Application of ChIP-Seq and related techniques to the study of immune function

Abstract

Behaviors observed at the cellular level such as development and acquisition of effector functions by immune cells result from transcriptional changes. The biochemical mediators of transcription are sequence-specific transcription factors (TFs), chromatin modifying enzymes, and chromatin, the complex of DNA and histone proteins. Covalent modification of DNA and histones, also termed epigenetic modification, influences the accessibility of target sequences for transcription factors on chromatin and the expression of linked genes required for immune functions. Genome-wide techniques such as ChIP-Seq have described the entire "cistrome" of transcription factors involved in specific developmental steps of B and T cells and started to define specific immune responses in terms of the binding profiles of critical effectors and epigenetic modification patterns. Current data suggest that both promoters and enhancers are prepared for action at different stages of activation by epigenetic modification through distinct transcription factors in different cells.

Figure 1. Epigenetic memories of different activation stages of promoters and enhancers

The upper panel shows the different status of promoter activation indicated with different colors below the cartoon. The distinctive epigenetic modifications associated with the promoter status and classes of genes that exhibit the epigenetic pattern in particular lineages or cell activation states are also indicated. The lower panel shows the different status of enhancer activation and the associated epigenetic modification with each status. The bound transcription factors and co-factors with each status are also indicated.

Figure 2. Signal dependent transcription factors lead to developmental decisions by sequentially activating epigenetically distinct sets of genes

Two different signals (A or B) activate, through pre-existing but signal-dependent transcription factors, shared gene set 2 and distinct gene set 1 or set 3, which are poised by active chromatin marks. Transcription factors, Tf_A or Tf_B, are induced and resolve the marks at bivalent genes, set 4 or set 5, allowing for expression of pioneer factors (Tf_pA or Tf_pB) that cause further epigenetic changes. The pioneer factors lead to epigenetic changes and induction of a new set, set 6 or set 7, of genes, resulting in a cell primed for a different set of responses.