Research
Chromosomal aberrations
Healthy human cells are diploid – they carry each chromosome in two copies. Errors in cell division result in aberrations from this normal chromosome content. Loss or gain of chromosomes strongly affect the physiology of eukaryotic cells and often associate with pathologies, such as in trisomy syndromes (e.g. Down syndrome) or in cancer cells. In our group we use cutting-edge technologies to study the causes and consequences of chromosomal aberrations.
Loss or gain of a single chromosome changes cellular homeostasis
Missegregation of even a single chromosome strongly affects physiology of human cells. Many cells with aberrant chromosome numbers (so called aneuploidy) fail to proliferate. Some can further propagate, but with severe consequences – the protein homeostasis is impaired, the genomic stability is compromised. We created a series of human cell lines that have one chromosome extra (trisomy) or less (monosomy) to study the molecular processes affected by aneuploidy. Using genomics, transcriptomics and proteomics, we analyze genome stability and protein homeostasis in aneuploid cells and how these changes contribute to human pathologies.
Impact of chromosome gain on DNA replication
Presence of extra chromosomes impairs proliferation of aneuploid cells and affects expression of DNA replication factors. These cells show several hallmarks of replication stress and accumulate DNA damage and additional chromosomal aberration. We elucidate the mechanisms that contribute to replication stress in aneuploid cells.
Consequences of chromosome loss
Loss of a single chromosome – monosomy – has severe consequences in human cells and is not compatible with survival. We have established a model system to elucidate what molecular mechanisms underlie the severe consequences of monosomy.
Maintenance of protein homeostasis
Comparision of genome, transciptome and proteome determined that genes from the extra chromosomes are normally transcribed and translated, but that expression levels of many proteins are adjusted to wild type levels. We study how autophagy, proteasomal degradation affect protein homeostasis in aneuploid cells on a global scale. Moreover, we elaborate the mechanism of autophagy activation in response to aneuploidy.
Whole genome doubling contributes to genome evolution
Failure of cytokinesis generates binucleated cells with a doubled genome content – a tetraploid cell. While most tetraploid cells cannot further proliferate, some cells survive with increased chromosomal instability (CIN) and extensive aneuploidy. Sequencing of cancer genomes suggests that about 40 % of all cancers have undergone whole-genome doubling at some point during tumorigenesis. We study molecular mechanisms that contribute to changes in tetraploid cells and how they contribute to tumor formation.
Consequences of whole genome doubling
Whole-genome doubling that leads to tetraploidy alters cellular metabolism, increases cell volume and decreases surface-per-volume-ratio. We use transcriptome and proteome analysis to determine the molecular causes of the specific changes of cellular metabolism. The main aim of this project is to understand why polyploidy becomes advantageous under some conditions.
Failure of cytokinesis generates binucleated cells with a doubled genome content – a tetraploid cell. While most tetraploid cells cannot further proliferate, some cells survive with increased chromosomal instability (CIN) and extensive aneuploidy. Sequencing of cancer genomes suggests that about 40 % of all cancers have undergone whole-genome doubling at some point during tumorigenesis. We study molecular mechanisms that contribute to changes in tetraploid cells and how they contribute to tumor formation.
Impact of aneuploidy on genome stability
Using flow cytometry and live cell imaging we found that presence of extra chromosomes impairs proliferation of aneuploid cells. Global transcriptome and proteome analysis enabled identification of pathways that are deregulated in aneuploid cells irrespective of the identity of the extra chromosome. This analysis has revealed a strong down-regulation of DNA replication factors. Consistently, aneuploid cells show several hallmarks of replication stress. We are currently elucidating the mechanisms that contribute to replication stress in aneuploid cells.
Protein homeostasis in aneuploid cells
Cross-omic analysis by comparing genome, transciptome and proteome quantitative changes we found that genes from the extra chromosomes are normally transcribed and translated, but that expression levels of many proteins are adjusted to wild type levels. We study how autophagy, proteoasomal degradation or protein folding affect protein homeostasis in aneuploid cells and protein stability on a global scale.
Finding the Achilles heel of tetraploid cells
Sequencing of cancer genomes suggests that about 40 % of all cancers have undergone whole-genome doubling at some point during the tumorigenesis. In contrast, normally proliferating human cells rarely survive whole-genome doubling. Using RNAi and CRISPR/Cas9 we aim to determine factors that promote survival of tetraploid cell s in order to identify molecular targets that may be exploited for selective killing of cancers cells with abnormal karyotypes.
Literature
Want to find out more about Aneuploidy?
Check out the book “Aneuploidy in health and disease”