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Nat Immunol. 2019 Oct;20(10):1372-1380. doi: 10.1038/s41590-019-0471-5. Epub 2019 Aug 26.

Selective deployment of transcription factor paralogs with submaximal strength facilitates gene regulation in the immune system.

Author information

1
Lymphocyte Development Group, MRC London Institute for Medical Sciences, London, UK.
2
Department of Biology, Boston University, Boston, MA, USA.
3
European Molecular Biology Laboratory (EMBL), European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK.
4
BenevolentAI, London, UK.
5
MRC London Institute for Medical Sciences, London, UK.
6
Molecular Virology, Department of Medicine, Imperial College London, London, UK.
7
Single Molecule Imaging Group, MRC London Institute of Medical Sciences, London, UK.
8
The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
9
Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia.
10
Nuclear Dynamics Programme, The Babraham Institute, Cambridge, UK.
11
Lymphocyte Development Group, MRC London Institute for Medical Sciences, London, UK. matthias.merkenschlager@lms.mrc.ac.uk.

Abstract

In multicellular organisms, duplicated genes can diverge through tissue-specific gene expression patterns, as exemplified by highly regulated expression of RUNX transcription factor paralogs with apparent functional redundancy. Here we asked what cell-type-specific biologies might be supported by the selective expression of RUNX paralogs during Langerhans cell and inducible regulatory T cell differentiation. We uncovered functional nonequivalence between RUNX paralogs. Selective expression of native paralogs allowed integration of transcription factor activity with extrinsic signals, while non-native paralogs enforced differentiation even in the absence of exogenous inducers. DNA binding affinity was controlled by divergent amino acids within the otherwise highly conserved RUNT domain and evolutionary reconstruction suggested convergence of RUNT domain residues toward submaximal strength. Hence, the selective expression of gene duplicates in specialized cell types can synergize with the acquisition of functional differences to enable appropriate gene expression, lineage choice and differentiation in the mammalian immune system.

PMID:
31451789
PMCID:
PMC6754753
[Available on 2020-02-26]
DOI:
10.1038/s41590-019-0471-5

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