HMG proteins: dynamic players in gene regulation and differentiation Marco E Bianchi 1 and Alessandra Agresti 2 Core histones package the genome into nucleosomes and control its accessibility to transcription factors. High mobility group proteins (HMGs) are, after histones, the second most abundant chromatin proteins and exert global genomic functions in establishing active or inactive chromatin domains. It is becoming increasingly clear that they also specifically control the expression of a limited number of genes. Moreover, they contribute to the fine tuning of transcription in response to rapid environmental changes. They do so by interacting with nucleosomes, transcription factors, nucleosome-remodelling machines, and with histone H1. Addresses 1 Universita ` Vita Salute San Raffaele, via Olgettina 58, 20132 Milano, Italy 2 Istituto Scientifico San Raffaele, via Olgettina 58, 20132 Milano, Italy Corresponding author: Bianchi, Marco E (bianchi.marco@hsr.it) Current Opinion in Genetics & Development 2005, 15:496–506 This review comes from a themed issue on Differentiation and gene regulation Edited by Tony Kouzarides and Andrew J Bannister Available online 15th August 2005 0959-437X/$ – see front matter # 2005 Elsevier Ltd. All rights reserved. DOI 10.1016/j.gde.2005.08.007 Introduction Chromatin functions as an integrated platform to process a variety of endogenous and exogenous signals, which are transformed into operational instructions for the accessi- bility, retrieval and execution of the biological programs that are stored as four-letter information in the genome of eukaryotes. DNA and the core histones (H2A, H2B, H3 and H4) make up the basic chromatin unit, the nucleo- some. Nucleosomes are modified, ‘remodelled’ and orga- nized into high-order structures by huge and diverse protein complexes. They are also bound non-stoichiome- trically and transiently by histone H1 and the high mobi- lity group (HMG) proteins, ‘architectural’ factors that organize chromatin by appropriately bending and plasti- cizing DNA. HMG proteins belong to three families (HMGA, HMGB and HMGN), members of each family having different structures but broadly similar functions. All HMGs are small nuclear proteins less than 30 kDa and undergo extensive post-translational modification. They bind to chromatin in a dynamic and reversible way, right inside nucleosomes (in the case of HMGN), to multiprotein complexes of transcription factors and cofactors (HMGA) or to both nucleosomes and transcription factors (HMGB). They have both global genomic functions in establishing active or inactive chromatin domains and specific control functions on a limited number of genes. HMGs compete with histone H1 for chromatin binding sites and affect its dynamics. The HMG–H1–nucleosome web of interactions might provide flexibility to chromatin structure and, most importantly, a fine tuning of gene transcription in response to rapid environmental changes. The structure and dynamics of all nuclear macromole- cular assemblages — from the individual nucleosomes to the nucleus as a whole — contain ‘epigenetic’ informa- tion: information that ultimately derives from a genetic (DNA sequence) source — although is not genetic in itself — and to which the environment and the history of the organism might contribute in significant ways. Epi- genetic information is the spice that turns a uniform endowment of genetic information for all cells of a multi- cellular organism into a rich diversity of cell identities and functions. A huge amount of work in the past 15 years has focused on epigenetic modification of DNA and core histones, and basic discovery continues at an unabated pace. The next simplest hierarchical level, the association to chromatin of architectural proteins, has been explored to a lesser degree. As far as it concerns the authors of this review, this is a good thing: a concise essay on HMGs can still be written. Likewise, the role of histone H1 was reviewed recently [1  ]. HMG families ‘High mobility group’ proteins were discovered more than 30 years ago as acid-extractable components of chromatin that had high electrophoretic mobility [2]. There are three families of HMG proteins (Figure 1), which have been renamed with systematic reference to the domains they contain: 1. HMGA proteins contain AT-hooks, nine amino acid segments that are unstructured in solution but bind AT-rich DNA stretches in the minor groove 2. HMGB proteins contain HMG Boxes, 80 amino acid domains that bind into the minor groove of DNA with limited or no sequence specificity 3. HMGN proteins bind inside Nucleosomes, between the DNA spires and the histone octamer. Current Opinion in Genetics & Development 2005, 15:496–506 www.sciencedirect.com