The chromatin and transcriptional landscape of senescent cells

Criscione, Steven W.

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Year:: 2016
Contributor:: Criscione, Steven W. (creator); Neretti, Nicola (Advisor); Sedivy, John (Advisor); Fairbrother, William (Reader); Reenan, Robert (Reader); Helfand, Stephen (Reader); Vijg, Jan (Reader); Brown University. Department of Molecular Biology, Cell Biology and Biochemistry (sponsor)
Genre:: theses
Subject:: Biotechnology; Cytology; Older people
Extent:: xix, 270 p.
DOI: https://doi.org/10.7301/Z0X928RG

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Abstract:: Abstract of “The chromatin and transcriptional landscape of senescent cells”, by Steven W. Criscione, Ph.D., Brown University, May 2017 Senescent cells are recognized as one of the hallmarks of human aging and their clearance in aging mouse models improves healthspan. Thus, pharmacologically targeting senescent cells for clearance could potentially alleviate pathologies of aging. A better understanding of cellular senescence will improve our chances of developing such interventions. While replicative senescence is hypothesized to include epigenetic components, little is known about the precise nature of chromatin alterations in senescent cells. By integrating chromatin accessibility data (FAIRE-seq), RNA expression profiling, and chromosome conformation capture (Hi-C) data, we have elucidated the chromatin and transcriptional landscape of senescent cells. Our studies demonstrate that senescent cells exhibit an overall closing of chromatin in euchromatic gene-rich regions and a relative opening in heterochromatic gene-poor regions. Hi-C revealed higher order alterations to the 3D structure of chromosomes in senescent cells. Senescent chromosomes display a global compaction characterized by a loss of long-range and a gain of short-range 3D interactions. Local changes to the 3D architecture of senescent cells include compartment switching between euchromatin and heterochromatin, which correlates with changes in gene expression. To address the alterations to repetitive DNA, we developed computational methods to examine repetitive elements in high throughput sequencing data (RepEnrich and Retrofind). Using these computational methods, we identified that normally heterochromatic centromeres increase accessibility and become distended in senescent cells. We also examined the autonomously active retrotransposon in humans, the long interspersed nuclear element L1, which can to jump to new locations in the genome. We identified that the L1 retrotransposon can form diverse RNA fusion transcripts between the L1 antisense promoter and its neighboring genes. We found that in senescent cells, L1 retrotransposons, normally heavily heterochromatized, display derepression, increased RNA expression, and active retrotransposition. This latter phenomenon also appears to occur in tissues during aging and in age-associated spontaneously-forming tumors and therefore may be a more fundamental feature of the aging process.
Notes:: Thesis (Ph. D.)--Brown University, 2016

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Criscione, Steven W., "The chromatin and transcriptional landscape of senescent cells" (2016). Molecular Biology, Cell Biology, and Biochemistry Theses and Dissertations. Brown Digital Repository. Brown University Library. https://doi.org/10.7301/Z0X928RG

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Molecular Biology, Cell Biology, and Biochemistry Theses and Dissertations

Theses and Dissertations for the Molecular Biology, Cell Biology, and Biochemistry department.
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