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Identification of transcriptional regulators in the mouse immune system

Abstract

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.

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Figure 1: Mouse cell populations in the ImmGen compendium.
Figure 2: Related cells have very similar expression profiles.
Figure 3: Overview of Ontogenet.
Figure 4: Ontogenet regulatory model for coarse–grained module C33.
Figure 5: Ontogenet regulatory model for coarse-grained modules.
Figure 6: Changes in activity weights across the hematopoietic lineage tree.
Figure 7: ETV5 is a regulator of γδ T cells.

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Acknowledgements

We thank the ImmGen core team (including M. Painter and S. Davis) for help with data generation and processing; eBioscience, Affymetrix and Expression Analysis for support of ImmGen; L. Gaffney for help with figure preparation and layout of the lineage tree; S. Hart for initial layout of the lineage tree; and A. Liberzon (Molecular Signatures Database) for the positional gene sets for mouse. Supported by National Institute of Allergy and Infectious Diseases (R24 AI072073 to the ImmGen Consortium), the US National Institutes of Health (A.R.; and U54-CA149145 and 149644.0103 to V.J. and D.K.), the Burroughs Wellcome Fund (A.R.), the Klarman Cell Observatory (A.R.), the Howard Hughes Medical Institute (A.R.), the Merkin Foundation for Stem Cell Research at the Broad Institute (A.R.) and the National Science Foundation (DBI-0345474 to V.J. and D.K.).

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V.J., T.S., A.R. and D.K. designed the study; V.J. developed the algorithm, with input from T.S., A.R. and D.K.; T.S. analyzed the data; K.S. did experiments; O.Z. provided the motif-related code and participated in writing; X.S. generated a mouse model; J.K. designed the experiments and participated in writing the manuscript; and V.J., T.S., A.R. and D.K. wrote the manuscript with input from all authors.

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Correspondence to Aviv Regev or Daphne Koller.

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The authors declare no competing financial interests.

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Jojic, V., Shay, T., Sylvia, K. et al. Identification of transcriptional regulators in the mouse immune system. Nat Immunol 14, 633–643 (2013). https://doi.org/10.1038/ni.2587

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