Executive Director, director, professor
Ole Maaløes Vej 5, 2200 København N
Ole Maaløes Vej 5, 2200 København N
Primary fields of research
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.
Recent research highlights
MIR31HG: A long non-coding RNA modulating senescence
We have unveiled the molecular mechanism by which the long non-coding RNA MIR31HG represses the expression of the cell cycle inhibitor p16INK4A. In proliferating cells, MIR31HG binds the INK4A promoter together with the Polycomb Group proteins (PcG) to inhibit p16INK4A transcription. During senescence, MIR31HG and PcG proteins are released from the promoter allowing p16INK4A expression. Consequently, the cells stop growing and enter the process called senescence.
Figure 1: Human fibroblasts after knockdown of MIR31HG and stained for β-galactosidase (blue), an enzyme that is only active during senescence.
A microRNA regulating lysosomal function
We recently identified miR-95 as a potent regulator of lysosome function. miR-95 targets the activator of all cellular sulfatases, SUMF1. Mutations in SUMF1 lead to a condition known as multiple sulfatase deficiency (MSD). Our work shows that inhibiting miR-95 may partly restore SUMF1 and hence lysosome function and thereby points to a novel strategy for the treatment of MSD.
Figure 2. MCF7 cells expressing GFP-tagged LC3 located at autophagosomes.
PRDM11: A new tumor-suppressor
We recently identified and characterized a novel human tumor-suppressor, PRDM11. By creating a mutant mouse strain lacking Prdm11, we demonstrate accelerated tumorigenesis in B-cell overexpressing the Myc oncogene. Importantly, PRDM11 expression is lost in a subset of patients suffering from diffuse large B-cell lymphoma and this correlates with a poor prognosis. Mechanistically, we characterize PRDM11 as a transcriptional regulator repressing key oncogenes, such as JUN and FOS.
Figure 3. Staining for PRDM11 in diffuse large B-cell lymphomas from patients with lost (left) or normal expression of PRDM11 (right).
Translational codes identified in the genome
We recently published the intriguing finding that select tRNAs are either up- or down-regulated in cancer and that these tRNAs are uniquely required for the translation of functional gene groups of importance to the disease. Working together with the group of Yitzhak Pilpel from the Weizmann Institute, we found that superimposed upon our genetic code are translational codes allowing the cell to boost translation of functional gene groups by altering the expression of specific tRNAs. We further show that these programs are hijacked in cancer. This finding is conceptually novel and may be exploited in the clinic.
Figure 4. Different functional gene groups (GO categories) employ different codons and hence use different tRNAs. By varuing the composition of the tRNA pool translation of select functional gene groups can be favored.
A microRNA impacting on p53
p53 is the most important human tumor-suppressor. Using a functional screening approach to identify microRNAs impacting on the p53 pathway, we have identified miR-339-5p as a potent regulator of MDM2; a key mediator of p53 degradation. In agreement with this finding, we show that a negative correlation between miR-339-5p and MDM2 expression exists in human cancer, implying that the interaction is important for cancer development.
Figure 5. MCF7 cells treated with 5-FU and stained for p53 (red) and p21 (green).
Fields of interest
- Non-coding RNA
- Cancer mechanisms and models