Extracellular Matrix-Induced Chromatin Modifications in Normal and Malignant Human Breast Cells

摘要

Human mammary epithelial S1 cells cultured in a 3D reconstituted basement membrane (rBM) growth arrest and form polarized acini-like structures. This differentiation in 3D rBM is accompanied by rearrangements of the nuclear architecture. ECM itself influences gene expression and cellular function by diverse mechanisms including ligand-receptor interaction, promotion of cell-cell adhesion, and modulation of cell shape. The changes in gene expression that occur during differentiation or tumorigenesis are accompanied by characteristics patterns of chromatin reorganization, modulated, in part, through highly regulated, histone acetylation/deacetylation mechanisms. We found that the differentiation of 51 cells into acini is accompanied by deacetylation of histone H4. Here we tried to elucidate the mechanisms by which the cellular microenvironment signals to nuclear acetylation/deacetylation events in the 51 cells. The rBM induced histone 4 deacetylation is neither directly related to growth nor to the ECM-induced signaling. We assessed the role of cell shape on histone H4 acetylation. Cells cultured on the non-adhesive substratum polyHEMA round up and form multicellular agregates. In this context, they also display a significant deacetylation of histone 4. Using cytochalasin D to disturb the actin filaments, we are now analysing the role of actin organization in this process.