Key Points
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In eukaryotes, genomic DNA is packaged into chromatin, the basic repeating unit of which is the nucleosome. Nucleosomes consist of a histone octamer, which binds DNA tightly, protecting it from the enzymes and proteins in the nucleus, as well as enabling a large amount of genetic material to be packaged into the nucleus.
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Although the structure of chromatin protects DNA from harm and allows it to be efficiently packaged, it does not allow the DNA to be easily accessed by proteins that mediate transcription, replication, repair or recombination. To gain access to the DNA, cells often use chromatin-remodelling complexes (CRCs), which use energy to disrupt histone–DNA contacts. BAF (Brahma-related gene (BRG)/Brahma (BRM)-associated factor) complexes are the prototypical mammalian CRCs, and their role in the immune system is now becoming clearer.
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A nucleosome is positioned at the promoter of the human gene encoding interferon-β (IFN-β). This nucleosome covers the transcriptional start site and prevents the complete assembly of the transcriptional machinery. Following viral infection, BAF complexes are recruited to the promoter of the IFN-β gene, where they remodel the nucleosome, leading to the nucleosome sliding downstream. This clears the promoter, a prerequisite step for induction of IFN-β expression.
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A nucleosome is positioned at the promoter of the IFN-α-regulated gene that encodes IFITM1 (IFN-induced transmembrane protein 1). This nucleosome covers the binding site of ISGF3 (IFN-stimulated gene factor 3), the transcription factor complex that is crucial for the induction of IFITM1 transcription. BAF complexes constitutively bind and remodel the nucleosome, partially exposing the ISGF3-binding site. This primes the promoter for the rapid induction of gene expression. BAF complexes are required for the induction of most IFN-α-responsive genes.
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The transcription of MHC class II depends on the master transcriptional activator CIITA (MHC class II transactivator). BAF complexes are required not only for CIITA to activate MHC class II expression but also for the expression of CIITA per se.
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BAF complexes are essential for repression of CD4. They might function by exposing the DNA sequence of the silencer to transcriptional repressors and/or by establishing a repressive chromatin structure at the CD4 promoter and/or enhancers.
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Both the recruitment and activity of BAF complexes are subject to regulation. Signalling pathways can influence BAF complexes and control their location and/or activities through transcriptional activators, post-translational modifications and nuclear inositol derivatives. The assembly of BAF complexes might also be regulated.
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Viruses might have developed strategies to exploit BAF complexes to aid their own replication and/or transcription.
Abstract
Chromatin structure dictates whether DNA templates are accessible to nuclear proteins; therefore, it is tightly regulated. To reconfigure chromatin, cells often mobilize 'chromatin-remodelling complexes' that use energy to disrupt histone–DNA contacts. BAF complexes, which are related to the yeast SWI–SNF complex, are the prototypical mammalian chromatin-remodelling complexes. In the past few years, studies have revealed the crucial and diverse roles of BAF complexes in the regulation of the immune system — from lymphocyte development to immune responses. This review surveys these advances, highlighting the general insights these studies provide into the modes of action of BAF complexes, and it concludes with a discussion of some of the key opportunities and challenges in this field.
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Acknowledgements
I apologize to colleagues whose work could not be cited owing to space limitations. I thank G. Crabtree for continued support of my work, and I thank K. J. Zhao, R. Bremner and members of my laboratory for stimulating discussions.
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Glossary
- PRIMARY IMMUNE RESPONSES
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The immune mechanisms that are activated in response to a first exposure to a pathogen or antigen. In the case of CD8+ T-cell responses, they are usually measured at day 7–8 after immunization.
- ADP RIBOSYLATION
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The transfer, through an ADP ribosyltransferase, of one or more ADP-ribosyl groups from NAD+ to a protein.
- BROMODOMAINS
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Modules of ∼110 amino acids that are found in several transcriptional regulators. They consist of a four-helix bundle with a single binding pocket for Nε-acetyl-lysine on histone peptides.
- PRE-TCR
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(Pre-T-cell receptor). A receptor that is expressed by pre-T cells. It is formed by a TCR β-chain paired with a surrogate TCR α-chain (known as the invariant pre-Tα protein). The receptor complex includes CD3 proteins and transduces signals that allow further T-cell development.
- HOLOENZYME
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A catalytically active complex that contains the enzyme and an appropriate cofactor or cofactors.
- SMALL INTERFERING RNA
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(siRNA). Short (∼21-base pairs) double-stranded RNA fragments that can direct RNA-degradative machinery to homologous endogenous RNA sequences when introduced into cells, thereby inhibiting the expression of the targeted genes.
- REVERSE-TRANSCRIPTION PCR
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(RT-PCR). A type of PCR in which RNA is converted into double-stranded DNA, which is then amplified.
- CHROMATIN-IMMUNOPRECIPITATION ASSAYS
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A powerful method to assess the physical association of a known nuclear protein with a candidate target locus in vivo. Cells are first treated with a 'zero-length crosslinker' (formaldehyde), which crosslinks protein to DNA directly or through other proteins. Chromatin is then sheared to less than 500 base pairs, and the protein is immunoprecipitated. If the candidate target gene is co-precipitated (as measured by PCR), the target locus is likely to bind the protein (directly or indirectly) in vivo.
- DN3 THYMOCYTES
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(Double-negative 3). A subset of thymocytes defined as CD3−CD4−CD8−CD25+CD44−.
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Chi, T. A BAF-centred view of the immune system. Nat Rev Immunol 4, 965–977 (2004). https://doi.org/10.1038/nri1501
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DOI: https://doi.org/10.1038/nri1501
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