HMG chromosomal proteins in development and disease

Abstract

The high mobility group (HMG) proteins are a superfamily of abundant and ubiquitous nuclear proteins that bind to DNA and nucleosomes and induce structural changes in the chromatin fiber. They are important in chromatin dynamics and influence DNA processing in the context of chromatin. 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 can lead to developmental abnormalities and disease. Here, we focus on the biological function of HMG proteins and highlight their possible roles in cellular differentiation and in the etiology of various diseases.

Figure 1

Architectural functions of HMG proteins. (a) The main structural features of the HMGs. Family members are listed above each diagram. All HMGAs contain three AT hooks (green) and an acidic C-terminal part (blue), except HMGA1c, which contains only two hooks. Through these hooks HMGAs bind to AT-rich regions. Each of the three members of the HMGB family contains two HMG boxes (yellow) and an extended acidic C-terminus (blue). The HMGN proteins are characterized by a positively charged nucleosomal binding domain (NBD, red) and a negatively charged C-terminal region named chromatin unfolding domain (CHUD, blue). (b) HMG proteins alter chromatin structure by a variety of mechanisms. (i,ii) HMG proteins (green) alter the chromatin structure and facilitate the binding of additional factors (round shapes of various colors). This can be mediated through (i) their DNA bending activity, as has been shown for HMGA and HMGB proteins [2,5,7] or by (ii) either preventing or facilitating access of modulating factors to chromatin, as has been shown for HMGN proteins [50,65]. Given that HMGA proteins also bind to nucleosomes, a similar modulation of nucleosome accessibility is feasible. (iii) HMGs are part of the chromatin binding module of regulatory multiprotein complexes. A prominent example is the role of HMGA proteins in the formation of enhanceosomes [20]. (iv) HMG proteins facilitate structural transitions at sites to which they are targeted by specific regulatory factors. After targeting, HMGA or HMGB can induce DNA bending [5] and (v) chromatin unfolding by HMGN proteins or chromatin compaction by HMGA [25,66]. (vi) HMG proteins compete with other nuclear proteins for chromatin binding sites, altering the local or global structure of the chromatin fiber. The competition of HMG proteins with linker histones is an example of competition among chromatin binding proteins [67-69].

Figure 2

Differential expression of HMG proteins and the effects of HMG levels on development and cancer. (a) In normal developmental conditions, the expression of HMGs is related to differentiation. Thus, in undifferentiated and embryonic cells, HMG-containing chromatin is linked to increased cellular proliferation and cell type-specific gene expression. During cellular differentiation the levels of HMG is down-regulated, and terminally differentiated cells have a low content of HMGs. (b) Deregulation of HMG expression leads to an abnormal situation. Increasing or decreasing HMG levels causes alterations in the cellular transcription profile and can lead to developmental defects, disease and cancer.