Immunological Genome Project and systems immunology

Abstract

Immunological studies of single proteins in a single cell type have been complemented in recent years by larger studies, enabled by emerging high-throughput technologies. This trend has recently been exemplified by the discovery of gene networks controlling regulatory and effector αβ T cell subset development and human hematopoiesis. The Immunological Genome Project (ImmGen) aims to decipher the gene networks underpinning mouse hematopoiesis. The first phase, completed in 2012, profiled the transcriptome of 249 immune cell types. We discuss the utilities of the datasets in high-resolution mapping of the hematopoietic system. The immune transcriptome compendium has revealed unsuspected cell lineage relations and the network reconstruction has identified novel regulatory factors of hematopoiesis.

Keywords: hematopoiesis; systems immunology; transcriptional regulation.

Figure 1. The ImmGen compendium and its analysis

(a) ImmGen dataset (top, left), and the three types of studies performed by the ImmGen consortium: (1) Lineage focused studies that identified lineage specific genes (e.g. heatmaps of gene expression across cell subsets), described the relationship between lineages (represented by Pearson correlation matrix) and assigned cell types to the lineages tree. (2) System studies that defined modules of coexpressed genes across the entire dataset and reconstructed the modules’ regulatory program using Ontogenet. The resulting regulatory network described organizational principles governing the differentiation within the immune system, and identified candidate novel regulatory factors that can be experimentally verified. (3) Perturbations studies that investigated the transcriptional response to pathogens. ImmGen dataset can be integrated with other datasets, and methods from other disciplines can be applied to it, to gain new biological perspectives (Future studies). (b) The hematopoietic lineage tree constructed by ImmGen. Big rectangles with numbers represent a group of cell types, with the number of replicates listed. Small rectangles represent single cell type, typically with 3 replicates. Lines/edges between rectangles represent differentiation steps.

Figure 2. Lymphoid and myeloid specific modules and activators

Conserved pan-regulators of lymphoid and myeloid branches can be gleaned from the comparison of lymphoid and myeloid-specific modules. (a) Expression matrix of the genes in the modules that are induced in myeloid cells (Coarse modules 24, 25, 28, 29, 30, 31, 32, 45, 49, 74, 75 and 77). (b) Expression matrix of the activators assigned to the modules that are induced in myeloid cells with a maximal activity weight > 0.05 (arbitrary threshold). (c) Expression matrix of the genes in the modules that are induced in lymphoid cells (Coarse modules 16, 21 and 22). (d) Expression matrix of the activators assigned to the modules that are induced in lymphoid cells with a maximal activity weight > 0.5. Blue-red color bars show relative expression level

Text Box 1 Figure. Examples of ImmGen application for gene(s) focused studies

(a) Bar chart of the immune cell type(s) in which a Pax5 is expressed, using the Skyline viewer. (b) A heatmap of the gene expression of the genes in coarse-grained module C33. Each row is a gene, each column is a cell type. Colorbar below represents cell lineage. (c) Heatmap of coarse-grained modules predicted to be controlled by Pax5. Each row is a gene, each column is a cell type. Colorbar below represents cell lineage. (d) B-cells induce modules. Each row is a gene, each column is a cell type. Colorbar below represents cell lineage. (e) Heatmap of genes down-regulated (top) or up-regulated (bottom) in AIDS-related primary effusion lymphoma samples compared to other tumor subtypes and normal B lymphocytes[44], Fig. e). Only genes assigned to ImmGen modules are shown, sorted by module number. Selected gene symbols are shown to the left.