DREAM Research Group
Laboratory for Applied Genome Technologies and Regenerative Medicine
New publication
A new collaborative study from the DREAM group has recently been published in Nature Communications. This study illustrates the new roles of extrachromosomal circular DNA in shaping the architecture of genes and transcription activity in tissues.
A new collaborative study from the DREAM team is published in Nature Biotechnology. Link to full text.
In this new study, a cancer-specific long non-coding RNA (lncRNA, or calledTu-Stroma) was discovered in exosome from ovarian tomur cells. Tu-Stroma can specifically regulate the alternative splicing of the Flower gene, a gene which altertive splicing affect the cell fitness in tumor microenvironment. This discover has led to the development of a novel antibody-based therapy for tumor. 09 December 2024
Group leader Professor Yonglun Luo has received approximately DKK 5.7 million as part of a major EU-funded research project focused on animal welfare.
Read full news here. 4 December 2024 by Sebastian Alexander Skousgaard
Research raises hopes for new treatment of fusion-driven cancer
Researchers from Aarhus University have developed a new form of gene therapy that can stop cell division in a particularly aggressive type of cancer.
Link to full news 11 August 2023 by Line Rønn
From left: Associate Professor Maja Ludvigsen, PhD student Signe Neldeborg, PhD student Johannes Frasez Sørensen, Professor Christian Kanstrup Holm, Associate Professor Magnus Stougaard and Professor Yonglun Luo. The researchers have studied the new form of gene therapy in a fusion-driven subtype of acute myeloid leukaemia (AML). The results provide hope for a completely new method of treatment specifically aimed at fusion-driven cancers for which there is currently no cure. Photo: Line Rønn
Two DANDRITE affiliated researchers receives Ascending Investigator-grant from the Lundbeck Foundation
Associate professor Marina Romero-Ramos and professor Yonglun Luo are among the 11 research talents to receive a grant of 5 million Danish kroner over a period of 4 years. The grant is earmarked for new research projects within the field of neuroscience and is meant to support researchers at the associate professor or professor level who want to cultivate new research areas within their scientific field.
Link to full news on 21 November 2022 by Rikke Skovgaard Lindhard
New professor aims to find cure for degenerative diseases in our cells
Newly appointed Professor Yonglun Luo from Aarhus University hopes to help patients with degenerative diseases such as Duchenne Muscular Dystrophy by unlocking a cure with his research.
Link to full news 1 November 2022 by Vibe Bregendahl Noordeloos
New study identifies functionally distinct blood endothelial cells in breast cancer
September 20, 2022
The dream team is part of a new study published in Nature Communications, which discovers a new type of blood endothelial cells with lipid processing functions in human breast (cancer) tissues. The new study constructed a EC taxonomy in breast (cancer) tissues, and identified clinically relevant EC phenotypes. This type of endothelial cells, called LIPEC, express genes involved in lipid processing and are more abundant in peri-tumoral breast tissues.
Link to the article:
Geldhof V, de Rooij LPMH, Sokol L, Amersfoort J, De Schepper M, Rohlenova K, Hoste G, Vanderstichele A, Delsupehe AM, Isnaldi E, Dai N, Taverna F, Khan S, Truong AK, Teuwen LA, Richard F, Treps L, Smeets A, Nevelsteen I, Weynand B, Vinckier S, Schoonjans L, Kalucka J, Desmedt C, Neven P, Mazzone M, Floris G, Punie K, Dewerchin M, Eelen G, Wildiers H, Li X, Luo Y, Carmeliet P. Single cell atlas identifies lipid-processing and immunomodulatory endothelial cells in healthy and malignant breast. Nat Commun. 2022 Sep 20;13(1):5511. doi: 10.1038/s41467-022-33052-y. PMID: 36127427.
The DREAM team releases its pig single cell transcriptome landscape results in Nature Communications
On June 24, 2022, the DREAM team, together with a large international collaboration group, releases its interim results from the Pig Atlas in Nature Communications. In the new study [1], the authors complete the single cell RNA sequencing of over 200,000 pig cells from 20 different tissues and organs. The new study provides interesting insights into blood endothelial cell heterogeneity and the evolutionally conserved gene expression network in brain residing microglia.
1. Wang, F., Ding, P., Liang, X., Ding, X., Brandt, C. B., Sjöstedt, E., Zhu, J., Bolund, S., Zhang, L., de Rooij, L., Luo, L., Wei, Y., Zhao, W., Lv, Z., Haskó, J., Li, R., Qin, Q., Jia, Y., Wu, W., Yuan, Y., … Luo, Y. (2022). Endothelial cell heterogeneity and microglia regulons revealed by a pig cell landscape at single-cell level. Nature communications, 13(1), 3620. https://doi.org/10.1038/s41467-022-31388-z
Direct URL to the Pig Single Cell Atlas: https://dreamapp.biomed.au.dk/pigatlas/
New study unravels the mechanisms affecting CRISPR/Cas9 activity and specificity
A new joint study contributed the DREAM team discovered that free binding energy changes and PAM context affect CRISPR/Cas9 activity and specificity. This finding leads to the development of better CRISPR design tools to select gRNAs with high efficiency and specificity. This study was published in Nature Communications on May 30, 2022.
Link to the article: https://www.nature.com/articles/s41467-022-30515-0
Link to news release by CRISPR Medicine News. https://crisprmedicinenews.com/news/new-study-explains-why-grna-efficiency-varies-at-on-and-off-target-sites/
Genome-wide annotation of protein-coding genes in pig
We are pleased to share our latest publication on the genome-wide annotation of protein-coding genes in pigs. This international collaboration project was innitated back in 2017 with an aim to better annotation the genome, gene expression, gene regultion and cell functions in pigs.
Visit the newly arrived pig atlas!
Publication: Karlsson, M., Sjöstedt, E., Oksvold, P. et al. Genome-wide annotation of protein-coding genes in pig. BMC Biol 20, 25 (2022). https://doi.org/10.1186/s12915-022-01229-y
NEW GRANT STRENGTHENS RESEARCH INTO CURING MUSCULAR DYSTROPHY
Associate Professor Yonglun Luo from Aarhus University receives DKK 2.7 million from the Novo Nordisk Foundation to study whether muscular dystrophy can be cured with the help of gene editing and stem cell technologies. The research is of particular benefit to patients with a rare muscular dystrophy disease.
2022.01.20 | LENE HALGAARD
https://newsroom.au.dk/en/news/show/artikel/ny-bevilling-styrker-forskning-i-muskelsvind/
Science: Mammalian Brain Atlas
Today, we have joined forces to map the complex brain, which is what the brain is, in a new comparative atlas. The study has just been published in the journal Science and expands our understanding of the cerebellum as the base for coordinating motor functions. See the full news here:
JASN and Cancer Cell: Empower studying endothelial cell heterogeneity and functions by single cell RNA sequencing technology
The breakthrough in single cell sequencing technology now allows us to study somatic cell evolution and heterogeneity in speed and scale. This technology is based on the high-throughput generation of barcoded transcripts of individual cell. Combining with next generation sequencing technology, it allows us to profile the expression of all genes cell by cell. Based on the overall expression similarity and cell identity genes (which is also known as marker genes), this technology empowers the identification of classical and novel cell types, as well as novel phenotypes (cells, genes, pathways, metabolites) which response to e.g. treatments, allowing the development of more targeted treatment of human diseases.
One particular type of cells which plays indispensable role in human health and disease are the endothelial cells, which line the lumen of vascular systems. The phenotypic heterogeneity and metabolic reprogramming of endothelial cells across different vessel beds have been well-recognized, but the phenotypic heterogeneity of the endothelial cells at single cell level has not been inventoried in sufficient power. In collaboration with Prof. Peter Carmeliet from VIB, we have applied single cell RNA sequencing to reveal the heterogeneity and metabolic adaptation of endothelial cells in lung cancers and kidney compartments.
Read the full articles here:
1. Goveia J, Rohlenova K, Taverna F, et al. An Integrated Gene Expression Landscape Profiling Approach to Identify Lung Tumor Endothelial Cell Heterogeneity and Angiogenic Candidates. Cancer Cell. 2020;37(1):21–36.e13. doi:10.1016/j.ccell.2019.12.001
2. Dumas SJ, Meta E, Borri M, et al. Single-Cell RNA Sequencing Reveals Renal Endothelium Heterogeneity and Metabolic Adaptation to Water Deprivation. J Am Soc Nephrol. 2020;31(1):118–138. doi:10.1681/ASN.2019080832
3. Highlights of the Renal EC study by Nature Reviews Nephrology: www.nature.com/articles/s41581-020-0250-4
Cell: First endothelial cell Atlas in mouse revealed by single cell RNA sequencing
Feb.13 2020.
We are pleased to release the first murine endothelial cell Atlas in Cell together with Prof. Peter Carmeliet from VIB. This is the first single-cell RNA sequencing based profiling of endothelial cell phenotypes across 11 mouse tissues/organs. This joint study takes the first unprecedented effort to map the endothelial cell heterogeneity by single cell RNA sequencing. Our results and and discoveries from the study provide an important resource to overcome one of the urgent unmet needs in vascular biology, and provide a catalog to further understanding the endothelial cells in diseases.
Link to the study:
https://www.sciencedirect.com/science/article/pii/S0092867420300623
Early News
Young Scientist from the DREAM team is supported by DFF Sapere Aude starting grant
Assistant Professor and PhD Lin Lin from the Department of Biomedicine receives almost DKK six million from the Independent Research Fund Denmark. The grant will be used to develop new technologies for pig-to-human organ transplants. The support from the Independent Research Fund Denmark’s Sapere Aude programme also gives her the opportunity to establish herself as research group leader.
2018.12.07 | SABINA BJERRE HANSEN
The Independent Research Fund Denmark has selected Lin Lin as one of 34 Sapere Aude research group leaders with the potential to shape future research that benefits Denmark. Photo: Tariq Mikkel Khan/Independent Research Fund Denmark.
A shortage of organs for transplants poses a serious challenge – a challenge that Lin Lin has taken up. She conducts research in transplant medicine and her ambition is to generate the best genetically modified pigs for organ transplantations.
Pigs have long been considered one of the most promising alternative sources of organs due to their anatomical and physiological similarities with humans. However, two of the central remaining barriers to pig-to-human organ transplantation – also called xenotransplantation – are viral transmission and immunological rejection.
Lin Lin is working to develop technologies for the generation of pigs that are resistant to immunological rejection and viral infections, thereby eliminating the two barriers. To achieve this, she utilises CRISPR gene editing and cloning in her research.
Read more about Lin Lin and her research on the Independent Research Fund Denmark's website.
Contact
Assistant Professor and PhD Lin Lin
Aarhus University, Department of Biomedicine
Direct tel.: (+45) 8716 7015
Email: lin.lin@biomed.au.dk
Grants and awards, People news, Health and disease, Public/Media, PhD students, Technical / administrative staff, Academic staff, Department of Biomedicine, Health, Health
Uncover novel STAT3 functions in lysosomal machinery
【Aug. 29. 2018】
Dysregulated intracellular pH is emerging as a hallmark of cancer. In spite of their acidic environment and increased acid production, cancer cells maintain alkaline intracellular pH that promotes cancer progression by inhibiting apoptosis and increasing glycolysis, cell growth, migration, and invasion. Here we identify signal transducer and activator of transcription-3 (STAT3) as a key factor in the preservation of alkaline cytosol. STAT3 associates with the vacuolar H+-ATPase in a coiled-coil domain-dependent manner and increases its activity in living cells and in vitro. Accordingly, STAT3 depletion disrupts intracellular proton equilibrium by decreasing cytosolic pH and increasing lysosomal pH, respectively. This dysregulation can be reverted by reconstitution with wild-type STAT3 or STAT3 mutants unable to activate target genes (Tyr705Phe and DNA-binding mutant) or to regulate mitochondrial respiration (Ser727Ala). Upon cytosolic acidification, STAT3 is transcriptionally inactivated and further recruited to lysosomal membranes to reestablish intracellular proton equilibrium. These data reveal STAT3 as a regulator of intracellular pH and, vice versa, intracellular pH as a regulator of STAT3 localization and activity.
Article is published in Cell Research.
Liu B., Palmfeldt J., Lin L., Colaço A., Clemmensen KKB., Huang J., Xu F., Liu X., Maeda K., Luo Y., Jäättelä M. STAT3 associates with vacuolar H+-ATPase and regulates cytosolic and lysosomal pH.Cell Res. 2018 Aug 20. doi: 10.1038/s41422-018-0080-0. [Epub ahead of print]
Populær gen-saks kan bruges til at efterligne kræftceller
GENTEKNOLOGI
Et dansk forskningsstudie viser, at CRISPR-teknologien, som kan klippe og klistre i gener, kan bruges til at danne cirkelformet DNA. Denne form for DNA kan bære på kræftgener, så den nye viden kan være central i forståelsen af, hvordan kræft opstår.
I laboratorier verden over anvendes I dag en teknologi kaldet CRISPR, som gør det muligt at klippe uønskede gener ud og sætte nye ind. Nu har forskere fra Aarhus Universitet og Københavns Universitet, som de førstevist, at man kan danne cirkelformet DNA i celler ved at bruge disse ’gen-sakse’.
- ”CRISPR et kærkomment værktøj, som nu tillader meget mere nærgående studier af DNA-cirklers indflydelse på celler og mulige akkumulering over tid i levende celler. Desuden har vi med CRISPR vist, at store ring-kromosomer kan dannes med relativ høj frekvens, hvilket baner vej for mere dybdegående undersøgeler af ring-kromosomer i menneskeceller, der indtil nu har været begrænset til eksempler fra patienter med sådanne kromosomale anormaliteter”, forklarer Yonglun Luo fra Aarhus Universitet som, sammen med Birgitte Regenberg og Henrik Devitt Møller fra Københavns Universitet, står bag undersøgelsen. Deres resultater er netop publiceret i det internationale tidsskrift, Nucleic Acids Research.
Forskerne ved, at ca. halvdelen af alle tilfælde af kræft indeholder ringformet DNA elementer. Indtil nu har kræftforskere manglet metoder til at danne cirkulært DNA og undersøge, hvordan en rask celle bliver til en kræftcelle, når en cirkel dannes. Ved at klippe i et kromosom med CRISPR, kan forskerne nu danne et cirkulært DNA i en rask celle for at lære mere om deres betydning.
- ”Disse resultater er helt centrale for at forstå, hvordan kræft opstår., siger Birgitte Regenberg fra Københavns Universitet. Og hendes kollega Henrik Devitt Møller uddyber, ”Foruden kræft kan vi også studere, hvordan cirkulært DNA ellers påvirker vores krop. Vi har tidligere på året vist, at raske mennesker også bærer cirkulært DNA i cellerne, men hvad cirkulært DNA uden kræftgener gør, ved vi meget lidt om’.
Denne forskning kan på sigt få afgørende betydning for udvikling af mere effektiv medicin mod kræft og til at forstå den cirkulære DNAs funktion i cellen. Og den kan også være med til belyse, hvordan laboratorieteknikker – ved brug af CRISPR metoden - mest hensigtsmæssigt kan benyttes.
Forskningen er støttet af Carlsbergfonden, Lundbeckfonden og Danmarks Frie Forskningsfond.
Link to Article:
https://academic.oup.com/nar/advance-article/doi/10.1093/nar/gky767/5078801
Henrik Devitt Møller, Lin Lin, Xi Xiang, Trine Skov Petersen, Jinrong Huang, Luhan Yang, Eigil Kjeldsen, Uffe Birk Jensen, Xiuqing Zhang, Xin Liu, Xun Xu, Jian Wang, Huanming Yang, George M Church, Lars Bolund, Birgitte Regenberg, Yonglun Luo.
CRISPR-C: circularization of genes and chromosome by CRISPR in human cells. Nucleic Acids Research, gky767, doi.org/10.1093/nar/gky767.
CRISPR-directed site specific DNA methylation made easier but requires further improvement
One of the most beautiful features of the CRISPR-Cas9 system is its flexibility. By introducing two inactivating mutations to the nuclease catalytic domains of the Cas9 protein, the activity of cleaving DNA by Cas9 is inactivated, which is commonly referred as dead Cas9, or dCas9. However, dCas9 is not completely "dead". It is can be directed to a specific genomic locus via a small guide RNA (gRNA). Furthermore, by fusing dCas9 to another protein or domains, dCas9 can be engineered to acquire a new function. One such application is fusing dCas9 to the epigenetic regulating enzymes.
Aberrant DNA methylation have long been discovered to be the cause of many human diseases, including cancers. During the last few years, we have been working on engineering the CRISPR system for targeted DNA methylation to inactivate oncogenes in cancers. In our recently study published in GigaScience, we reported generating two generations of CRISPR dCas9 methyltransferases, named as CRISPRme. Using a 3-5 gRNAs, we shown that CRISPRme can efficiently methylation and inhibit oncogenes in cancer cell lines.
To fully characterize the specificity of CRISPRme, we conducted whole-genome bisulfide sequencing of the CRISPRme treated cells. We discovered that there are certain genomic hot spots that are prone to be unspecifically methylated, including euchromatin, promoter, 5'UTR, and CpG islands. The discovery of these hot spots will enable us to develop a next generation CRISPRme which will be more specific and efficient, as well as presenting a potential role for cancer therapy and for studying of functional epigenetics.
Re. Article:
Genome-wide determination of on-target and off-target characteristics for RNA-guided DNA methylation by dCas9 methyltransferases
Lin Lin Yong Liu Fengping Xu Jinrong Huang Tina Fuglsang Daugaard Trine Skov Petersen Bettina Hansen Lingfei Ye Qing ZhouFang Fang Ling Yang Shengting Li Lasse Fløe Kristopher Torp Jensen Ellen Shrock Fang Chen Huanming Yang Jian Wang Xin LiuXun Xu Lars Bolund Anders Lade Nielsen Yonglun Luo Author Notes
GigaScience, Volume 7, Issue 3, 1 March 2018, giy011, https://doi.org/10.1093/gigascience/giy011
PERV inactivated pigs
One major unmet medical need in transplantation is the great shortage of donor organs. Over millions of patients globally are suffering from organ failure and in urge need of organ transplantation. One promising solution to this medical challenge is looking for transplantable organs from other species. Pigs have been regarded as the most suitable donor for transplant medicine regarding their availability, anatomy and physiology similarity with humans. However, the risk of virus transmission from pigs to humans and immune rejection are two major barriers against this medical application.
In collaboration with Prof. George M. Church from US and scientists from China, we have generated the first pig model free of porcine endogenous retroviruses. This breakthrough in porcine genome engineering paves the way for safer pig-to-human organ transplantation. Using a combination of CRISPR-Cas9 genome editing in fibroblasts (skin cells) and somatic cell nuclear transfer (cloning) technologies, the first PERV pig was generated which was phenotypical normal and healthy at birth. This article is published in Science.
More news release on this article and story can be found here:
videnskab.dk/krop-sundhed/taet-paa-at-kunne-bruge-grise-som-organdonorer-til-mennesker
http://www.sciencemag.org/news/2017/08/crispr-slices-virus-genes-out-pigs-will-it-make-organ-transplants-humans-safer
https://www.nature.com/articles/nrg.2017.73
Ref: Dong Niu*, Hongjiang Wei*, Lin Lin*, Haydy George*, Tao Wang*, I-Hsiu Lee*, Yong Wang, Yinan Kan, Ellen Shrock, Emal Lesha, Gang Wang, Yonglun Luo, Yubo Qing, Deling Jiao, Heng Zhao, Hongye Zhao, Xiaoyang Zhou, Shouqi Wang, Hong Wei, Marc Guell#, George M. Church#, Luhan Yang# (2017) Inactivation of porcine endogenous retrovirus in pigs using CRISPR-Cas9. Science 2017. 357(6357): p. 1303-1307.
About
The DREAM group leader Yonglun Luo (Alun) is a Professor in Gene and Stem Cell Technology at the Department of Biomedicine, Aarhus University, and Steno Diabetes Center Aarhus, Aarhus University Hospital. Alun is also an affilicated researcher at DANDRITE, Ascending Investigator awarded by the Lundbeck Foundation, and working group leaders in several national and EU research consortium.
Alun obtaind his PhD in medicine in 2012 at the Institute of Human Genetics, Faculty of Health, Aarhus University. He had been conducted his postdoctoral trainings at Novo Nordisk A/S (STAR postdoc programme), The Roslin Institute, and Harvard Medicine School. From 2018 to 2024, Alun had together with his formal PhD supervisor Lars Bolund established the Lars Bolund Institute of Regenerative Medicine, focusing on deciphering the genetic, molecular, and cellular mechanisms underlying the degeneration and regenerative processes. From July 2024, Alun has been appointed and employed as a full professor at Aarhus University, leading the DREAM team to develop next-generation gene and cell therapeutics for human diseases, particularly for neuromuscular disorders such as DMD and cardiometabolic diseases.