Organization of transcriptional regulatory machinery in nuclear microenvironments: implications for biological control and cancer.

Abstract

The nucleus is highly compartmentalized and contains a multiplicity of specialized functional microenvironments involved in gene expression, DNA replication and DNA repair. We have demonstrated that the Runx(AML) class of transcription factors, which are key regulators of cell growth and differentiation during myeloid lineage maturation and mesenchymal tissue development, is associated with the nuclear matrix by a specific C terminal subnuclear targeting signal (Nuclear Matrix Targeting Signal, NMTS). We have shown that expression of mutant Runx(AML) proteins with a subnuclear targeting defect causes a profound alteration of cellular phenotypes in both myeloid progenitor cells and metastatic breast cancer cells. We have established that Runx(AML) proteins are associated with metaphase chromosomes at multiple distinct foci indicating a regulatory function for sequence-specific transcription factors at genomic loci and a mechanism for mitotic distribution of regulatory factors. We propose that transcription factors that include the Runx(AML) proteins have an active role in epigenetically retaining phenotype during cell division to support lineage-specific gene expression and cell fate determination in progeny cells. The contributions of nuclear organization in control of replication and transcription are evident despite gaps in our understanding of the rules that govern gene expression. Insight into regulatory parameters of organization and assembly of machinery for transcription, replication and repair in nuclear microenvironments provide a new dimension to cancer diagnosis and targeted therapy.