Identification of transcriptional regulators in the mouse immune system

• Published in: Nature immunology Vol. 14; no. 6; pp. 633 - 643
• Main Authors: Jojic, Vladimir, Shay, Tal, Sylvia, Katelyn, Zuk, Or, Sun, Xin, Kang, Joonsoo, Regev, Aviv, Koller, Daphne
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.06.2013; Nature Publishing Group
• Subjects: 631/250/232; 631/250/2502; Algorithms; Analysis; Animals; Biomedicine; Cell Differentiation; Cell Differentiation - genetics; Cell Differentiation - immunology; Cell Lineage; Cell Lineage - genetics; Cell Lineage - immunology; DNA-Binding Proteins; DNA-Binding Proteins - genetics; DNA-Binding Proteins - immunology; Gene Expression Profiling; Gene Expression Regulation; Gene Expression Regulation - immunology; Gene Regulatory Networks; Gene Regulatory Networks - immunology; Genetic aspects; Genetic transcription; Health aspects; Hematopoietic stem cells; Humans; Immune System; Immune System - cytology; Immune System - metabolism; Immunology; Infectious Diseases; Life Sciences; Mammals; Mice; Oligonucleotide Array Sequence Analysis; Physiological aspects; Receptors, Antigen, T-Cell, gamma-delta; Receptors, Antigen, T-Cell, gamma-delta - immunology; Receptors, Antigen, T-Cell, gamma-delta - metabolism; Repressor Proteins; Repressor Proteins - genetics; Repressor Proteins - immunology; resource; Stem cells; T cells; T-Lymphocytes; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; Trans-Activators; Trans-Activators - genetics; Trans-Activators - immunology; Transcription Factors; Transcription Factors - genetics; Transcription Factors - immunology; Transcription, Genetic; Transcription, Genetic - immunology; Transcriptome; Transcriptome - genetics; Transcriptome - immunology; United States
• ISSN: 1529-2908; 1529-2916
• DOI: 10.1038/ni.2587

The transcriptional circuitry that controls the differentiation of hematopoietic stem cells into cells of the immune system is only partially understood. Koller and colleagues use a computational algorithm to identify previously unknown differentiation stage–specific regulators of mouse hematopoiesis. The differentiation of hematopoietic stem cells into cells of the immune system has been studied extensively in mammals, but the transcriptional circuitry that controls it is still only partially understood. Here, the Immunological Genome Project gene-expression profiles across mouse immune lineages allowed us to systematically analyze these circuits. To analyze this data set we developed Ontogenet, an algorithm for reconstructing lineage-specific regulation from gene-expression profiles across lineages. Using Ontogenet, we found differentiation stage–specific regulators of mouse hematopoiesis and identified many known hematopoietic regulators and 175 previously unknown candidate regulators, as well as their target genes and the cell types in which they act. Among the previously unknown regulators, we emphasize the role of ETV5 in the differentiation of γδ T cells. As the transcriptional programs of human and mouse cells are highly conserved, it is likely that many lessons learned from the mouse model apply to humans.