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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.

Original publication

DOI

10.1038/ni.2587

Type

Journal article

Journal

Nat Immunol

Publication Date

06/2013

Volume

14

Pages

633 - 643

Keywords

Algorithms, Animals, Cell Differentiation, Cell Lineage, DNA-Binding Proteins, Gene Expression Profiling, Gene Expression Regulation, Gene Regulatory Networks, Humans, Immune System, Mice, Oligonucleotide Array Sequence Analysis, Receptors, Antigen, T-Cell, gamma-delta, Repressor Proteins, T-Lymphocytes, Trans-Activators, Transcription Factors, Transcription, Genetic, Transcriptome