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First published online 28 August 2007
doi: 10.1242/jcs.012328

Journal of Cell Science 120, 3262-3270 (2007)
Published by The Company of Biologists 2007
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Research Article

P-STAT1 mediates higher-order chromatin remodelling of the human MHC in response to IFN{gamma}

Rossitza Christova1,2,*, Tania Jones1,2,*, Pei-Jun Wu1,*, Andreas Bolzer1, Ana P. Costa-Pereira3,4, Diane Watling3,4, Ian M. Kerr3 and Denise Sheer1,2,{ddagger}

1 Human Cytogenetics Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London, WC2A 3PX, UK
2 Institute of Cell and Molecular Science, Queen Mary's School of Medicine and Dentistry, 4 Newark St, London, E1 2AT, UK
3 Biochemical Regulatory Mechanisms Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London, WC2A 3PX, UK
4 Imperial College London, Faculty of Medicine, Department of Oncology/SORA, Hammersmith Hospital, Du Cane Road, London, W21 ONN, UK

{ddagger} Author for correspondence (e-mail: d.sheer{at}qmul.ac.uk)

Accepted 13 July 2007

Transcriptional activation of the major histocompatibility complex (MHC) by IFN{gamma} is a key step in cell-mediated immunity. At an early stage of IFN{gamma} induction, chromatin carrying the entire MHC locus loops out from the chromosome 6 territory. We show here that JAK/STAT signalling triggers this higher-order chromatin remodelling and the entire MHC locus becomes decondensed prior to transcriptional activation of the classical HLA class II genes. A single point mutation of STAT1 that prevents phosphorylation is sufficient to abolish chromatin remodelling, thus establishing a direct link between the JAK/STAT signalling pathway and human chromatin architecture. The onset of chromatin remodelling corresponds with the binding of activated STAT1 and the chromatin remodelling enzyme BRG1 at specific sites within the MHC, and is followed by RNA-polymerase recruitment and histone hyperacetylation. We propose that the higher-order chromatin remodelling of the MHC locus is an essential step to generate a transcriptionally permissive chromatin environment for subsequent activation of classical HLA genes.

Key words: JAK/STAT signalling, MHC, Chromatin architecture, Decondensation, Looping


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