Runx1 and Runx3 drive progenitor to T-lineage transcriptome conversion in mouse T cell commitment via dynamic genomic site switching.

Autor:	Shin B; Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125., Hosokawa H; Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125.; Department of Immunology, Tokai University School of Medicine, Isehara, Kanagawa 259-1193, Japan., Romero-Wolf M; Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125., Zhou W; Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125., Masuhara K; Department of Immunology, Tokai University School of Medicine, Isehara, Kanagawa 259-1193, Japan., Tobin VR; School of Veterinary Medicine, University of California, Davis, CA 95616., Levanon D; Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76001, Israel., Groner Y; Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76001, Israel., Rothenberg EV; Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125; evroth@its.caltech.edu.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2021 Jan 26; Vol. 118 (4).
DOI:	10.1073/pnas.2019655118
Abstrakt:	Runt domain-related (Runx) transcription factors are essential for early T cell development in mice from uncommitted to committed stages. Single and double Runx knockouts via Cas9 show that target genes responding to Runx activity are not solely controlled by the dominant factor, Runx1. Instead, Runx1 and Runx3 are coexpressed in single cells; bind to highly overlapping genomic sites; and have redundant, collaborative functions regulating genes pivotal for T cell development. Despite stable combined expression levels across pro-T cell development, Runx1 and Runx3 preferentially activate and repress genes that change expression dynamically during lineage commitment, mostly activating T-lineage genes and repressing multipotent progenitor genes. Furthermore, most Runx target genes are sensitive to Runx perturbation only at one stage and often respond to Runx more for expression transitions than for maintenance. Contributing to this highly stage-dependent gene regulation function, Runx1 and Runx3 extensively shift their binding sites during commitment. Functionally distinct Runx occupancy sites associated with stage-specific activation or repression are also distinguished by different patterns of partner factor cobinding. Finally, Runx occupancies change coordinately at numerous clustered sites around positively or negatively regulated targets during commitment. This multisite binding behavior may contribute to a developmental "ratchet" mechanism making commitment irreversible. Competing Interests: Competing interest statement: E.V.R. is a member of the Scientific Advisory Board of Century Therapeutics, LLC.
Databáze:	MEDLINE
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