New Horizons for Diagnostic Applications of Circulating Nucleosomes in Blood?

Abstract

In 1974, Kornberg proposed a model of the organization of human chromatin as a nucleosomal chain formed by repeating histone–DNA sequences (1). Subsequent x-ray crystallographic analyses have confirmed his electron microscopy findings as advances in methodology and crystallographic resolution have revealed more and more details of the structure of nucleosomal core particles (2). Today, it is clear that nucleosomes consist of a central protein core of the doubly represented histones H2A-H2B and H3-H4 plus 147 bp of double-stranded DNA twisted around this complex (2)(3). Another histone, H1, is located outside the nucleosomes at the so-called linker DNA, which connects the various 206-kDa disk-like nucleosomes. This histone stabilizes the chain in its tertiary structure as chromatin fiber (2)(3). Beyond the essential role of DNA packaging and stabilization, the arrangement of chromatin into multinucleosomal order has other important functions, particularly in regulating the transcription, replication, and repair of DNA. Transcription factors and polymerases gain access to specific DNA sequences only if they are released from their close association with the histone core (3)(4). The flexible and dynamic structure of the nucleosomal organization is facilitated by ATP-dependent chromatin-remodeling complexes that cause uncoupling of the close DNA–histone connection, the transfer of a histone octamer to another DNA molecule, or the core particle to slide along the DNA (3)(4). As more details of these processes have been elucidated, it has become increasingly evident that their coordination is quite complex and can be easily disturbed by various diseases. Recent findings have revealed that in addition to genetic mutations, such epigenetic modifications as DNA methylation, histone modifications, and the production of noncoding micro-RNAs are key features in the regulation of gene transcription, replication, and DNA repair (5)(6). Those epigenetic patterns are regarded as heritable markers that …