miR‐191 modulates B‐cell development and targets transcription factors E2A, Foxp1, and Egr1

The interdependence of posttranscriptional gene regulation via miRNA and transcriptional regulatory networks in lymphocyte development is poorly understood. Here, we identified miR‐191 as direct upstream modulator of a transcriptional module comprising the transcription factors Foxp1, E2A, and Egr1....

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Published in:European journal of immunology 2019-01, Vol.49 (1), p.121-132
Main Authors: Blume, Jonas, Ziętara, Natalia, Witzlau, Katrin, Liu, Yanshan, Sanchez, Oskar Ortiz, Puchałka, Jacek, Winter, Samantha J., Kunze‐Schumacher, Heike, Saran, Namita, Düber, Sandra, Roy, Bishnudeo, Weiss, Siegfried, Klein, Christoph, Wurst, Wolfgang, Łyszkiewicz, Marcin, Krueger, Andreas
Format: Article
Language:English
Subjects:
B cells
Clonal deletion
Ectopic expression
EGR-1 protein
Foxp1 protein
Gene regulation
Lymphocyte development
Lymphocytes B
miRNA
miR‐191
Post-transcription
Recombination
Transcription factors
Transcriptional factors
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Summary:The interdependence of posttranscriptional gene regulation via miRNA and transcriptional regulatory networks in lymphocyte development is poorly understood. Here, we identified miR‐191 as direct upstream modulator of a transcriptional module comprising the transcription factors Foxp1, E2A, and Egr1. Deletion as well as ectopic expression of miR‐191 resulted in developmental arrest in B lineage cells, indicating that fine tuning of the combined expression levels of Foxp1, E2A, and Egr1, which in turn control somatic recombination and cytokine‐driven expansion, constitutes a prerequisite for efficient B‐cell development. In conclusion, we propose that miR‐191 acts as a rheostat in B‐cell development by fine tuning a key transcriptional program. Through CRISPR/Cas9‐mediated deletion and retrogenic overexpression of miR‐191, we demonstrate that a defined window of expression of this miRNA is required to allow for efficient B‐cell development beyond the proB/preBI stage. Furthermore, we suggest that control of B‐cell development by miR‐191 is mediated through its targets Foxp1, E2A, and/or Egr1.
ISSN:0014-2980
1521-4141
DOI:10.1002/eji.201847660