Research | Ljungman Lab

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 were one of 8 “Mapping Centers” where we were 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. 

In a collaboration with Dr. John Prensner at the Department of Pediatrics, we represent University of Michigan in the world-wide GENCODE Consortium. We are investigating and annotating "the dark genome" coding for non-canonical short peptides. These peptides are very abundant and have different expression profiles in different diseases such as cancer. Their functions are largely unknown and using nascent RNA Bru-seq and Ribo-seq our studies will provide deep data sets across several primary human tissue types that should help illuminate the dark places of the genome. 

With the development of whole genome sequencing and CRISPR technology, it is now possible to identify sequence features that are unique to an individual’s cancer genome and to precisely target these genomic features. Such personalized precision therapy holds the promise of ushering in a new era of safe and effective cancer treatments with minimal side-effects. To specifically target the cancer genome, we have developed a CRISPR-based therapeutic approach, “KLIPP,” which is designed to target structural variants junctions (SVJs) common and specific to cancer genomes, with few, or no off-target effects expected in normal cell.  Using the KLIPP approach, we have obtained strong proof-of-concept that it can specifically target cancer-unique SVJs and induce DSBs leading to cell death in cancer cells both in culture and in vivo. Junctions in oncogenic fusion genes and in extrachromosomal DNA (ecDNA) harboring amplified oncogenes represents particularly valuable targets. We show effective targeting of the EWS:FLI1 fusion oncogene in Ewing sarcoma as well as targeting ecDNA in leukemia cells. To specifically home in on cancer cells in vivo we are developing "weaponized" LNPs armed with antibodies specifically binding to surface proteins expressed on the cancer cells. This paradigm-shifting personalized therapy could revolutionize how we treat cancers without inflicting long-term side effects.  Our goal is to develop KLIPP Therapy based on whole genome sequence information from patient’s tumors and to rapidly synthesize CRISPR reagents, package them in weaponized lipid nanoparticles and provide this personalized precision medicine to individual patients. This project is currently funded by an R01 grant from NCI (5 R01 CA285730 02) and by the Little Warriors Foundation for Ewing sarcoma.