Repurposing of the enhancer-promoter communication underlies the compensation of Mesp2 by Mesp1

Organisms are inherently equipped with buffering systems against genetic perturbations. Genetic compensation, the compensatory response by upregulating another gene or genes, is one such buffering mechanism. Recently, a well-conserved compensatory mechanism was proposed: transcriptional adaptation o...

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Bibliographic Details
Published in:PLoS genetics 2022-01, Vol.18 (1), p.e1010000-e1010000
Main Authors: Okada, Hajime, Saga, Yumiko
Format: Article
Language:English
Subjects:
Animals
Artificial chromosomes
Basic Helix-Loop-Helix Transcription Factors - genetics
Biology and Life Sciences
Cells, Cultured
Computer and Information Sciences
Dosage Compensation, Genetic
Enhancer Elements, Genetic
Gene expression
Gene Expression Regulation, Developmental
Genetic aspects
Mesoderm
Mice
Microbial colonies
mRNA turnover
Mutation
Nonsense Mediated mRNA Decay
Promoter Regions, Genetic
Proteins
Somites - cytology
Somites - metabolism
Transcription factors
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Summary:Organisms are inherently equipped with buffering systems against genetic perturbations. Genetic compensation, the compensatory response by upregulating another gene or genes, is one such buffering mechanism. Recently, a well-conserved compensatory mechanism was proposed: transcriptional adaptation of homologs under the nonsense-mediated mRNA decay pathways. However, this model cannot explain the onset of all compensatory events. We report a novel genetic compensation mechanism operating over the Mesp gene locus. Mesp1 and Mesp2 are paralogs located adjacently in the genome. Mesp2 loss is partially rescued by Mesp1 upregulation in the presomitic mesoderm (PSM). Using a cultured PSM induction system, we reproduced the compensatory response in vitro and found that the Mesp2-enhancer is required to promote Mesp1. We revealed that the Mesp2-enhancer directly interacts with the Mesp1 promoter, thereby upregulating Mesp1 expression upon the loss of Mesp2. Of note, this interaction is established by genomic arrangement upon PSM development independently of Mesp2 disruption. We propose that the repurposing of this established enhancer-promoter communication is the mechanism underlying this compensatory response for the upregulation of the adjacent gene.
ISSN:1553-7404
1553-7390
1553-7404
DOI:10.1371/journal.pgen.1010000