The HMGN family of chromatin-binding proteins: Dynamic modulators of epigenetic processes

https://doi.org/10.1016/j.bbagrm.2012.01.013Get rights and content

Abstract

The HMGN family of proteins binds to nucleosomes without any specificity for the underlying DNA sequence. They affect the global and local structure of chromatin, as well as the levels of histone modifications and thus play a role in epigenetic regulation of gene expression. This review focuses on the recent studies that provide new insights on the interactions between HMGN proteins, nucleosomes, and chromatin, and the effects of these interactions on epigenetic and transcriptional regulation. This article is part of a Special Issue entitled: Chromatin in time and space.

Highlights

► HMGN proteins bind to nucleosomes and affect epigenetic processes. ► The mechanism of HMGN binding to the core particle has recently been elucidated. ► HMGN proteins affect global and local chromatin organization. ► Each HMGN variant affects transcription of a separate set of genes.

Introduction

Chromatin-binding architectural proteins modulate nucleosome dynamics and changes in both global and local chromatin structure, but are still a poorly understood facet of chromosome biology. One such family of proteins, the HMGNs (High Mobility Group N), has been shown to play a role in epigenetic regulation of gene expression. ‘Epigenetics’ is the study of heritable non-sequence-based variations in DNA, and at the molecular level, epigenetic regulation of gene expression is mediated through changes in chromatin structure and nucleosome composition, as well as through chemical modifications in DNA and histones. HMGNs function by binding to the nucleosome core particle (CP), and the details of the interaction between the two have recently been elucidated. The binding of HMGNs to nucleosomes is a dynamic process that affects chromatin structure and post-translational histone modifications, and impacts the cellular transcription profile. HMGN proteins can therefore be considered to function as modulators of epigenetic processes that affect the fidelity of gene expression. This review focuses on the interactions between HMGN proteins, nucleosomes, and chromatin, and the effects of these interactions on epigenetic and transcriptional regulation. Other aspects of the HMGN protein family are reviewed in [1], [2], [3], [4], [5], [6], [7], [8], [9], [10].

Section snippets

HMGN proteins bind specifically to nucleosomes

The HMGN protein family, which is found in all vertebrates, contains 5 members. All HMGN proteins contain a highly conserved nucleosomal binding domain (NBD), which is the hallmark of the HMGN family [8], [11], [12]. Within the NBD, the invariant sequence RRSARLSA is the core sequence that specifically anchors HMGN proteins to the 147 bp nucleosome core particle, the building block of the chromatin fiber [12]. In addition, all HMGNs have a bipartite nuclear localization signal (NLS) in their

HMGN proteins modulate global chromatin structure

Using simian virus 40 minichromosomes as an in vitro model system, it was found that HMGN1 partially disrupted histone H1-dependent chromatin condensation, and thus counteracted H1-mediated transcription inhibition [29]. In living cells, wild-type HMGN1 or HMGN2, but not their nucleosome-binding deficient mutants, increased the mobility of histone H1 [26], suggesting HMGNs compete with H1 by binding to the same nucleosomes. Thus, HMGNs compete with linker histone H1 for nucleosome binding and

HMGNs and post-translational histone modifications

Post-translational modifications of histones are epigenetic marks shown to play an important role in modulating cellular processes such as gene expression and cell cycle progression [33]. These reversible modifications include methylation and acetylation of lysine residues, and phosphorylation of serine residues [33], all of which are added and removed from the histone tail in a dynamic manner by enzymes which modify specific histone residues in nucleosomes. Due to the frequent interactions

Global organization of HMGNs in chromatin

HMGNs bind dynamically to chromatin and continuously turn over on the surface of the nucleosomes, without any specificity for the underlying DNA sequence. A major outstanding question is whether the proteins bind randomly to all nucleosomes or whether they preferentially turn over at selected sites. Global chromatin immunoprecipitation sequence analysis in human T cells revealed that HMGN1 co-localizes with DNase I hypersensitive sites, promoters, functional enhancers, and transcription factor

Transcriptional effects of HMGNs

While the structure of the various members of the HMGN protein family is quite uniform, except for HMGN5, which has a large c-terminal domain [15], their biological effects are not identical. Part of the biological specificity of some of the variants, such as HMGN3, can be attributed to tissue-specific expression [2], [44], [46]. Since HMGN proteins affect transcription [29], [30], their biological effects are most likely due to their effects on the cellular transcription profile.

The extent to

Future directions

Although the biochemical properties of HMGN proteins and their interactions with chromatin have been extensively studied, the physiological functions of HMGN proteins are still largely unknown, and are currently being studied in knockout mice. As elaborated above, analysis of Hmgn1−/− mice revealed that loss of this variant leads to an increase in tumorigenicity, hypersensitivity to stress such as heat shock or DNA damage induced by either UV or ionizing radiation, and mild developmental

Acknowledgment

The research described was supported by the Center for Cancer Research, intramural program of the National Cancer Institute, National Institutes of Health.

References (49)

  • M. Rochman et al.

    The interaction of NSBP1/HMGN5 with nucleosomes in euchromatin counteracts linker histone-mediated chromatin compaction and modulates transcription

    Mol. Cell

    (2009)
  • P.J. Alfonso et al.

    The footprint of chromosomal proteins HMG-14 and HMG-17 on chromatin subunits

    J. Mol. Biol.

    (1994)
  • Y.V. Postnikov et al.

    Homodimers of chromosomal proteins HMG-14 and HMG-17 in nucleosome cores

    J. Mol. Biol.

    (1995)
  • M. Bergel et al.

    Acetylation of novel sites in the nucleosomal binding domain of chromosomal protein HMG-14 by p300 alters its interaction with nucleosomes

    J. Biol. Chem.

    (2000)
  • B.P. Rattner et al.

    HMGN proteins act in opposition to ATP-dependent chromatin remodeling factors to restrict nucleosome mobility

    Mol. Cell

    (2009)
  • D.A. Hill et al.

    Effects of HMGN1 on chromatin structure and SWI/SNF-mediated chromatin remodeling

    J. Biol. Chem.

    (2005)
  • J.H. Lim et al.

    Chromosomal protein HMGN1 modulates histone H3 phosphorylation

    Mol. Cell

    (2004)
  • P. Cheung et al.

    Signaling to chromatin through histone modifications

    Cell

    (2000)
  • G.I. Belova et al.

    Chromosomal protein HMGN1 enhances the heat shock-induced remodeling of Hsp70 chromatin

    J. Biol. Chem.

    (2008)
  • L. Abuhatzira et al.

    The Chromatin Binding Protein HMGN1 Regulates the Expression of Methyl CpG Binding Protein 2 (MECP2) and Affects the Behavior of Mice

    J. Biol. Chem.

    (2011)
  • E.A. Pogna, A.L. Clayton, L.C. Mahadevan, Signalling to chromatin through post-translational modifications of HMGN,...
  • T. Ueda et al.

    Delineation of the protein module that anchors HMGN proteins to nucleosomes in the chromatin of living cells

    Mol. Cell. Biol.

    (2008)
  • R. Hock et al.

    Chromosomal proteins HMG-14 and HMG-17 are released from mitotic chromosomes and imported into the nucleus by active transport

    J. Cell Biol.

    (1998)
  • L. Trieschmann et al.

    Incorporation of chromosomal proteins HMG-14/HMG-17 into nascent nucleosomes induces an extended chromatin conformation and enhances the utilization of active transcription complexes

    EMBO J.

    (1995)
  • Cited by (40)

    • Unspinning chromatin: Revealing the dynamic nucleosome landscape by NMR

      2019, Progress in Nuclear Magnetic Resonance Spectroscopy
    • Different measures of HMGB1 location in cancer immunology

      2019, Methods in Enzymology
      Citation Excerpt :

      During cell division, HMGNs are phosphorylated and this prevents homodimerization, leaving only one molecule of the protein weakly attached to the nucleosome (Cherukuri et al., 2008). There is also evidence suggesting that phosphorylation of HMGNs is an early event in gene transcription, providing access to kinases that phosphorylate histones H3 (Lim et al., 2004) and H4 (Kugler, Deng, & Bustin, 2012). HMGN proteins compete with histone H1 for binding DNA, which could also facilitate initiation of transcription (Catez, Brown, Misteli, & Bustin, 2002; Ding, Bustin, & Hansen, 1997).

    • Histone interaction landscapes visualized by crosslinking mass spectrometry in intact cell nuclei

      2018, Molecular and Cellular Proteomics
      Citation Excerpt :

      We also probed the interaction surface between HMGN2 and the nucleosome. This intrinsically disordered protein belongs to the High Mobility Group N (HMGN) protein family and binds the nucleosome through a conserved NBD (70) and regulates nucleosome dynamics and affects chromatin organization (70). The complementation of available NMR and mutagenesis data defining the HMGN2-nucleosome interaction (71) with the crosslinks identified allowed us to obtain a better defined and more comprehensive model of the interaction between an extended NBD of HMGN2 and the nucleosome compared with using NMR and mutagenesis data only (Figs. 5F and 5G).

    • High-mobility group nucleosome binding domain 1 (HMGN1) functions as a Th1-polarizing alarmin

      2018, Seminars in Immunology
      Citation Excerpt :

      The NBD contains a core sequence of eight amino acid residues, RRSARLSA, that functions to anchor HMGN proteins to the nucleosome core particle consisting of an octamer of eight histones (H2A, H2B, H3, and H4) and about 146 bp of DNA wrapped in left-handed superhelical turns around the histone octamer [14,15]. The RD domain facilitates chromatin de-compaction by interacting with certain histones [10,13]. Due to the presence of the bipartite NLS, HMGN family of proteins naturally translocate to the nucleus right after synthesis in the cytoplasm.

    • Functional interplay between histone H1 and HMG proteins in chromatin

      2016, Biochimica et Biophysica Acta - Gene Regulatory Mechanisms
      Citation Excerpt :

      Genome wide, HMGN proteins preferentially bind to DNase I hypersensitive sites, the hallmark of regulatory chromatin sites [21–23]. HMGNs have been shown to modulate the global and local structure of chromatin [24], and the levels of histone modifications [25,26], factors which may be involved in their ability to affect gene expression [27]. HMGB proteins contain two HMG boxes, and a negatively charged C-terminal domain [28].

    View all citing articles on Scopus

    This article is part of a Special Issue entitled: Chromatin in time and space.

    1

    Equal contribution.

    View full text