Selective deployment of transcription factor paralogs with submaximal strength facilitates gene regulation in the immune system
File(s)
Accepted version
Author(s)
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.
Date Issued
2019-08-26
Date Acceptance
2019-07-16
Citation
Nature Immunology, 2019, 20, pp.1372-1380
ISSN
1529-2908
Publisher
Nature Research
Start Page
1372
End Page
1380
Journal / Book Title
Nature Immunology
Volume
20
Copyright Statement
© 2019 Springer Nature Limited.
Sponsor
Wellcome Trust
Medical Research Council (MRC)
Identifier
https://www.nature.com/articles/s41590-019-0471-5
Grant Number
099276/Z/12/Z
PO4050659629
Subjects
Science & Technology
Life Sciences & Biomedicine
Immunology
RUNT DOMAIN
DUPLICATE GENES
BINDING SITES
EXPRESSION
AML1
MICROARRAYS
MECHANISMS
PROTEINS
COMPLEX
CELLS
Animals
Cell Differentiation
Cell Lineage
Conserved Sequence
Core Binding Factor alpha Subunits
Evolution, Molecular
Gene Duplication
Humans
Immune System
Langerhans Cells
Mammals
Organ Specificity
Signal Transduction
T-Lymphocytes, Regulatory
Transcriptome
Langerhans Cells
Immune System
Animals
Mammals
Humans
Evolution, Molecular
Signal Transduction
Cell Differentiation
Organ Specificity
Gene Duplication
Conserved Sequence
Cell Lineage
T-Lymphocytes, Regulatory
Core Binding Factor alpha Subunits
Transcriptome
1107 Immunology
Immunology
Publication Status
Published
Date Publish Online
2019-08-26