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

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Title: Selective deployment of transcription factor paralogs with submaximal strength facilitates gene regulation in the immune system
Authors: Bruno, L
Ramlall, V
Studer, RA
Sauer, S
Bradley, D
Dharmalingam, G
Carroll, T
Ghoneim, M
Chopin, M
Nutt, SL
Elderkin, S
Rueda, DS
Fisher, AG
Siggers, T
Beltrao, P
Merkenschlager, M
Item Type: Journal Article
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 non-equivalence 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 towards sub-maximal 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.
Issue Date: 26-Aug-2019
Date of Acceptance: 16-Jul-2019
URI: http://hdl.handle.net/10044/1/71508
ISSN: 1529-2908
Publisher: Nature Research
Journal / Book Title: Nature Immunology
Sponsor/Funder: Wellcome Trust
Medical Research Council (MRC)
Funder's Grant Number: 099276/Z/12/Z
PO4050659629
Keywords: 1107 Immunology
Immunology
Publication Status: Accepted
Embargo Date: 2020-02-26
Appears in Collections:Clinical Sciences
Molecular Sciences



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