Tissue phenotype depends on reciprocal interactions between the extracellular matrix and the structural organization of the nucleus

What determines the nuclear organization within a cell and whether this org anization itself can impose cellular function within a tissue remains unkno wn. To explore the relationship between nuclear organization and tissue arc hitecture and function, we used a model of human mammary epithelial cell ac inar morphogenesis. When cultured within a reconstituted basement membrane (rBM), HMT-3522 cells form polarized and growth-arrested tissue-like acini with a central lumen and deposit an endogenous BM. We show that rBM-induced morphogenesis is accompanied by relocalization of the nuclear matrix prote ins NuMA, splicing factor SRm160, and cell cycle regulator Rb. These protei ns had distinct distribution patterns specific for proliferation, growth ar rest, and acini formation, whereas the distribution of the nuclear lamina p rotein, lamin B, remained unchanged. NuMA relocalized to foci, which coales ced into larger assemblies as morphogenesis progressed. Perturbation of his tone acetylation in the acini by trichostatin A treatment altered chromatin structure, disrupted NuMA foci, and induced cell proliferation. Moreover, treatment of transiently permeabilized acini with a NuMA antibody led to th e disruption of NuMA foci, alteration of histone acetylation, activation of metalloproteases, and breakdown of the endogenous BM. These results experi mentally demonstrate a dynamic interaction between the extracellular matrix , nuclear organization, and tissue phenotype. They further show that rather than passively reflecting changes in gene expression, nuclear organization itself can modulate the cellular and tissue phenotype.