Functional consequences of errors in mitosis - Chromatin State Dysregulation

1 PhD project offered in the IPP winter call 2022

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: “Chromatin state dysregulation due to abnormal mitosis”

Under what exact circumstances cell division errors can give birth to massive DNA lesions and other chromatin alterations, their inheritance in the progeny and their functional significance remain a mystery. The potential involvement of additional mitosis-mediated mechanisms – other than micronucleation – that initiate cascades of non-genetic alterations is also a black box.
We are excited to welcome a PhD candidate to attack these questions. We will combine cutting edge techniques, such as targeted chromosome manipulation and gene engineering, with the development of advanced systems to track mis-segregated chromosomes by live-cell imaging over multiple generations. We will identify additional sources of inherited abnormal nuclear structures, investigate their DNA damage/repair dynamics and determine the immediate and long-term effects on these nuclear bodies’ epigenome.

If you are interested in this project, please select Papathanasiou (CSD) 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

Contact

Dr. Stamatis Papathanasiou
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