Article ; Online: Runx1 and Runx3 drive progenitor to T-lineage transcriptome conversion in mouse T cell commitment via dynamic genomic site switching.
Proceedings of the National Academy of Sciences of the United States of America
2021 Volume 118, Issue 4
Abstract: 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 ... ...
| Abstract | 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. |
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| MeSH term(s) | Animals ; Cell Differentiation ; Cell Lineage/genetics ; Cell Lineage/immunology ; Core Binding Factor Alpha 2 Subunit/genetics ; Core Binding Factor Alpha 2 Subunit/immunology ; Core Binding Factor Alpha 3 Subunit/genetics ; Core Binding Factor Alpha 3 Subunit/immunology ; Female ; Gene Expression Profiling ; Gene Expression Regulation ; Interleukin-2 Receptor alpha Subunit/genetics ; Interleukin-2 Receptor alpha Subunit/immunology ; Male ; Mice ; Precursor Cells, T-Lymphoid/cytology ; Precursor Cells, T-Lymphoid/immunology ; Primary Cell Culture ; Repressor Proteins/genetics ; Repressor Proteins/immunology ; T-Lymphocytes/classification ; T-Lymphocytes/cytology ; T-Lymphocytes/immunology ; Transcriptome ; Tumor Suppressor Proteins/genetics ; Tumor Suppressor Proteins/immunology |
| Chemical Substances | Bcl11b protein, mouse ; Core Binding Factor Alpha 2 Subunit ; Core Binding Factor Alpha 3 Subunit ; Il2ra protein, mouse ; Interleukin-2 Receptor alpha Subunit ; Repressor Proteins ; Runx1 protein, mouse ; Runx3 protein, mouse ; Tumor Suppressor Proteins |
| Language | English |
| Publishing date | 2021-02-08 |
| Publishing country | United States |
| Document type | Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't |
| ZDB-ID | 209104-5 |
| ISSN | 1091-6490 ; 0027-8424 |
| ISSN (online) | 1091-6490 |
| ISSN | 0027-8424 |
| DOI | 10.1073/pnas.2019655118 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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