In the Neretti Lab @ Brown we are interested in the genomic and chromosome architecture changes that accompany replicative senescence. We studied this irreversible growth arrest in human diploid fibroblast (HDF) cells through the high-throughput chromatin conformation capture method Hi-C.
We compared Hi-C interaction data from healthy proliferating, synchronized quiescent and fully senescent cells. The main takeaways from the experiment were as follows.
- A general decrease in long-range chromatin contacts in senescence. We found that chromosomes in senescent cells are more likely to participate in short-range contacts when compared with proliferating. This mens that stable, long-range interactions are less likely and that the chromatin has become more compact. Importantly, we validated this result with several independent biochemical assays, including 3D-FISH, FAIRE and chromosome painting.
- Chromatin domains that switch from an active compartment to a inactive compartment, or vice-versa. A subset of topologically associated domains, TADs, switch A/B compartments in senescence. This is interesting because the cells could theoretically use this method to direct transcription of senescence-associated genes, something we found by comparing with previously annotated gene sets.
Our paper detailing this research was recently published in Science Advances [1]. Check it out here! I did a lot of computational work for this research, taking the data from raw sequences to normalized Hi-C contact maps, and finally interpreting them in various ways, so it feels great to have the results published. We were also featured in Brown’s science news.
[1] Criscione, S. W., De Cecco, M., Siranosian, B., Zhang, Y., Kreiling, J. A., Sedivy, J. M., & Neretti, N. (2016). Reorganization of chromosome architecture in replicative cellular senescence. Science Advances, 2(2), e1500882.