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Pygo-F773W 突变揭示了 Wnt 信号以外的新功能 。

Pygo-F773W Mutation Reveals Novel Functions beyond Wnt Signaling in .

机构信息

The Laboratory of Heart Development Research, College of Life Science, Hunan Normal University, Changsha 410081, China.

出版信息

Int J Mol Sci. 2024 May 30;25(11):5998. doi: 10.3390/ijms25115998.

DOI:10.3390/ijms25115998
PMID:38892188
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11172468/
Abstract

Pygopus (Pygo) has been identified as a specific nuclear co-activator of the canonical Wingless (Wg)/Wnt signaling pathway in . Pygo proteins consist of two conserved domains: an N-terminal homologous domain (NHD) and a C-terminal plant homologous domain (PHD). The PHD's ability to bind to di- and trimethylated lysine 4 of histone H3 (H3K4me2/3) appears to be independent of Wnt signaling. There is ongoing debate regarding the significance of Pygo's histone-binding capacity. Pygo orthologs have a tryptophan (W) > phenylalanine (F) substitution in their histone pocket-divider compared to vertebrates, leading to reduced histone affinity. In this research, we utilized CRISPR/Cas9 technology to introduce the Pygo-F773W point mutation in , successfully establishing a viable homozygous mutant line for the first time. Adult mutant flies displayed noticeable abnormalities in reproduction, locomotion, heart function, and lifespan. RNA-seq and cluster analysis indicated that the mutation primarily affected pathways related to immunity, metabolism, and posttranslational modification in adult flies rather than the Wnt signaling pathway. Additionally, a reduction in H3K9 acetylation levels during the embryonic stage was observed in the mutant strains. These findings support the notion that Pygo plays a wider role in chromatin remodeling, with its involvement in Wnt signaling representing only a specific aspect of its chromatin-related functions.

摘要

Pygopus（Pygo）已被确定为经典 Wingless（Wg）/Wnt 信号通路在果蝇中的特定核共激活因子。Pygo 蛋白由两个保守结构域组成：一个 N 端同源结构域（NHD）和一个 C 端植物同源结构域（PHD）。PHD 结合二甲基化和三甲基化组蛋白 H3 赖氨酸 4（H3K4me2/3）的能力似乎独立于 Wnt 信号。关于 Pygo 组蛋白结合能力的意义，目前仍存在争议。Pygo 同源物在其组蛋白结合口袋分隔物中的色氨酸（W）>苯丙氨酸（F）取代与脊椎动物相比，导致组蛋白亲和力降低。在这项研究中，我们利用 CRISPR/Cas9 技术在果蝇中引入了 Pygo-F773W 点突变，首次成功建立了一种可行的纯合突变系。成年突变果蝇在繁殖、运动、心脏功能和寿命方面表现出明显的异常。RNA-seq 和聚类分析表明，该突变主要影响成年果蝇中与免疫、代谢和翻译后修饰相关的途径，而不是 Wnt 信号通路。此外，在突变株中还观察到胚胎阶段 H3K9 乙酰化水平降低。这些发现支持这样一种观点，即 Pygo 在染色质重塑中发挥着更广泛的作用，其在 Wnt 信号通路中的作用仅代表其与染色质相关功能的特定方面。

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