Regeneration-specific promoter switching facilitates Mest expression in the mouse digit tip to modulate neutrophil response.

IF 6.4 1区 医学 Q1 CELL & TISSUE ENGINEERING
Vivian Jou, Sophia M Peña, Jessica A Lehoczky
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引用次数: 0

Abstract

The mouse digit tip regenerates following amputation, a process mediated by a cellularly heterogeneous blastema. We previously found the gene Mest to be highly expressed in mesenchymal cells of the blastema and a strong candidate pro-regenerative gene. We now show Mest digit expression is regeneration-specific and not upregulated in post-amputation fibrosing proximal digits. Mest homozygous knockout mice exhibit delayed bone regeneration though no phenotype is found in paternal knockout mice, inconsistent with the defined maternal genomic imprinting of Mest. We demonstrate that promoter switching, not loss of imprinting, regulates biallelic Mest expression in the blastema and does not occur during embryogenesis, indicating a regeneration-specific mechanism. Requirement for Mest expression is tied to modulating neutrophil response, as revealed by scRNAseq and FACS comparing wildtype and knockout blastemas. Collectively, the imprinted gene Mest is required for proper digit tip regeneration and its blastema expression is facilitated by promoter switching for biallelic expression.

再生特异性启动子转换促进了小鼠指尖Mest的表达,从而调节中性粒细胞的反应。
小鼠的指尖在截肢后会再生,这一过程由细胞异质性的胚泡介导。我们之前发现,Mest 基因在囊泡的间充质细胞中高度表达,是一个强有力的候选促再生基因。现在,我们发现Mest基因在断肢后纤维化的近端指骨中表达是再生特异性的,而不是上调的。Mest同源基因敲除小鼠表现出骨再生延迟,但父系基因敲除小鼠未发现表型,这与Mest明确的母系基因组印记不一致。我们证明,启动子切换(而非印记缺失)可调控胚泡中双亲的 Mest 表达,且不会在胚胎发育过程中发生,这表明存在一种再生特异性机制。ScRNAseq 和 FACS 对野生型和基因敲除型胚泡的比较显示,Mest 的表达与中性粒细胞反应的调节有关。总之,印记基因 Mest 是正常指尖再生的必需基因,其胚泡表达可通过启动子切换实现双倍表达。
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来源期刊
npj Regenerative Medicine
npj Regenerative Medicine Engineering-Biomedical Engineering
CiteScore
10.00
自引率
1.40%
发文量
71
审稿时长
12 weeks
期刊介绍: Regenerative Medicine, an innovative online-only journal, aims to advance research in the field of repairing and regenerating damaged tissues and organs within the human body. As a part of the prestigious Nature Partner Journals series and in partnership with ARMI, this high-quality, open access journal serves as a platform for scientists to explore effective therapies that harness the body's natural regenerative capabilities. With a focus on understanding the fundamental mechanisms of tissue damage and regeneration, npj Regenerative Medicine actively encourages studies that bridge the gap between basic research and clinical tissue repair strategies.
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