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RUNX1 controls the dynamics of cell cycle entry of naïve resting B cells by regulating expression of cell cycle and immunomodulatory genes in response to BCR stimulation

Inesa Thomsen, Natalia Kunowska, Roshni de Souza, Anne-Marie Moody, Greg Crawford, Yi-Fang Wang, Sanjay Khadayate, Jessica Strid, Mohammad M. Karimi, Alexis Barr, Niall Dillon, Pierangela Sabbattini
doi: https://doi.org/10.1101/2020.12.01.406744
Inesa Thomsen
1Gene Regulation and Chromatin Group, MRC London Institute of Medical Sciences, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK.
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Natalia Kunowska
1Gene Regulation and Chromatin Group, MRC London Institute of Medical Sciences, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK.
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Roshni de Souza
1Gene Regulation and Chromatin Group, MRC London Institute of Medical Sciences, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK.
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Anne-Marie Moody
1Gene Regulation and Chromatin Group, MRC London Institute of Medical Sciences, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK.
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Greg Crawford
2Department of Immunology and Inflammation, Imperial College London, Hammersmith Hospital Campus, Du Cane London W12 0NN, UK.
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Yi-Fang Wang
3Bioinformatics and Computing, MRC London Institute of Medical Sciences, Imperial College, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK.
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Sanjay Khadayate
3Bioinformatics and Computing, MRC London Institute of Medical Sciences, Imperial College, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK.
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Jessica Strid
2Department of Immunology and Inflammation, Imperial College London, Hammersmith Hospital Campus, Du Cane London W12 0NN, UK.
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Mohammad M. Karimi
3Bioinformatics and Computing, MRC London Institute of Medical Sciences, Imperial College, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK.
4Comprehensive Cancer Centre, School of Cancer & Pharmaceutical Sciences, Faculty of Life Sciences & Medicine, King’s College London, London SE5 8AF, UK
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Alexis Barr
5Cell Cycle Control Group, MRC London Institute of Medical Sciences, Imperial College, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK.
6Institute of Clinical Sciences, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK.
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Niall Dillon
1Gene Regulation and Chromatin Group, MRC London Institute of Medical Sciences, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK.
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  • For correspondence: niall.dillon@lms.mrc.ac.uk
Pierangela Sabbattini
1Gene Regulation and Chromatin Group, MRC London Institute of Medical Sciences, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK.
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ABSTRACT

RUNX1 is a transcription factor that plays key roles in haematopoietic development and in adult haematopoiesis and lymphopoiesis. Here we report that RUNX1 is also involved in controlling the dynamics of cell cycle entry of naïve resting B cells in response to stimulation of the B cell receptor (BCR). Conditional knockout of Runx1 in mouse resting B cells resulted in accelerated entry of the cells into S-phase following BCR engagement. Our results indicate that Runx1 regulates the cyclin D2 (Ccnd2) gene, the immediate early genes, Fosl2, Atf3 and Egr2, and the Notch effector Rbpj, in B cells, reducing the rate at which transcription of these genes increases following BCR stimulation. RUNX1 interacts with the chromatin remodeller SRCAP, recruiting it to promoter and enhancer regions of the Ccnd2 gene. BCR-mediated activation triggers switching between binding of RUNX1 and its paralog RUNX3 and between SRCAP and the SWI/SNF remodelling complex member BRG1. We also find that RUNX1 regulates expression of a number of immunomodulatory genes in resting B cells. These include the interferon receptor subunit gene Ifnar1, which is upregulated in B cells from lupus patients, the Ptpn22 gene, which has been identified as a major lupus risk allele, and the Lrrk2 gene, which is mutated in familial Parkinson’s disease. The hyperresponsiveness of the Runx1 knockout B cells to antigen stimulation and its role in regulating a suite of genes that are known to be associated with autoimmune disease suggest that RUNX1 is a major regulator of B cell tolerance and autoimmunity.

Competing Interest Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted December 02, 2020.
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RUNX1 controls the dynamics of cell cycle entry of naïve resting B cells by regulating expression of cell cycle and immunomodulatory genes in response to BCR stimulation
Inesa Thomsen, Natalia Kunowska, Roshni de Souza, Anne-Marie Moody, Greg Crawford, Yi-Fang Wang, Sanjay Khadayate, Jessica Strid, Mohammad M. Karimi, Alexis Barr, Niall Dillon, Pierangela Sabbattini
bioRxiv 2020.12.01.406744; doi: https://doi.org/10.1101/2020.12.01.406744
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RUNX1 controls the dynamics of cell cycle entry of naïve resting B cells by regulating expression of cell cycle and immunomodulatory genes in response to BCR stimulation
Inesa Thomsen, Natalia Kunowska, Roshni de Souza, Anne-Marie Moody, Greg Crawford, Yi-Fang Wang, Sanjay Khadayate, Jessica Strid, Mohammad M. Karimi, Alexis Barr, Niall Dillon, Pierangela Sabbattini
bioRxiv 2020.12.01.406744; doi: https://doi.org/10.1101/2020.12.01.406744

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