Transgenerational Tracking of Chromosomes from Micronuclei

A hallmark consequence of errors in mitosis is the generation of aberrant nuclear structures, such as micronuclei and chromosome bridges, which have long been associated with disease like cancer. Groundbreaking recent work showed that whole chromosomes or chromosome segments that transit through such structures can accumulate severe rearrangements and thus contribute to the evolution of complex genetic structural events, collectively called "chromoanagenesis". Despite strong interest in the field of genomic instability, a detailed mechanistic understanding of the choreography of transgenerational events that lead to chromoanagenesis is lacking. This is partly due to limited methodologies currently available for temporally-resolved analysis of the genetic and chromatin properties of chromoanagenesis-generating nuclear structures. Here, we review two novel imaging-based cellular systems that we presented recently, which allow transgenerational tracking of micronucleated chromosomes. Together, we include detailed methodologies for the analysis of their functional properties, specifically transcription and chromatin state. Linking the functional analysis of abnormal chromosomes from micronuclei with their prior history of cellular events offers an invaluable and novel approach towards the dissection of the origins and consequences of chromoanagenesis.