Conserved protein Pir2ARS2 mediates gene repression through cryptic introns in lncRNAs

Gobi Thillainadesan, Hua Xiao, Sahana Holla, Jothy Dhakshnamoorthy, Lisa M. Miller Jenkins, David Wheeler and Shiv I. S. Grewal ()
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Gobi Thillainadesan: Laboratory of Biochemistry and Molecular Biology, National Cancer Institute, National Institutes of Health
Hua Xiao: Laboratory of Biochemistry and Molecular Biology, National Cancer Institute, National Institutes of Health
Sahana Holla: Laboratory of Biochemistry and Molecular Biology, National Cancer Institute, National Institutes of Health
Jothy Dhakshnamoorthy: Laboratory of Biochemistry and Molecular Biology, National Cancer Institute, National Institutes of Health
Lisa M. Miller Jenkins: Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health
David Wheeler: Laboratory of Biochemistry and Molecular Biology, National Cancer Institute, National Institutes of Health
Shiv I. S. Grewal: Laboratory of Biochemistry and Molecular Biology, National Cancer Institute, National Institutes of Health

Nature Communications, 2020, vol. 11, issue 1, 1-11

Abstract: Abstract Long non-coding RNAs (lncRNAs) are components of epigenetic control mechanisms that ensure appropriate and timely gene expression. The functions of lncRNAs are often mediated through associated gene regulatory activities, but how lncRNAs are distinguished from other RNAs and recruit effector complexes is unclear. Here, we utilize the fission yeast Schizosaccharomyces pombe to investigate how lncRNAs engage silencing activities to regulate gene expression in cis. We find that invasion of lncRNA transcription into the downstream gene body incorporates a cryptic intron required for repression of that gene. Our analyses show that lncRNAs containing cryptic introns are targeted by the conserved Pir2ARS2 protein in association with splicing factors, which recruit RNA processing and chromatin-modifying activities involved in gene silencing. Pir2 and splicing machinery are broadly required for gene repression. Our finding that human ARS2 also interacts with splicing factors suggests a conserved mechanism mediates gene repression through cryptic introns within lncRNAs.

Date: 2020
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DOI: 10.1038/s41467-020-16280-y

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