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The lack of chromosomal protein Hmg1 does not disrupt cell growth but causes lethal hypoglycaemia in newborn mice

Nature Genetics volume 22, pages 276–280 (1999)Cite this article

Abstract

High mobility group 1 (HMG1) protein is an abundant component of all mammalian nuclei, and related proteins exist in all eukaryotes1,2. HMG1 binds linear DNA with moderate affinity and no sequence specificity3, but bends the double helix significantly on binding through the minor groove4. It binds with high affinity to DNA that is already sharply bent, such as linker DNA at the entry and exit of nucleosomes5,6,7; thus, it is considered a structural protein of chromatin. HMG1 is also recruited to DNA by interactions with proteins required for basal and regulated transcription8,9,10,11,12,13 and V(D)J recombination14,15. Here we generate mice harbouring deleted Hmg1. Hmg1–/– pups are born alive, but die within 24 hours due to hypoglycaemia. Hmg1-deficient mice survive for several days if given glucose parenterally, then waste away with pleiotropic defects (but no alteration in the immune repertoire). Cell lines lacking Hmg1 grow normally, but the activation of gene expression by the glucocorticoid receptor (GR, encoded by the gene Grl1) is impaired. Thus, Hmg1 is not essential for the overall organization of chromatin in the cell nucleus, but is critical for proper transcriptional control by specific transcription factors.

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Figure 1: Replacement of Hmg1 by homologous recombination.
Figure 2: Hmg1–/– mice develop neonatal hypoglycaemia.
Figure 3: The absence of Hmg1 reduces the activity of GR in transfection assays.
Figure 4: Altered glucocorticoid responses in Hmg1–/– mice in vivo and ex vivo.

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Acknowledgements

We thank G. Bouvier and F. Watrin for generating ES mutant clones; A. Plück and the EMBL Transgenic Facility for generating Hmg1 +/- mice on a pure 129Sv genetic background; M. Pezzo for mouse blood tests; A. De Luigi and M.G. De Simoni for corticosterone measurements; L. Ronfani for control experiments; T. Ravasi for establishing cell lines; F. Duranti for personal support; and D. Edwards, F. Barbetti, L. Falqui, P. Dellabona, G. Ferrari, F. Tronche and G. Schütz for help with reagents and suggestions. S.C. was a recipient of fellowships from Universita' di Milano and Centro Italiano Biotecnologie. Supported by Associazione Italiana Ricerca sul Cancro, Ministero dell'Universita' e della Ricerca Scientifica and the European Union (grant FMRX-CT97-0109).

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Authors and Affiliations

  1. DIBIT, San Raffaele Scientific Institute, via Olgettina 58, Milano, 20132, Italy

    Sabina Calogero, Fabio Grassi & Marco E. Bianchi

  2. Dipartimento di Biologia e Genetica per le Scienze Mediche, Università di Milano, via Olgettina 58, Milano, 20132, Italy

    Fabio Grassi

  3. Institut für Neuropathologie, Universitätsspital , Schmelzbergstrasse 12, Zürich, CH-8091, Switzerland

    Adriano Aguzzi & Till Voigtländer

  4. Centre d'Immunologie INSERM-CNRS de Marseille-Luminy , Marseille, France

    Pierre Ferrier

  5. Dipartimento di Genetica e di Biologia dei Microrganismi, Università di Milano, via Celoria 26, Milano, 20133, Italy

    Simona Ferrari & Marco E. Bianchi

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  1. Sabina Calogero
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Correspondence to Marco E. Bianchi.

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Calogero, S., Grassi, F., Aguzzi, A. et al. The lack of chromosomal protein Hmg1 does not disrupt cell growth but causes lethal hypoglycaemia in newborn mice. Nat Genet 22, 276–280 (1999). https://doi.org/10.1038/10338

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