb, resulting in the reduced binding capability to mRNAs containing IRAlus. Right, upon appropriate stimulation, such as upon poly(I:C) treatment, actions of CARM1 are attenuated, resulting in an increased expression of NEAT1 RNA, unmethylated p54nrb and enhanced nuclear retention of IRAlus mRNAs at paraspeckles.
(Image provided by Prof. CHEN Lingling`s group)
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