Mechanisms of cellular response to errors in mitosis: a new, non-genetic approach to an old question

Introduction

One of the holy grails in cancer biology is to understand how genomic instability, a hallmark source of mutagenesis, arises. However, surprisingly little is known about non-genetic drivers of tumorigenesis. My proposal will delve into the old question of how Mitotic Errors and nuclear Abnormalities (MitErrA) affect cellular homeostasis, from a fresh perspective: the elucidation of non-genetic effects on genome function and cellular adaptation.

Discovery of Micronuclei

I recently discovered that micronuclei, a prominent type of errors in mitosis, are a previously unappreciated source of epigenetic instability. This discovery, together with the novel technologies that I developed, will serve as the springboard to address four fundamental questions:

1. How is chromatin state affected in abnormally segregated chromosomes?
2. What are the mechanisms of transcriptional (dys)regulation following errors in mitosis?
3. How is genome organization perturbed in imbalanced genomes?
4. What is the physiological significance of abnormal chromosomes generated by mitotic errors?

Methodology

I will combine cutting-edge techniques, such as targeted chromosome manipulation and single-cell genomics, with advanced systems to track mis-segregated chromosomes by live-cell imaging over multiple generations.

Additional Investigations

I will identify additional sources of inherited abnormal nuclear structures (termed “Mit-bodies”) and characterize their DNA damage/repair dynamics and epigenetic alterations.

Transcription Dynamics

I will study how transcription dynamics are perturbed in daughter cells upon abnormal mitosis and define higher-order genome organization, nuclear positioning, and lamina association of mis-segregated chromosomes.

Long-term Adaptations

Finally, I will investigate long-term cellular adaptations and assess the tumorigenic potential of these abnormal chromosomes.

Conclusion

Altogether, these studies will offer the first comprehensive assessment of the non-genetic mechanisms by which errors in mitosis may drive cellular adaptation and tumorigenesis.