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Evidence for a critical role of gene occlusion in cell fate restriction
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Evidence for a critical role of gene occlusion in cell fate restriction
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Journal Article
Evidence for a critical role of gene occlusion in cell fate restriction
2012
Overview
The progressive restriction of cell fate during lineage differentiation is a poorly understood phenomenon despite its ubiquity in multicellular organisms. We recently used a cell fusion assay to define a mode of epigenetic silencing that we termed ＂occlusion＂, wherein affected genes are silenced by cis-acting chromatin mechanisms irrespective of whether trans-acting transcriptional activators are present. We hypothesized that occlusion of lineage-inappropriate genes could contribute to cell fate restriction. Here, we test this hypothesis by introducing bacterial artificial chro- mosomes （BACs）, which are devoid of chromatin modifications necessary for occlusion, into mouse fibroblasts. We found that BAC transgenes corresponding to occluded endogenous genes are expressed in most cases, whereas BAC transgenes corresponding to silent but non-occluded endogenous genes are not expressed. This indicates that the cel- lular milieu in trans supports the expression of most occluded genes in fibroblasts, and that the silent state of these genes is solely the consequence of occlusion in cis. For the BAC corresponding to the occluded myogenic master regu- lator MyfS, expression of the Myf5 transgene on the BAC triggered fibroblasts to acquire a muscle-like phenotype. These results provide compelling evidence for a critical role of gene occlusion in cell fate restriction.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ BACS
/ Bacterial artificial chromosomes
/ Biomedical and Life Sciences
/ Chromosomes, Artificial, Bacterial - genetics
/ Chromosomes, Artificial, Bacterial - metabolism
/ Mice
/ Myogenic Regulatory Factor 5 - genetics
/ Myogenic Regulatory Factor 5 - metabolism
/ Original
/ 分化过程
/ 基因阻断
/ 多细胞
/ 成纤维细胞
/ 细菌人工染色体
/ 证据
/ 转基因表达
