Description:

“A kilobase resolution analysis of the senescent genome reveals novel architectural features supporting cell cycle arrest and inflammation”

Abstract:

Cellular senescence is one of the drivers of aging. This irreversible state of proliferative arrest is caused by progressive DNA damage and leads to an adverse inflammatory response. Cellular senescence is associated with many epigenetic changes, including alterations to the genomic architecture. To better understand how changes to the genome’s structure drive cellular senescence and thus aging, we created the highest resolution Hi-C maps to date (~3kb) of proliferating, quiescent, and replicative senescent lung fibroblasts. We also included the highest resolution Hi-C maps of oncogene-induced senescence (>10kb) in our analysis for comparison. These maps have reinforced our understanding of how architectural changes support senescence and significantly expanded our knowledge at new levels of organization, notably subcompartments, and loops. With senescence, we see a loss of heterochromatin, with a shift towards the A compartment and the A subcompartments. Furthermore, we observe that senescence features many more unique loops (~20x) as compared to proliferating cells. Functionally, these changes help to support senescence, as they are associated with cell cycle arrest and inflammation. Structural changes also help to support the derepression of the LINE1 retrotransposon, which is known to contribute to the chronic inflammation seen with senescence.

Brief Personal Statement:

My primary research is the study of epigenetic and transcriptional changes in aging and senescence. Over my career, I have obtained training in several disciplines relevant to this project, including computational biology, genomics, and the biology of aging. Thanks to a K25 NIH Mentored Quantitative Research Career Development Award, I trained and performed research in the biomedical sciences, focusing on transcriptional and epigenetic regulation in aging. I performed this training as a Research Assistant Professor and moved to an independent position as Assistant Professor first, then as a tenured Associate Professor in Biology. I am a core faculty member of Brown University’s Center for Computational Molecular Biology; I teach functional genomics and computational biology courses and mentor multiple graduate students from the Computational Biology graduate program. I am also a member of the Brown Center for the Biology of Aging and mentor students from our MCB Program. Over the past ten years, my laboratory has devoted significant effort to studying genomic and epigenomic instability in aging and cellular senescence and developing biomarkers of aging and senescence. In my laboratory, we utilize high-throughput experimental techniques such as single-cell transcriptomics/epigenomics and oligopaints microscopy to study the epigenomic and transcriptional changes in aging and cellular senescence. In recent years, we have used single-cell techniques to study the heterogeneity in senescent cells, both in cell culture (Evans et al. Aging Biology 2023 (In press); Teo et al. Cell Rep. 2019; 27(4)) and in tissue (Teo et al. Aging 2023; 15(1):6-20; Ogrodnik et al. Aging Cell. 2021; 20(2)). I am an active member of the Common Fund’s Cellular Senescence Network (SenNet) Program, established to identify and characterize senescent cells in aging tissue. My research program has been active in defining biomarkers for different forms of senescence.