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(American Journal of Pathology. 2005;166:1187-1203.)
© 2005 American Society for Investigative Pathology

Chromatin Organization Measured by AluI Restriction Enzyme Changes with Malignancy and Is Regulated by the Extracellular Matrix and the Cytoskeleton

Andrew J. Maniotis*{dagger}, Klara Valyi-Nagy*{dagger}, John Karavitis*, Jonas Moses*, Viveka Boddipali*, Ying Wang*, Rafael Nuñez*{dagger}, Suman Setty*, Zarema Arbieva{ddagger}, Mina J. Bissell§ and Robert Folberg*{dagger}

From the Department of Pathology,* the Cancer Center,{dagger} and the Core Genomics Facility,{ddagger} the University of Illinois at Chicago, Chicago, Illinois; and the Life Sciences Division,§ Lawrence Berkeley National Laboratory, Berkeley, California

Given that expression of many genes changes when cells become malignant or are placed in different microenvironments, we asked whether these changes were accompanied by global reorganization of chromatin. We reasoned that sequestration or exposure of chromatin-sensitive sites to restriction enzymes could be used to detect this reorganization. We found that AluI-sensitive sites of nonmalignant cells were relatively more exposed compared to their malignant counterparts in cultured cells and human tumor samples. Changes in exposure and sequestration of AluI-sensitive sites in normal fibroblasts versus fibrosarcoma or those transfected with oncogenes, nonmalignant breast cells versus carcinomas and poorly metastatic versus highly invasive melanoma were shown to be independent of the cell cycle and may be influenced by proteins rich in disulfide bonds. Remarkably, regardless of degree of malignancy, AluI-sensitive sites became profoundly sequestered when cells were incubated with laminin, Matrigel, or a circular RGD peptide (RGD-C), but became exposed when cells were placed on collagen I or in serum-containing medium. Disruption of the actin cytoskeleton led to exposure, whereas disruption of microtubules or intermediate filaments exerted a sequestering effect. Thus, AluI-sensitive sites are more sequestered with increasing malignant behavior, but the sequestration and exposure of these sites is exquisitely sensitive to information conferred to the cell by molecules and biomechanical forces that regulate cellular and tissue architecture.




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