In eukaryotes DNA is packaged with proteins to form chromatin. Consequently, nuclear architecture and DNA-dependent processes rely on a regulated DNA-packaging into nucleosomal chromatin and supranucleosomal chromatin. Among the most abundant chromatin proteins associated with nucleosomal chromatin are members of the high mobility group (HMG) protein superfamily. They are considered as architectural elements of chromatin. Today it is clear that HMG-proteins belong to a network of dynamic chromatin proteins that constantly move around the chromatin fiber and thereby dynamically either promote or suppress DNA-dependent processes such as transcription, replication and DNA-repair.
Besides the modulation of local chromatin near regulatory DNA-elements, HMG proteins affect chromatin on a more global scale including chromatin loop formation, heterochromatin structure and chromosome condensation. Deregulated expression of HMG proteins impairs gene expression, affects differentiation processes and causes several diseases. Thus, we propose that investigations on HMG-protein functions are ideal to understand local and global aspects of chromatin modulation during normal and abnormal cellular differentiation.
Several recent investigations have shown that nuclear architecture and function depends on dynamic behavior of proteins. High mobility of nuclear proteins guarantees their rapid and permanent availability at diverse nuclear sites, including chromatin. Whereas the basic elements of chromatin, the nucleosomes, are fairly stable basic units of DNA packaging, the nucleosomal chromatin is surrounded by a highly mobile protein crowd including HMG proteins that dynamically binds and modulates chromatin structure and function.
During cellular differentiation and embryonic development the composition of chromatin changes and influences the expression of genes and the stability of the genome. Results emerging from studies of human disease, genetically modified mice, and cells with altered HMG expression indicate that the expression of the HMG proteins is developmentally regulated and that changes in HMG protein levels alter the cellular phenotype and may lead to developmental abnormalities and disease. For example, HMGA proteins are overexpressed in many tumours and are linked to malignancy and growth of tumor cells.
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