Senescence-specific gene expression fingerprints reveal cell-type-dependent physical clustering of up-regulated chromosomal loci - PubMed (original) (raw)

Senescence-specific gene expression fingerprints reveal cell-type-dependent physical clustering of up-regulated chromosomal loci

Hong Zhang et al. Proc Natl Acad Sci U S A. 2003.

Abstract

Replicative senescence is the state of irreversible proliferative arrest that occurs as a concomitant of progressive telomere shortening. By using cDNA microarrays and the gabriel system of computer programs to apply domain-specific and procedural knowledge for data analysis, we investigated global changes in gene transcription occurring during replicative senescence in human fibroblasts and mammary epithelial cells (HMECs). Here we report the identification of transcriptional "fingerprints" unique to senescence, the finding that gene expression perturbations during senescence differ greatly in fibroblasts and HMECs, and the discovery that despite the disparate nature of the chromosomal loci affected by senescence in fibroblasts and HMECs, the up-regulated loci in both types of cells show physical clustering. This clustering, which contrasts with the random distribution of genes down-regulated during senescence or up-regulated during reversible proliferative arrest (i.e., quiescence), supports the view that replicative senescence is associated with alteration of chromatin structure.

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Figures

Figure 1

Figure 1

Genes showing altered transcription in human fibroblasts during senescence or quiescence. Biological processes (A) and cellular locations (B) associated with products of genes bearing gene ontology annotations are shown. The number of genes in each group is given in parentheses. The likelihood of enrichment of genes in a group due to random events (P value) is indicated by asterisks: *, P < 0.05; **, P < 0.01; ***, P < 0.001.

Figure 2

Figure 2

Chromosomal clustering of fibroblast genes up-regulated specifically during senescence. (A) Normalized numbers of genes having expression that was up-regulated specifically during senescence in human fibroblasts on each chromosome were obtained by dividing up-regulated genes by total genes on that chromosome having measurements that satisfied filter parameters (Materials and Methods). (B) Numbers for chromosomal gene clusters and clustered genes on each chromosome were compared with the average values estimated from randomly selected lists containing the same number of genes. P value limits are indicated by asterisks: *, P < 0.05; **, P < 0.01; ***, P < 0.001.

Figure 3

Figure 3

Chromosomal distribution of genes up-regulated in common during replicative senescence in fibroblasts (F) or two HMEC lines. Black lines indicate the chromosomal positions of up-regulated genes, and red lines designate gene clusters.

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