P-STAT1 mediates higher-order chromatin remodelling of the human MHC in response to IFNgamma.
Transcriptional activation of the major histocompatibility complex (MHC) by IFNgamma is a key step in cell-mediated immunity. At an early stage of IFNgamma 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.
Christova
Rossitza
R
Human Cytogenetics Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London, WC2A 3PX, UK.
Jones
Tania
T
Wu
Pei-Jun
PJ
Bolzer
Andreas
A
Costa-Pereira
Ana P
AP
Watling
Diane
D
Kerr
Ian M
IM
Sheer
Denise
D
D000107:Acetylation / Q000187:drug effects; D000998:Antiviral Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D042002:Chromatin Assembly and Disassembly / Q000187:drug effects / Q000502:physiology*; D004265:DNA Helicases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D006657:Histones / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007111:Immunity, Cellular / Q000187:drug effects / Q000502:physiology; D007371:Interferon-gamma / Q000494:pharmacology*; D008285:Major Histocompatibility Complex / Q000187:drug effects / Q000502:physiology*; D009687:Nuclear Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects / Q000502:physiology*; D040641:Quantitative Trait Loci / Q000187:drug effects / Q000502:physiology; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology
D000998:Antiviral Agents; D006657:Histones; D009687:Nuclear Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D014157:Transcription Factors; D007371:Interferon-gamma; C084108:SMARCA4 protein, human; D004265:DNA Helicases