Nuclear matrix: application to diagnosis of cancer and role in transcription and modulation of chromatin structure

Summary The nuclear matrix is involved in the processing of the genetic information and in the organization of chromatin. In recent years we have come to appreciate the organization of functional domains within the nucleus (e.g., transcript domains, RNA processing sites, sites of replication). The nuclear matrix is the foundation from which this organization is built, providing a scaffold upon which nuclear processes such as DNA replication and transcription occur. Chromatin is arranged into loop domains through the attachment of matrix associated regions (MARs) at the base of the loop to nuclear matrix proteins. Considering the role of the nuclear matrix in the organization and processing of the genetic information, it is not surprising to find that nuclear matrix proteins are informative in distinguishing cell types and disease states. For example, nuclear matrix proteins informative in the diagnosis of cancer, including breast cancer have been identified. Typically nuclear matrices are obtained following the salt extraction of nuclease-digested nuclei. However, recent studies show that cisplatin preferentially crosslinks MAR DNA to nuclear matrix proteins in situ , providing a complimentary method to identify informative nuclear matrix proteins. Transcribed, but not repressed chromatin, is associated with the nuclear matrix. Regions of a chromatin loop engaged in transcription are associated with the nuclear matrix through multiple dynamic interactions with nuclear matrix proteins. Nuclear matrix bound transcription factors, the transcription machinery and histone modifying enzymes are thought to mediate these dynamic attachments between the nuclear matrix and transcriptionally active chromatin. Core histones of transcriptionally active chromatin are dynamically acetylated, with histone acetyltransferases (HATs) and deacetylases (HDACs) catalyzing this reaction. Both of these enzymes, which are now known to be transcriptional coactivators and modulators, are associated with the nuclear matrix. We have proposed that these enzymes participate in the dynamic attachment of transcriptionally active chromatin with the nuclear matrix. Our recent studies show that cisplatin crosslinks nuclear matrix-bound transcription factors and transcription modulators to nuclear DNA in situ. This suggests that cisplatin will be most useful in the discovery of nuclear matrix MAR binding proteins involved in the organization of DNA and nuclear matrix bound transcription factors/modulators participating in the nuclear matrix association of transcriptionally active chromatin. (Supported by Medical Research Council of Canada)