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Genomic views of STAT function in CD4+ T helper cell differentiation

Key Points

  • Signal transducer and activator of transcription (STAT) proteins have crucial immunoregulatory functions, and are particularly important for T helper cell differentiation.

  • Chromatin immunoprecipitation followed by next-generation sequencing (ChIP–seq) analysis has mapped the DNA binding sites of transcription factors such as STATs on a genome-wide scale.

  • ChIP–seq technology also allows researchers to gain a genomic view of the histone epigenetic modifications that constitute the 'epigenome'.

  • Genomic approaches enable us to link transcription factor binding with epigenomic modifications and gene expression to comprehensively evaluate the regulation of these activities.

  • Genome-wide association studies have linked STAT genes and STAT-mediated cytokine signalling pathways to multiple immune deficiency and autoimmune disorders.

  • Further applications of next-generation sequencing technologies include mapping of the DNA methylome, nucleosome positioning and DNase I hypersensitive sites, as well as profiling of the transcriptome (using RNA-seq) and microRNAs, underscoring the versatility of this powerful tool.

Abstract

Signal transducer and activator of transcription (STAT) proteins are well known for their essential roles in transmitting cytokine-mediated signals and specifying T helper (TH) cell differentiation. Recent technological advances have revealed that STAT proteins have broad and complex roles in gene regulation and epigenetic control, including important roles as functional repressors. However, the challenge of how to link signal transduction, nucleosome biology and gene regulation remains. The relevance of tackling this problem is highlighted by genome-wide association studies that link cytokine signalling and STATs to various autoimmune or immune deficiency disorders. Defining exactly how extrinsic signals control the specification and plasticity of TH cells will provide important insights and perhaps therapeutic opportunities in these diseases.

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Figure 1: Experimental flow of ChIP–seq analysis.
Figure 2: Distinctive epigenetic patterns are formed by STAT proteins in differentiated T helper effector cells.
Figure 3: The STAT6 signalling network map identified during the initial TH2 cell differentiation stage.
Figure 4: Markers of genomic organization to define activities of chromosome regions.

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Glossary

Next-generation sequencing

High-throughput sequencing methods that rapidly and inexpensively produce accurate sequencing data that can cover entire genomes. Several different platforms, based on different chemistries, are available, including: the Illumina Genome Analyzer, the Roche 454 Sequencing System, the Applied Biosystems SOLiD System and the Helicos BioSciences HeliScope.

Chromatin immunoprecipitation

(ChIP). A technique used to detect the DNA binding sites of specific proteins within chromatin. These assays involve chemical crosslinking of the bound proteins to the DNA, followed by immunoprecipitation with an antibody that is specific for the protein of interest.

Epigenetic regulation

The heritable, but potentially reversible, states of gene activity that are imposed by the structure of chromatin, such as covalent modifications of DNA or of nucleosomal histones. The epigenome pertains to the aspects of heritable cellular phenotype that are not explained by DNA sequence.

Nucleosome

A nucleosome consists of a core of histone proteins with a segment of DNA wrapped around it. It is the minimum unit required to make up a chromosome.

ChIP–seq

A technique in which chromatin immunoprecipitation is followed by high-throughput sequencing to generate a genome-wide distribution map of protein–DNA interactions. This technique can be used to measure transcription factor binding or histone modifications.

ChIP-on-chip

A technique that combines chromatin immunoprecipitation (ChIP) with microarray technology ('chip') to investigate protein–DNA interactions in vivo on a genome-wide basis.

Enhancer element

A control element in DNA that is bound by regulatory proteins that influence the rate of transcription of the associated gene(s). Enhancers function in an orientation- and position-independent manner, so they can be located either upstream or downstream of the associated gene, or in an intron.

Genome-wide association study

A study in which genome-wide genetic variation is linked to a particular phenotype, most often a clinical disorder, by applying high-throughput genotyping techniques to profile single nucleotide polymorphisms (SNPs) of control subjects compared with patients.

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O'Shea, J., Lahesmaa, R., Vahedi, G. et al. Genomic views of STAT function in CD4+ T helper cell differentiation. Nat Rev Immunol 11, 239–250 (2011). https://doi.org/10.1038/nri2958

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