Transcriptional repression and enhancer decommissioning silence cell cycle genes in postmitotic tissues.

IF 2.1 3区 生物学 Q3 GENETICS & HEREDITY
Elizabeth A Fogarty, Elli M Buchert, Yiqin Ma, Ava B Nicely, Laura A Buttitta
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Abstract

The mechanisms that maintain a non-cycling status in postmitotic tissues are not well understood. Many cell cycle genes have promoters and enhancers that remain accessible even when cells are terminally differentiated and in a non-cycling state, suggesting their repression must be maintained long term. In contrast, enhancer decommissioning has been observed for rate-limiting cell cycle genes in the Drosophila wing, a tissue where the cells die soon after eclosion, but it has been unclear if this also occurs in other contexts of terminal differentiation. In this study, we show that enhancer decommissioning also occurs at specific, rate-limiting cell cycle genes in the long-lived tissues of the Drosophila eye and brain, and we propose this loss of chromatin accessibility may help maintain a robust postmitotic state. We examined the decommissioned enhancers at specific rate-limiting cell cycle genes and showed that they encode for dynamic temporal and spatial expression patterns that include shared, as well as tissue-specific elements, resulting in broad gene expression with developmentally controlled temporal regulation. We extend our analysis to cell cycle gene expression and chromatin accessibility in the mammalian retina using a published dataset and find that the principles of cell cycle gene regulation identified in terminally differentiating Drosophila tissues are conserved in the differentiating mammalian retina. We propose a robust, non-cycling status is maintained in long-lived postmitotic tissues through a combination of stable repression at most cell cycle genes, alongside enhancer decommissioning at specific rate-limiting cell cycle genes.

转录抑制和增强子退役抑制了有丝分裂后组织中的细胞周期基因。
目前还不十分清楚有丝分裂后组织维持非周期性状态的机制。许多细胞周期基因的启动子和增强子即使在细胞末期分化并处于非周期性状态时仍可被利用,这表明它们的抑制作用必须长期保持。与此相反,在果蝇翅膀中观察到限速细胞周期基因的增强子退役,而果蝇翅膀组织的细胞在羽化后不久就会死亡,但这种情况是否也会发生在其他末期分化的环境中,目前还不清楚。在这项研究中,我们发现增强子退役也发生在果蝇眼和脑等长寿命组织中特定的限速细胞周期基因上,我们认为这种染色质可及性的丧失可能有助于维持稳健的有丝分裂后状态。我们研究了特定限速细胞周期基因的退役增强子,结果表明这些增强子编码动态的时间和空间表达模式,其中包括共享的以及组织特异性的元素,从而形成具有发育控制时间调节的广泛基因表达。我们利用已发表的数据集将分析扩展到哺乳动物视网膜的细胞周期基因表达和染色质可及性,发现在终末分化果蝇组织中发现的细胞周期基因调控原则在分化中的哺乳动物视网膜中是一致的。我们提出,在长寿命的有丝分裂后组织中,通过对大多数细胞周期基因的稳定抑制,以及对特定限速细胞周期基因的增强子退役,可以维持一种稳健的非周期性状态。
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来源期刊
G3: Genes|Genomes|Genetics
G3: Genes|Genomes|Genetics GENETICS & HEREDITY-
CiteScore
5.10
自引率
3.80%
发文量
305
审稿时长
3-8 weeks
期刊介绍: G3: Genes, Genomes, Genetics provides a forum for the publication of high‐quality foundational research, particularly research that generates useful genetic and genomic information such as genome maps, single gene studies, genome‐wide association and QTL studies, as well as genome reports, mutant screens, and advances in methods and technology. The Editorial Board of G3 believes that rapid dissemination of these data is the necessary foundation for analysis that leads to mechanistic insights. G3, published by the Genetics Society of America, meets the critical and growing need of the genetics community for rapid review and publication of important results in all areas of genetics. G3 offers the opportunity to publish the puzzling finding or to present unpublished results that may not have been submitted for review and publication due to a perceived lack of a potential high-impact finding. G3 has earned the DOAJ Seal, which is a mark of certification for open access journals, awarded by DOAJ to journals that achieve a high level of openness, adhere to Best Practice and high publishing standards.
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