Abstract A56: H3K9me3-based ChIP-seq analysis unveils global reprogramming in Cyclin D1-driven cellular senescence

Abstract

Abstract Senescence is a permanent G1 cell-cycle arrest that can be triggered by acute stresses such as activated oncogenes and chemotherapeutic agents, and serves as a barrier to cancer development. Senescent cells exhibit distinct chromatin features compared with proliferating cells, known as senescence-associated heterochromatin foci (SAHF). These foci are enriched with histone H3 trimethylated at lysine 9 (H3K9me3), and are thought to impose a repressive state on regional genes. We performed genome-wide identification of elements associated with H3K9me3 by ChIP-seq technology, using an in vivo model of senescent pineal cells driven by Cyclin D1 oncogenic signaling, and compared them to non-senescent (Cyclin D1 expressing but p53-null) counterparts. We identified a set of genes whose H3K9me3 enrichment level was significantly changed (>2-fold). We also analyzed gene expression profiles on Affymetrix transcriptome chips. We found that about 50% of genes associated with H3K9me3 exhibited significant reduction in expression, while other genes were either upregulated or showed no change in expression. Gene ontology analysis clustered the genes into several functional groups, including cell-cycle control, transcription regulation, protein metabolism, cellular differentiation, and cellular adhesion. Notably, the gene ontology clustering showed that genes associated with H3K9me3 in senescent cells clustered into distinctly different functional programs than those associated with H3K9me3 in cells that had bypassed senescence. Our data indicate that chromatin changes in cellular senescence are informative regarding a distinct functional phenotype of the senescent condition. The mechanisms by which such changes contribute to tumor suppression are under active investigation. Citation Format: Mohammad Harajly, Noel Ghanem, Raya Saab. H3K9me3-based ChIP-seq analysis unveils global reprogramming in Cyclin D1-driven cellular senescence. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Jun 19-22, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2013;73(13 Suppl):Abstract nr A56.