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PUMILIO hyperactivity drives premature aging of Norad-deficient mice

Florian Kopp, Mehmet Yalvac, Beibei Chen, He Zhang, Sungyul Lee, Frank Gillett, Mahmoud Elguindy, Sushama Sivakumar, Hongtao Yu, Yang Xie, Prashant Mishra, Zarife Sahenk, Joshua T Mendell

Preprint posted on October 01, 2018 https://www.biorxiv.org/content/early/2018/10/01/432112

An (un)expected surprise? NORAD lncRNA regulates tissue homeostasis, genome integrity and mitochrondrial function in vivo.

Selected by Carmen Adriaens

Introduction/background

After the realization that a substantial amount of the transcribed genome does not code for proteins, long non-coding RNAs have been an intense subject of study in the past couple of decades. However, still few have been shown to be essential in vivo, and even less are really functionally and mechanistically understood. One of the more recently studied lncRNAs is Noncoding RNA activated by DNA damage, NORAD, named after its induction upon doxorubicin treatment. NORAD has been initially shown to interact with Pumilio proteins involved in post-transcriptional regulation of RNA targets in the cytoplasm. With its 15+ conserved Pumilio Response Elements (PREs), NORAD was shown to be the preferential binding partner of these proteins, thus serving as a decoy (much like lncRNA can serve as a decoy for microRNAs), so that other PUMILIO targets are not downregulated when they are needed in the cell1,2. An important subset of these targets are mRNAs involved in processes such as chromosomal segregation in cell division and DNA replication1,2. When NORAD is lost, Pumilio proteins become hyperactive and excessively inhibit these targets thus causing aberrant mitosis and aneuploidy. Another recent study has identified NORAD as a central scaffold of a novel nuclear complex, NARC1 (NORAD Activated Ribonucleoprotein Complex 1), which is built on the RNA binding protein RBMX3. Upon DNA damage, NARC1 is formed by shuttling NORAD from the cytoplasm back to the nucleus, where it tethers Topoisomerase I and other factors important for genomic stability together with RBMX.

Although a variety of functions and binding partners of NORAD have been investigated by different groups using cultured mammalian cells1–5, its functions have so far not been explored in vivo. In a recent preprint, the group of Prof. J.T. Mendell tackled the question of whether Norad was also, and similarly, functional in living tissues by making a mouse model constitutively deleted for the mouse Norad ortholog, and comparing the phenotypes in these mice with those overexpressing PUM2.

What are the main findings?

First, the authors found that although Norad KO mice were viable and developed initially in a similar fashion as their WT littermates, soon after they reached adulthood they showed signs of premature aging. For instance, they observed increased baldness, greying hairs, spine deformations, weight loss and muscle and neuronal malfunction in Norad KO mice, and noted they had shorter lifespans as compared to wild types. When looking at the molecular cause for these phenotypes, they initially focused their attention to the well-studied interaction of Norad with Pumilio proteins, which had previously been implicated in aging. The authors could indeed identify a conserved interaction between Norad and Pum2, and found that the published canonical Pumilio targets were largely the same in vivo as they were in cultured cells. Furthermore, Pumilio occupancy on its targets was significantly increased in Norad KO mice, which led to a decrease in their expression in this model.

Next, the authors assessed if the aging phenotypes were due to aberrant mitosis previously reported in vitro. For this, they assessed the highly proliferative blood lineage and could indeed establish that both lymphocytes and splenocytes displayed increased aneuploidy.

Because muscle cells were heavily affected by Norad loss and the observed phenotypes pointed to aging-related diseases, the authors assessed if mitochondrial function was affected (for instance, it is known that mitochondrial defects can lead to premature aging6). They noted that Norad KO mice displayed severe mitochondrial abnormalities, including in their morphology and function, which led to a pathological accumulation of reactive oxygen species and oxidative damage, as well as faulty cellular metabolism and decreased mitochondrial respiration rates. Upon further investigation, they found that Norad-depleted tissues and cell lines showed significantly decreased levels of mitochondria-related genes, a subset of which were shown in PUM2 CLIP experiments to be direct targets of this protein.

As Norad was known to tether away Pum2 to prevent unwanted downregulation of its mRNA targets, the authors hypothesized that Norad KO phenotypes could be phenocopied upon Pum2 overexpression if it functioned in the same way in tissues as it does in vitro. Thus, to definitively establish the link between the Norad KO observed phenotypes and Pum2 hyperactivity, they created a mouse model in which doxycycline (dox) administration ubiquitously induced Flag-PUM2 expression. In this model, dox induction did not cause a significant increase in the levels of PUM2 protein, but rather seemed to replace endogenous protein with the tagged version, an observation potentially explained by the known tight regulation of PUM proteins via negative and positive feedback loops. When PUM2 was forcibly expressed, the mice neatly phenocopied, but with an even faster onset, the absence of Norad, both on the gross physiological level and on the cell biological level including the mitochondrial dysfunction.

Overall, the data in this preprint make a compelling case for Norad lncRNA function in adult tissue physiology through interactions with a tightly regulated RNA binding protein.

What do I think about the work?

In short: I really, really like it. It’s a well-controlled study with a beautiful design and compelling results in living animals. I think it is eye-opening that this abundant lncRNA can have such late-onset phenotypes, and I believe it urges the research community to look further than just the binary “viable or not” question. As this study shows, very highly conserved proteins can undergo lineage-specific fine tuning by less conserved RNAs (eg. here, in the mammalian lineage). Furthermore, I am always captivated by the idea that the biology of adult tissues can differ so significantly from these same tissues during development (why do the phenotypes only occur upon reaching adulthood? What changes are made, for instance in the chromatin, that cells become more sensitive to replication stress, and how are developing tissues protected from it when they need to quickly proliferate?).

Some more topical questions, of course, always remain. For instance, in light of the recent study by Munschauer et al., is the NARC1 conserved in mouse tissues, and if so, are any of the observed phenotypes related to NARC1 and the DNA damage regulating factors bound within it? The authors also mention that not all Norad KO mice show the same degree of phenotype. It would be interesting to determine what drives the penetrance of such phenotype, and if in tissues or individuals in which it is less severe, compensatory mechanisms can be identified. Finally, and this maybe just out of curiosity, are Norad KO mice more cancer prone as well? For instance, are blood cancers more prevalent due to the increased aneuploidy, and could this be an important cause of early death?

Ps. I initially named this paper when I saved its PDF “Norad KO pumilio gone mad”. Maybe not appropriate, but since I still like it as a title, I’ll make it my bottomline! :- ).

References

  1. Lee, S. et al. Noncoding RNA NORAD Regulates Genomic Stability by Sequestering PUMILIO Proteins. Cell (2016). doi:10.1016/j.cell.2015.12.017
  2. Tichon, A. et al. A conserved abundant cytoplasmic long noncoding RNA modulates repression by Pumilio proteins in human cells. Nat. Commun. (2016). doi:10.1038/ncomms12209
  3. Munschauer, M. et al. The NORAD lncRNA assembles a topoisomerase complex critical for genome stability. Nature 561, 132–136 (2018).
  4. Spiniello, M. et al. HyPR-MS for multiplexed discovery of MALAT1, NEAT1, and NORAD lncRNA protein interactomes. J. Proteome Res. 17, 3022–3038 (2018).
  5. Tichon, A., Perry, R. B. T., Stojic, L. & Ulitsky, I. SAM68 is required for regulation of pumilio by the NORAD long noncoding RNA. Genes Dev. (2018). doi:10.1101/gad.309138.117
  6. Trifunovic, A. et al. Premature ageing in mice expressing defective mitochondrial DNA polymerase. Nature (2004). doi:10.1038/nature02517

 

 

 

Tags: aging, lncrna, mitochondria, mouse models, norad

Posted on: 9th October 2018

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    Simultaneous multiplexed amplicon sequencing and transcriptome profiling in single cells

    Mridusmita Saikia, Philip Burnham, Sara H Keshavjee, et al.

    AND

    High-throughput targeted long-read single cell sequencing reveals the clonal and transcriptional landscape of lymphocytes

    Mandeep Singh, Ghamdan Al-Eryani, Shaun Carswell, et al.



    Selected by Samantha Seah

    The microbial basis of impaired wound healing: differential roles for pathogens, "bystanders", and strain-level diversification in clinical outcomes

    Lindsay Kalan, Jacquelyn S Meisel, Michael A Loesche, et al.



    Selected by Snehal Kadam

    Comparative analysis of droplet-based ultra-high-throughput single-cell RNA-seq systems

    Xiannian Zhang, Tianqi Li, Feng Liu, et al.



    Selected by Samantha Seah

    PUMILIO hyperactivity drives premature aging of Norad-deficient mice

    Florian Kopp, Mehmet Yalvac, Beibei Chen, et al.



    Selected by Carmen Adriaens

    LCM-seq reveals unique transcriptional adaption mechanisms of resistant neurons in spinal muscular atrophy

    Susanne Nichterwitz, Helena Storvall, Jik Nijssen, et al.

    AND

    Axon-seq decodes the motor axon transcriptome and its modulation in response to ALS

    Jik Nijssen, Julio Cesar Aguila Benitez, Rein Hoogstraaten, et al.



    Selected by Yen-Chung Chen

    LADL: Light-activated dynamic looping for endogenous gene expression control

    Mayuri Rege, Ji Hun Kim, Jacqueline Valeri, et al.



    Selected by Ivan Candido-Ferreira

    Also in the molecular biology category:

    The autophagic membrane tether ATG2A transfers lipids between membranes

    Shintaro Maeda, Chinatsu Otomo, Takanori Otomo



    Selected by Sandra Malmgren Hill

    LTK is an ER-resident receptor tyrosine kinase that regulates secretion

    Federica G. Centonze, Veronika Reiterer, Karsten Nalbach, et al.



    Selected by Nicola Stevenson

    1

    Accurate detection of m6A RNA modifications in native RNA sequences

    Huanle Liu, Oguzhan Begik, Morghan C Lucas, et al.



    Selected by Christian Bates

    1

    Blue light induces neuronal-activity-regulated gene expression in the absence of optogenetic proteins

    Kelsey M. Tyssowski, Jesse M. Gray



    Selected by Zheng-Shan Chong

    Slide-seq: A Scalable Technology for Measuring Genome-Wide Expression at High Spatial Resolution

    Samuel G Rodriques, Robert R Stickels, Aleksandrina Goeva, et al.

    AND

    High-density spatial transcriptomics arrays for in situ tissue profiling

    Sanja Vickovic, Goekcen Eraslan, Johanna Klughammer, et al.



    Selected by Carmen Adriaens

    Optical determination of absolute membrane potential

    Julia R. Lazzari-Dean, Anneliese M.M. Gest, Evan Miller



    Selected by James Marchant

    MicroRNA-mediated control of developmental lymphangiogenesis

    Hyun Min Jung, Ciara Hu, Alexandra M Fister, et al.



    Selected by Rudra Nayan Das

    Microfluidic protein isolation and sample preparation for high resolution cryo-EM

    Claudio Schmidli, Stefan Albiez, Luca Rima, et al.



    Selected by David Wright

    A DNA-based voltmeter for organelles

    Anand Saminathan, John Devany, Kavya S Pillai, et al.



    Selected by Robert Mahen

    1

    Structures of the Otopetrin Proton Channels Otop1 and Otop3

    Kei Saotome, Bochuan Teng, Che Chun (Alex) Tsui, et al.



    Selected by David Wright

    Central spindle microtubules are strongly coupled to chromosomes during both anaphase A and anaphase B

    Che-Hang Yu, Stefanie Redemann, Hai-Yin Wu, et al.



    Selected by Federico Pelisch

    1

    Cell growth dilutes the cell cycle inhibitor Rb to trigger cell division

    Evgeny Zatulovskiy, Daniel F. Berenson, Benjamin R. Topacio, et al.



    Selected by Zaki Ahmad

    1

    Distinct ROPGEFs successively drive polarization and outgrowth of root hairs

    Philipp Denninger, Anna Reichelt, Vanessa Aphaia Fiona Schmidt, et al.



    Selected by Marc Somssich

    Inactive USP14 and inactive UCHL5 cause accumulation of distinct ubiquitinated proteins in mammalian cells

    Jayashree Chadchankar, Victoria Korboukh, Peter Doig, et al.



    Selected by Mila Basic

    Bacteriophage resistance alters antibiotic mediated intestinal expansion of enterococci

    Anushila Chatterjee, Cydney N Johnson, Phat Luong, et al.



    Selected by Yasmin Lau

    On-site ribosome remodeling by locally synthesized ribosomal proteins in axons

    Toshiaki Shigeoka, Max Koppers, Hovy Ho-Wai Wong, et al.



    Selected by Srivats Venkataramanan
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