1 PhD project offered in the IPP winter call 2023/2024

Scientific Background

Proper division of the genomic material is fundamental for cell homeostasis. Although cells have developed a plethora of mechanisms to ensure error-free division, mistakes during mitosis are common in normal physiology and a hallmark in disease. Such mistakes give birth to dysbalanced, aneuploid genomes. A prominent manifestation of mitotic errors is the generation of abnormal nuclear structures, such as micronuclei and chromosome bridges, common features of nuclear atypia in cancer with major physiological significance. Micronuclei are miniature, additional nuclei that form when a chromosome lags during mitosis and then recruits its own nuclear envelope. These structures accumulate massive DNA damage and can lead to severe rearrangements by mechanisms that are now starting to be understood. Yet, we do not fully understand the effects of dysbalanced genomes on cellular function and how these abnormalities contribute to disease initiation and progression.

We recently discovered a new phenomenon of heritable chromatin and transcriptional defects mediated by micronuclei. These alterations are inherited after the micronuclei reincorporate into the normal nuclear environment of daughter cells and are strongly associated with long-lived DNA damage. This work showed that chromosomal instability is inherently coupled to variation in gene expression, which may impact tumor evolution and provided significant insight into the elusive mechanisms leading to non-genetic, cell-to-cell epigenetic variability observed in pathophysiology.

PhD Project: “Genome architecture and transcription dysregulation due to abnormal mitosis”

How transcription is (dys)regulated in the context of mitotically-derived abnormal nuclear structures - or aneuploidy in general - is poorly understood. Another fascinating and understudied question is how genome organization is affected when these abnormal chromosomes reintegrate into the normal nuclei of daughter cells.
An interested PhD student will take advantage and build upon novel methods we developed recently to spearhead the investigation of these questions, such as a new experimental and computational framework that links phenotype to function at the single-cell level (named “Look-Seq2”). We will study how transcription dynamics are perturbed in daughter cells upon abnormal mitosis and delineate the mechanisms of transcription dysregulation. We will also define how reincorporation of abnormal chromosomes from micronuclei and bridges into the primary nucleus affects genome organization by cutting-edge single-cell-based sequencing and imaging approaches in combination with genome engineering.

If you are interested in this project, please select Papathanasiou (TRAN) as your group preference in the IPP application platform.

Publications relevant to this project

#Papathanasiou S, Mynhier NA, Liu S, Jacob E, Stokasimov E, van Steensel B, #Zhang C-Z, #Pellman D. (2022) Transgenerational transcriptional heterogeneity from cytoplasmic chromatin. BioRxiv  doi:10.1101/2022.01.12.475869

*Leibowitz M, *Papathanasiou S, Doerfler P, Blaine L, Sun L, Yao Y, Zhang CZ, Weiss M, Pellman D. (2021) Chromothripsis as an on-target consequence of CRISPR-Cas9 genome editing. Article in Nature Genetics 53, 895-905

Umbreit, N. T. et al. (2020) Mechanisms generating cancer genome complexity from a single cell division error. Science 368, doi:10.1126/science.aba0712

Zhang, C. Z. et al. (2015) Chromothripsis from DNA damage in micronuclei. Nature 522, 179-184, doi:10.1038/nature14493