Jussi Taipale Group
The main scientific questions addressed in our laboratory relate to the understanding of molecular mechanisms that control gene regulation through the use of high-throughput biology to characterize transcription factor binding specificities and sites in human cancer cells.
TFs are analyzed both alone, and in combination with other TFs and scaffolding proteins such as the mediator complex. The resulting knowledge is then applied to the interpretation of large data sets such as whole cancer genomes, and genome-wide association studies that have revealed genomic regions associated with a wide variety of diseases, including heart disease, diabetes and different types of cancer. The work in the laboratory is interdisciplinary, and has impact both to basic scientific understanding of gene regulation, and to mechanisms of formation of cancer and other diseases.
The specific objectives of our research are the following:
- To identify mechanisms that govern transcription factor binding in vitro and in live cells
- To use the resulting information in the interpretation of cancer genomes and genome wide-association studies
- To validate the findings in mouse genetic models
About the laboratory
Professor Jussi Taipale got his Ph.D. from the University of Helsinki in 1996, and continued with postdoctoral work at the University of Helsinki and at Johns Hopkins University (Baltimore, MD, USA). He has headed an independent research laboratory since 2003, focusing on systems biology of growth control and cancer. The main expertise of the Taipale group is high-throughput screening using cDNA and RNA interference, computational and experimental methods to identify causative regulatory mutations in non-protein coding DNA and to analyze genetic networks. In addition, Taipale group has extensive expertise on mouse models of gene and regulatory region function. The group at Karolinska Institutet consists of four senior scientists, six postdoctoral fellows, two graduate students a research engineer and two technicians.
Jolma et al., Nature 2015
Many TFs are known to cooperate with another TF to bind DNA together. To analyse the occurrence of these kind of dimeric complexes and to find out the DNA-sequences that they bind we developed a new assay, consecutive affinity purification SELEX (CAP-SELEX). In CAP-SELEX assay two TFs are mixed together with a library of DNA with partially randomised sequence, which is then followed by two purification steps to capture the DNA sequences that interact with both of the two TFs at the same time. After the selection process the DNA-sequences selected by the experiment are sequenced and these DNA sequences are analysed to find either novel composite sites that combine partial specificities of the two TFs or cases where there are clear orientation and spacing preferences between the individual TF’s motifs.
Yan et al., Cell 2013
Here, we have developed a high-throughput ChIP-seq method, and mapped the binding patterns of hundreds of TFs in a human cell-line. Global analysis of the binding patterns indicate that TF binding cluster to a much larger degree than previously anticipated, with TF clusters occupying less than 1% of the genome. The TF clusters were strongly enriched in binding motifs, evolutionary conserved, and predictive of gene expression. Interestingly, virtually all TF clusters contained cohesin, a ring-shaped molecule known to be important in transcription and in sister chromatid cohesion in mitosis. Follow-up experiments indicate that cohesin has a causative role in maintaining the pattern of TF binding across cell division, by enriching DNA throughout replication and at chromatin condensation, when TFs are displaced from chromatin. Thus, we propose that cohesin acts as a cellular memory, that helps replicate the accessibility information imprinted by TFs displacing nucleosomes on DNA.
Jolma et al., Cell 2013
In this work, we describe binding specificity models for the majority of all human TFs, approximately doubling the coverage compared to existing systematic studies. Our results also reveal additional specificity determinants for a large number of factors for which a partial specificity was known before, including a commonly observed A- or T-rich stretch flanking core-binding motifs. Global analysis of the data reveals that homodimer orientation and spacing preferences, and base stacking interactions have a larger role in TF-DNA binding than what has been previously appreciated. We further describe a binding model incorporating these features that is required to understand binding of TFs to DNA.
Sur et al., Science 2012
In this work, we generated mice deficient in Myc-335, a putative MYC regulatory element that contains rs6983267, a SNP accounting for more human cancer-related morbidity than any other genetic variant or mutation. In Myc-335 null mice, Myc transcripts were expressed in the intestinal crypts in a pattern similar to that in wild-type mice but at modestly reduced levels. The mutant mice displayed no overt phenotype but were markedly resistant to intestinal tumorigenesis induced by the APCmin mutation. These results highlight the fact that although a disease-associated polymorphism typically has a relatively modest effect size, the element that it affects can be critically important for the underlying pathological process. The finding also indicates that normal growth control and pathological growth induced by cancer can utilize different mechanisms.
DNA-binding specificities of human transcription factors.
Jolma A, Yan J, Whitington T, Toivonen J, Nitta KR, Rastas P, et al
Cell 2013 Jan;152(1-2):327-39
Mice lacking a Myc enhancer that includes human SNP rs6983267 are resistant to intestinal tumors.
Sur IK, Hallikas O, Vähärautio A, Yan J, Turunen M, Enge M, et al
Science 2012 Dec;338(6112):1360-3
Transcription factor binding in human cells occurs in dense clusters formed around cohesin anchor sites.
Yan J, Enge M, Whitington T, Dave K, Liu J, Sur I, et al
Cell 2013 Aug;154(4):801-13
Counting absolute numbers of molecules using unique molecular identifiers.
Kivioja T, Vähärautio A, Karlsson K, Bonke M, Enge M, Linnarsson S, et al
Nat. Methods 2011 Nov;9(1):72-4
The role of enhancers in cancer.
Sur I, Taipale J
Nat. Rev. Cancer 2016 08;16(8):483-93