HMG proteins: dynamic players in gene regulation and differentiation
Introduction
Chromatin functions as an integrated platform to process a variety of endogenous and exogenous signals, which are transformed into operational instructions for the accessibility, 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 nucleosome. Nucleosomes are modified, ‘remodelled’ and organized into high-order structures by huge and diverse protein complexes. They are also bound non-stoichiometrically and transiently by histone H1 and the high mobility group (HMG) proteins, ‘architectural’ factors that organize chromatin by appropriately bending and plasticizing 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 macromolecular assemblages — from the individual nucleosomes to the nucleus as a whole — contain ‘epigenetic’ information: 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. Epigenetic information is the spice that turns a uniform endowment of genetic information for all cells of a multicellular 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••].
Section snippets
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
HMGA
HMGAs are abundant early in embryonic life and are expressed at low levels in most adult cells [3•].
HMGAs are directly involved in the transcriptional control of specific genes. They are key actors within enhanceosomes, which are complex assemblages of transcription factors and cofactors on nucleosome-free control regions of genes. The best-studied enhanceosome is situated on the interferon β (IFN-β) promoter: it contains HMGA1a together with the transcription factors NF-κB, IRF (interferon
Mammalian HMGBs
Mammalian HMGBs are characterized by two tandem HMG box domains followed by a long acidic tail (Figure 1). The two boxes are structurally similar, and their motions are completely independent; the acidic tail appears to be unstructured [24].
HMG box domains are present in many proteins, and contain three α-helices that fold up into a typical wedge shape, the concave surface of which can delve into the minor groove of DNA [25]. All HMG boxes, whether present alone, in tandem or embedded into
Non-mammalian HMGBs
Recently, our understanding of the transcriptional control exerted by mammalian HMGBs has been vastly increased by the study of HMG box proteins of Drosophila and yeast. Whereas HMGN proteins appear to be late inventions in evolution, and are typical of vertebrates only, HMGB proteins are as old as multicellular animals — even sponges have a clearly recognizable HMGB with two tandem HMG boxes [45]. Plants, fungi and unicellular eukaryotes rarely have proteins containing tandem HMGB boxes.
HMGN
HMGNs unfold higher-order chromatin structure and enhance several DNA-dependent activities: transcription, and DNA repair and replication [59]. HMGNs are the only non-histone proteins known to specifically bind inside the nucleosomes — between the histone core and the DNA; the H3 histone tail and H2B are involved in the interaction. Stretches of contiguous nucleosomes contain a uniform population of HMGN homodimers, either HMGN1 or HMGN2, but not mixed HMGN1/2 populations; HMGN1 and HMGN2 are
Conclusion: a web of architectural proteins
It has progressively become clear that HMGs (10 proteins, including the splice variants) and histone H1 (eight similar but subtly different proteins) play similar yet opposing roles within chromatin. Chromatin is an active and dynamic structure, which in living cells is constantly kept far from equilibrium by ATP-consuming machineries. The accessibility of DNA within chromatin depends at the most basic level on the localization and mobility of nucleosomes and on the post-translational
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
The authors thank Luca Sessa for critical reading of the manuscript. Research in the authors’ laboratory is supported by the Italian Association for Cancer Research (AIRC), Fondazione del Monte dei Paschi di Siena, Fondazione Cariplo, and the Ministries for Health and for Education, University and Research.
Glossary
- Consensus half-site/full-site
- Steroid hormone receptors (class I) bind preferentially as preformed homodimers to a hexameric core DNA sequence (HRE, hormone response element) arranged as an inverted repeat. In contrast, class II and orphan receptors can recognize the hexameric core HRE arranged as an inverted repeat, a direct repeat or a single HRE half-site. Class I receptors can also bind to half-sites, but with much reduced efficiency. Once bound to hormone and DNA, nuclear receptors enhance
References (70)
- et al.
The dynamics of histone H1 function in chromatin
Mol Cell
(2005) - et al.
HMGB proteins and gene expression
Curr Opin Genet Dev
(2003) - et al.
IFN-γ gene expression is controlled by the architectural transcription factor HMGA1
Int Immunol
(2005) - et al.
In vivo modulation of Hmgic reduces obesity
Nat Genet
(2000) - et al.
The role of the C-terminal extension (CTE) of the estrogen receptor α and β DNA binding domain in DNA binding and interaction with HMGB
J Biol Chem
(2004) - et al.
GR and HMGB1 interact only within chromatin and influence each other's residence time
Mol Cell
(2005) - et al.
The DNA architectural protein HMGB1 facilitates RTA-mediated viral gene expression in gamma-2 herpesviruses
J Virol
(2004) - et al.
Borna disease virus phosphoprotein represses p53-mediated transcriptional activity by interference with HMGB1
J Virol
(2003) - et al.
Intracellular high mobility group B1 protein (HMGB1) represses HIV-1 LTR-directed transcription in a promoter- and cell-specific manner
Virology
(2003) - et al.
HMGB2 protein from the marine sponge Suberites domuncula
Food Technol Biotechnol
(2003)