PUMILIO hyperactivity drives premature aging of Norad-deficient mice
- University of Texas Southwestern Medical Center, United States
- Nationwide Children's Hospital, United States
Abstract
Although numerous long noncoding RNAs (lncRNAs) have been identified, our understanding of their roles in mammalian physiology remains limited. Here we investigated the physiologic function of the conserved lncRNA Norad in vivo. Deletion of Norad in mice results in genomic instability and mitochondrial dysfunction, leading to a dramatic multi-system degenerative phenotype resembling premature aging. Loss of tissue homeostasis in Norad-deficient animals is attributable to augmented activity of PUMILIO proteins, which act as post-transcriptional repressors of target mRNAs to which they bind. Norad is the preferred RNA target of PUMILIO2 (PUM2) in mouse tissues and, upon loss of Norad, PUM2 hyperactively represses key genes required for mitosis and mitochondrial function. Accordingly, enforced Pum2 expression fully phenocopies Norad deletion, resulting in rapid-onset aging-associated phenotypes. These findings provide new insights and open new lines of investigation into the roles of noncoding RNAs and RNA binding proteins in normal physiology and aging.
Data availability
RNA-seq and eCLIP data has been deposited in the Gene Expression Omnibus (GEO) at NCBI (Accession numbers GSE121684, GSE121688, and GSE125539).
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Identification of RNAs bound to PUM2 in Norad+/+ and Norad-/- brains [CLIP-seq]NCBI Gene Expression Omnibus, GSE121684.
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Gene expression profiles in Norad+/+ and Norad-/- brains and spleens [RNA-seq]NCBI Gene Expression Omnibus, GSE121688.
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Gene expression profiles in double transgenic (DT, Pum2;rtTA3) and control (CTR, Pum2 and wild-type) spleensNCBI Gene Expression Omnibus, GSE125539.
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Gene expression profiles in NORAD knockout and PUMILIO overexpressing cellsNCBI Gene Expression Omnibus, GSE75440.
Article and author information
Author details
Mahmoud M Elguindy
Funding
Howard Hughes Medical Institute
- Hongtao Yu
- Joshua T Mendell
National Institutes of Health (R35CA197311)
- Joshua T Mendell
Cancer Prevention and Research Institute of Texas (RP160249)
- Yang Xie
- Joshua T Mendell
Welch Foundation (I-1961-20180324)
- Joshua T Mendell
German National Academy of Sciences Leopoldina (LPDS 2014-12)
- Florian Kopp
National Institutes of Health (P30CA142543)
- Joshua T Mendell
National Institutes of Health (P50CA196516)
- Joshua T Mendell
Cancer Prevention and Research Institute of Texas (RP150596)
- Yang Xie
- Joshua T Mendell
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All animals were handled according to approved institutional animal care and use committee (IACUC) protocols of The University of Texas Southwestern Medical Center (Animal Protocol Number 2017-102001) and The Ohio State University, Nationwide Children's Hospital (Animal Protocol Number AR12-00014).
Copyright
© 2019, Kopp et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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PUMILIO hyperactivity drives premature aging of Norad-deficient mice
eLife 8:e42650.
https://doi.org/10.7554/eLife.42650
Further reading
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- Chromosomes and Gene Expression
- Genetics and Genomics
Deleting a long noncoding RNA drives premature aging in mice.
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- Cancer Biology
- Chromosomes and Gene Expression
Telomeres are crucial for cancer progression. Immune signalling in the tumour microenvironment has been shown to be very important in cancer prognosis. However, the mechanisms by which telomeres might affect tumour immune response remain poorly understood. Here, we observed that interleukin-1 signalling is telomere-length dependent in cancer cells. Mechanistically, non-telomeric TRF2 (telomeric repeat binding factor 2) binding at the IL-1-receptor type-1 (IL1R1) promoter was found to be affected by telomere length. Enhanced TRF2 binding at the IL1R1 promoter in cells with short telomeres directly recruited the histone-acetyl-transferase (HAT) p300, and consequent H3K27 acetylation activated IL1R1. This altered NF-kappa B signalling and affected downstream cytokines like IL6, IL8, and TNF. Further, IL1R1 expression was telomere-sensitive in triple-negative breast cancer (TNBC) clinical samples. Infiltration of tumour-associated macrophages (TAM) was also sensitive to the length of tumour cell telomeres and highly correlated with IL1R1 expression. The use of both IL1 Receptor antagonist (IL1RA) and IL1R1 targeting ligands could abrogate M2 macrophage infiltration in TNBC tumour organoids. In summary, using TNBC cancer tissue (>90 patients), tumour-derived organoids, cancer cells, and xenograft tumours with either long or short telomeres, we uncovered a heretofore undeciphered function of telomeres in modulating IL1 signalling and tumour immunity.
