Writ large: Genomic dissection of the effect of cellular environment on immune response

Abstract

Cells of the immune system routinely respond to cues from their local environment and feed back to their surroundings through transient responses, choice of differentiation trajectories, plastic changes in cell state, and malleable adaptation to their tissue of residence. Genomic approaches have opened the way for comprehensive interrogation of such orchestrated responses. Focusing on genomic profiling of transcriptional and epigenetic cell states, we discuss how they are applied to investigate immune cells faced with various environmental cues. We highlight some of the emerging principles on the role of dense regulatory circuitry, epigenetic memory, cell type fluidity, and reuse of regulatory modules in achieving and maintaining appropriate responses to a changing environment. These provide a first step toward a systematic understanding of molecular circuits in complex tissues.

Figure 1. Key modes of immune-environment interaction

A) Transient responses to signals. (B) Balanced differentiation along hematopoiesis; (C) Stable yet plastic cell type polarization; (D) Malleable adaptation of tissue resident cells.

Figure 2. Genomic tools for dissecting immune-environment interactions

Shown are key components of the current genomic tool box, including profiling of RNA, protein and protein modification levels in bulk samples (A) and single cells (B), epigenomic measurements of TF binding, histone modification, DNA methylation, and chromatin accessibility (C), the ability to systematically perturb genes through genome engineering (D) or natural variation, tracing of cells with engineered molecular barcodes or TcR and BcR clonality (E), and computational algorithms that use profiling and perturbation data to infer genetic causality and molecular mechanisms (F).

Figure 3. Key features, hypotheses and principles revealed by genomic studies of immune-environment interactions

Three key genomic tools used to analyze transcription and epigenetic mechanisms that participate in immune cell responses. Bottom: The main features characterized by each tool, testable hypotheses derived by computational analysis; and current emerging principles from such studies.