The aim of the laboratory is to unveil fundamental biological mechanisms and understand how these become perturbed during diseases, most prominently cancer, with the ambition that our findings may contribute to the development of clinical tools.
We focus mainly on various classes of non-coding RNAs, such as microRNAs, snoRNAs, tRNAs and lncRNAs. In addition, we study RNA binding proteins and RNA modifications. Special focus areas include the regulation of central tumor suppressor pathways and autophagy.
With the realization that 80% of the genome is transcribed and only 2% serve as coding regions, the non-coding part of the transcriptome is likely to hold key to understanding many essential biological phenomena as well as pathologies.
Technically, the lab spans widely from the identification of disease-relevant genes in functional screens or genome-wide studies, over genetic and biochemical studies in cell culture models to advanced mouse genetics.
- SNHG5: A lncRNA promoting tumor cell survival in colorectal cancer
- MIR31HG: A long non-coding RNA modulating senescence
- A microRNA regulating lysosomal function
- PRDM11: A new tumor suppressor
- Translational codes identified in the genome
- A microRNA impacting on p53
Long non-coding RNA
Data from our ncRNA array dataset, along with accompanying RNA-seq data from individual cancers and model systems, constitute a rich source for hypotheses linking lncRNAs to cancer biology, which we will continue to explore over the next years.
We have over the year developed a series of projects linking various aspects of RNA biology to autophagy regulation. RNAi screens for regulators of autophagy: Using a custom-designed siRNA library targeting >1500 RNA binding proteins we have screened for regulators of autophagosome formation and validated several interesting proteins, which we will pursue over the coming years
This project portfolio will likely constitute a substantial part of our work in 2018-2022. The work originates from our ncRNA arrays, were snoRNAs came out as the most deregulated ncRNA class when comparing cancers to their corresponding normal tissues.
This project potentially can provide a paradigm shift in our understanding of one of the most central complexes in all living organisms. Understanding how the ribosome is regulated to tune translation would:
- Provide a better understanding of how gene expression programs are faithfully executed by the ribosome.
- Provide insight on diseases in which translational control is pathologically hijacked, such as cancers.
- Enable ribosome manipulations to control translation, for instance, of biologics.
SNHG5 promotes colorectal cancer cell survival by counteracting STAU1-mediated mRNA destabilization. Damas ND, Marcatti M, Côme C, Christensen LL, Nielsen MM, Rundsten CF, Seemann SE, Rapin N, Baumgartner R, Thezenas S, Gylling HM, Maglieri G, Vang S, Ørntoft T, Andersen CL, Pedersen JS, and Lund AH (2016). Nature Communications. Doi:10.1038/ncomms13875
The lncRNA MIR31HG regulates p16INK4A expression to modulate senescence. M Montes, MM Nielsen, G Maglieri, A Jacobsen, J Højfeldt, S Agrawal-Singh, K Hansen, K Helin, HJG van de Werken, JS Pedersen and AH Lund. Nature Communications, 6 2015:6967.
A non-conserved miRNA regulates lysosomal function and impacts on a human lysosomal storage disorder. Frankel LB, DI Malta C, Wen J, Eskelinen EL, Ballabio A, Lund AH. Nature Communications, 5 2014:5840.
Loss of PRDM11 promotes MYC-driven lymphomagenesis. Fog CK, Asmar F, Côme C, Jensen KT, Johansen JV, Kheir TB, Jacobsen L, Friis C, Louw A, Rosgaard L, Oebro NF, Marquart HV, Anthonsen K, Braat AK, van Lohuizen M, Ralfkiaer E, Groenbaek K, Lund AH. Blood 2014 Dec 12.
A dual program for translation regulation in cellular proliferation and differentiation. Gingold H, Tehler D, Christoffersen NR, Nielsen MM, Asmar F, Kooistra SM, Christophersen NS, Christensen LL, Borre M, Sørensen KD, Andersen LD, Andersen CL, Hulleman E, Wurdinger T, Ralfkiær E, Helin K, Grønbæk K, Orntoft T, Waszak SM, Dahan O, Pedersen JS, Lund AH, Pilpel Y. Cell. 2014 Sep 11;158(6):1281-92. doi: 0.1016/j.cell.2014.08.011. PubMed PMID: 25215487.
miR-339-5p regulates the p53 tumor-suppressor pathway by targeting MDM2. Jansson MD, Damas ND, Lees M, Jacobsen A, Lund AH. Oncogene. 2014 Jun 2. doi: 10.1038/onc.2014.130. [Epub ahead of print] PubMed PMID: 24882579.
Loss of miR-10a activates lpo and collaborates with activated Wnt signaling in inducing intestinal neoplasia in female mice. Stadthagen G, Tehler D, Høyland-Kroghsbo NM, Wen J, Krogh A, Jensen KT, Santoni-Rugiu E, Engelholm LH, Lund AH. PLoS Genet. 2013 Oct;9(10):e1003913. doi:10.1371/journal.pgen.1003913. Epub 2013 Oct 24. PubMed PMID: 24204315; PubMed Central PMCID: PMC3812087.
Genomic and proteomic analyses of Prdm5 reveal interactions with insulator binding proteins in embryonic stem cells. Galli GG, Carrara M, Francavilla C, de Lichtenberg KH, Olsen JV, Calogero RA, Lund AH. Mol Cell Biol. 2013 Nov;33(22):4504-16. doi: 10.1128/MCB.00545-13. Epub 2013 Sep 16. PubMed PMID:24043305; PubMed Central PMCID: PMC3838183.
microRNA-9 targets the long non-coding RNA MALAT1 for degradation in the nucleus. Leucci E, Patella F, Waage J, Holmstrøm K, Lindow M, Porse B, Kauppinen S, Lund AH. Sci Rep. 2013;3:2535. doi: 10.1038/srep02535. PubMed PMID: 23985560; PubMed Central PMCID: PMC3756333
Prdm5 suppresses Apc(Min)-driven intestinal adenomas and regulates monoacylglycerol lipase expression. Galli GG, Multhaupt HA, Carrara M, de Lichtenberg KH, Christensen IB, Linnemann D, Santoni-Rugiu E, Calogero RA, Lund AH. Oncogene. 2014 Jun 19;33(25):3342-50. doi: 10.1038/onc.2013.283. Epub 2013 Jul 22. PubMed PMID: 23873026.
MicroRNA and cancer. Jansson MD, Lund AH. Mol Oncol. 2012 Oct 9. pii: S1574-7891(12)00098-1. doi: 10.1016/j.molonc.2012.09.006.
MicroRNA regulation of autophagy. Frankel LB, Lund AH. Carcinogenesis. 2012 Nov;33(11):2018-25. doi: 10.1093/carcin/bgs266. Epub 2012 Aug 17. Review. PubMed PMID: 22902544.
Prdm5 Regulates Collagen Gene Transcription by Association with RNA Polymerase II in Developing Bone. Galli GG, Honnens de Lichtenberg K, Carrara M, Hans W, Wuelling M, Mentz B, Multhaupt HA, Fog CK, Jensen KT, Rappsilber J, Vortkamp A, Coulton L, Fuchs H, Gailus-Durner V, Hrabě de Angelis M, Calogero RA, Couchman JR, Lund AH. PLoS Genet. 2012 May;8(5):e1002711. Epub 2012 May 10.
Inhibition of miR-9 de-represses HuR and DICER1 and impairs Hodgkin lymphoma tumour outgrowth in vivo. Leucci E, Zriwil A, Gregersen LH, Jensen KT, Obad S, Bellan C, Leoncini L, Kauppinen S, Lund AH. Oncogene. 2012 Feb 6. doi: 10.1038/onc.2012.15.
PRDM proteins: important players in differentiation and disease. Fog CK, Galli GG, Lund AH. Bioessays. 2012 Jan;34(1):50-60. doi: 10.1002/bies.201100107. Epub 2011 Oct 26. Review.
microRNA-101 is a potent inhibitor of autophagy. Frankel LB, Wen J, Lees M, Høyer-Hansen M, Farkas T, Krogh A, Jäättelä M, Lund AH. EMBO J. 2011 Sep 13. doi: 10.1038/emboj.2011.331.
RNA-TRAIN is a European RNA training network devoted to educating the next generation of European researchers in the field of ncRNA biology. The network is funded by the Marie Curie initiatives of the European Commission.