Mats Ljungman, PhD
- Professor, Radiation Oncology
- Professor, Environmental Health Science
Professor Ljungman grew up in Stockholm, Sweden. After attending four years of college studies in the USA, Ljungman performed his graduate studies at Stockholm University and then my postdoctoral work at Stanford University. In 1994, Professor Ljungman became Assistant Professor in the Department of Radiation Oncology at the University of Michigan Medical School where he has been ever since. Professor Ljungman's early work identified blockage of transcription as a major trigger of p53 and apoptosis after DNA damage. To map transcription genome-wide and to investigate the effect of DNA damage on ongoing transcription, Ljungman developed Bru-seq, which is based on bromouridine labeling of nascent RNA followed by immunocapturing and deep sequencing of the Bru-labeled RNA. Professor Ljungman have been fortunate to be part of the ENCODE Consortium for the last 10 years. Recently Ljungman developed Precision KLIPP Therapy as a universal and specific cancer-targeting approach. Professor Ljungman is the co-director of the Center for RNA Biomedicine at the University of Michigan and am leading the work to develop "M-RNA Therapeutics" as a global resource to aid RNA therapeutics. Professor Ljungman has published >150 peer-reviewed articles.
- Postdoc, Stanford University, 1994
- PhD, Stockholm University, 1990
- BS, Murray State University, 1983
Precision oncology, personalized medicine, transcription, RNA dynamics, DNA damage response
Our lab has been a member of and funded by the ENCODE Consortium since 2012. During ENCODE III we were one of the "Technology development groups" developing our nascent RNA Bru-seq techniques and during ENCODE IV we are one of 8 "Mapping Centers" where we are using our Bru-seq technique to profile the transcriptional and post-transcriptional profiles across many cell types as well as assessing co-transcriptional splicing and mapping active enhancer elements genome-wide. This is a very computational focused project working with big data sets across multiple cell lines. One of the projects are exploring the immediate transcriptional response following exposure to ionizing radiation across 16 cell lines, many of them cancer cell lines. This study should yield important novel insights about how cell re-program their transcriptome to respond ionizing radiation and could lead to the identification of new pathways for radiosensitization.
In this project we are exploring the quality control mechanisms that cells use to purge the transcriptome of certain RNA species such as enhancer RNA (eRNA) and aberrantly spliced transcripts. The RNA exosome degradation complex is the focus and we are performing studies using cell lines where we can induce rapid degradation of key components of the RNA exosome using auxin. Our hypothesis is that the RNA exosome may be an impactful cancer therapy target. In collaboration with Nouri Neamati and his lab, we have set up a high throughput screening assay and we have screened >80,000 small molecules and are currently performing validation studies of our preliminary positive hits from the screen. The long-term goal is to test the lead compounds for their anti-cancer activities in mouse models and potentially in clinical trials.
Precision targeting of cancer with CRISPR
The innovation of this CRISPR approach is that it targets cancer-specific chromosome rearrangement junctions (CRJ), common to almost all tumors. We have called this approach "Precision KLIPP therapy" and it is based on the use of a "split" enzyme approach consisting of inactivated dCas9 fused to the endonuclease Fok1 (Fok1-dCas9). To activate the Fok1 endonucleases, two Fok1 proteins need to homodimerize; this will occur by using CRJ-targeting guide RNAs to nucleate two Fok1-dCas9 complexes at the CRJ, leading to the specific induction of DNA double strand breaks (DSBs). We have obtained strong proof-of-concept for good efficacy of this approach in cell systems and are now developing lipid nanoparticles to deliver the CRISPR reagents to tumors in vivo. After obtaining in vivo data supporting a tumor inhibiting activity, we intend to set up clinical trials initially for bladder cancer and subsequently for other tumors. The long-term goal is to develop personalized KLIPP Therapy based on whole genome sequence information from patient's tumors and to rapidly synthesize CRISPR reagents, package them in lipid nanoparticles and provide this medicine to individual patients.
Ljungman M, Zhang F: Blocked RNA polymerase as a possible trigger for UV light-induced apoptosis. Oncogene 13:823-831, 1996.
Derheimer FA, O'Hagan HM, Krueger H, Hanasoge S, Paulsen MT and Ljungman M: RPA and ATR link transcriptional stress to p53, Proc. Natl. Acad. Sci. USA 104:12778-12783, 2007 PMC1937543
Paulsen MT, Veloso A, Prasad J, Bedi K, Ljungman EA, Tsan Y-C, Chang C-W, Tarrier B, Washburn JG, Lyons R, Robinson DR, Kumar-Sinha C, Wilson TE and Ljungman M: Coordinated regulation of synthesis and stability of RNA during the acute TNF-induced proinflammatory response, Proc. Natl. Acad. Sci. USA, 110:2240-2245, 2013, PMCID:3568384.
Veloso A, Kirkconnell K, Magnuson B, Biewen B, Paulsen MT, Wilson TE and Ljungman M: Rate of elongation by RNA polymerase II is associated with specific gene features and epigenetic modifications. Genome Research 26:896-905, 2014, PMCID:4032854.
Yana van der Weegen, Klaas de Lint, Diana van den Heuvel, Yuka Nakazawa, Ishwarya V. Narayanan, Noud Klaassen, Annelotte P. Wondergem, Marta San Martin Alonso, Shivani Rampersad, Yuichiro Hara, Kana Kato, Mayuko Shimada, Sylvie M. Noordermeer, Mats Ljungman, Tomoo Ogi, Rob M.F. Wolthuis, and Martijn S. Luijsterburg: ELOF1 is a transcription-coupled DNA repair factor that promotes DNA damage-induced RNAPII ubiquitylation, Nature Cell Biology, 23:595-607, 2021.
Brian Magnuson, Karan Bedi, Ishwarya Venkata Narayanan, Bartlomiej Bartkowiak, Hailey Blinkiewicz, Michelle T. Paulsen, Arno Greenleaf and Mats Ljungman: CDK12 regulates splicing and RNA turnover, iScience, 25:105030, 2022.
NCRC, B520 Room 1346
2800 Plymouth Rd.
Ann Arbor, Michigan 48109-2800
Areas of Expertise: Cancer, Genetics, Precision Health