Quantitative Nuclear Grade

Abstract

Changes in nuclear structure occur in response to normal physiological processes such as cell division, apoptosis, cell differentiation, and senescence, as well as in disease-related processes such as cancer, where they are manifested in response to numerous alterations in gene expression (1). Therefore, the accurate and reproducible measurement of nuclear structure changes can provide important objective information when assessing and managing the pathologic disease process (2–4). Several studies have demonstrated that transformation of a normal cell into a malignant cell requires a series of genetic changes (or hits) (5–7) such as mutations, DNA methylation events in promoters or exons, chromosome deletions, insertions, amplifications, and translocations (7–13). Additionally, several classes of well-characterized nuclear organelles (spliceosomes, centrosomes, telomeres, and nucleosomes), gene families (HMGA, SWI/SNF modifiers, RARs, MARs, etc.), and key structural and regulatory proteins (e.g., nuclear matrix proteins, HMG proteins, nuclear histones H1, H2A, H2B, H3, and H4, and SWI/SNF complex) have been identified as being important to maintenance of nuclear chromatin structure and function (13–27). One example in this area involves work on the combinatorial chemistry of the histone tails of the nucleosome’s protein core. There is evidence that acetylation, methylation, phosphorylation, glycosylation, and ubiquination of the histone tail can produce changes in chromatin structure directly related to differential patterns of gene expression (27).