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. This Review describes how next-generation sequencing has enriched our knowledge of how STAT proteins regulate cytokine-mediated T helper cell differentiation through direct DNA binding and by affecting epigenetic modifications. Signal transducer and activator of transcription (STAT) proteins are well known for their essential roles in transmitting cytokine-mediated signals and specifying T helper (T H ) 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 T H cells will provide important insights and perhaps therapeutic opportunities in these diseases.