己糖激酶在表观遗传调控中的作用:酵母中己糖激酶表达和染色质稳定性的改变。

IF 4.2 2区 生物学 Q1 GENETICS & HEREDITY Epigenetics & Chromatin Pub Date : 2024-08-27 DOI:10.1186/s13072-024-00551-9
Srinivasu Karri, Quinn Dickinson, Jing Jia, Yi Yang, Haiyun Gan, Zhiquan Wang, Yibin Deng, Chuanhe Yu
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引用次数: 0

摘要

背景:人类己糖激酶 2(HK2)在调节沃伯格效应方面发挥着重要作用,即使在氧气充足的情况下,沃伯格效应也会将葡萄糖代谢为乳酸,并提供中间代谢产物以支持癌细胞增殖和肿瘤生长。在各种癌症中都观察到 HK2 的过表达,针对 HK2 驱动的沃伯格效应被认为是一种潜在的癌症治疗策略。鉴于表观遗传酶利用代谢中间产物作为底物或辅助因子对细胞中的组蛋白和核酸修饰进行翻译后修饰,我们假设改变 HK2 的表达可能会影响表观遗传组,进而影响酵母中染色质的稳定性。为了验证这一假设,我们在酿酒酵母细胞中建立了不同酵母己糖激酶2(HXK2)表达的遗传模型,并研究了HXK2依赖性代谢对亲代核小体转移(一个关键的DNA复制偶联表观遗传过程)和染色质稳定性的影响:通过比较单缺失hxk1Δ、hxk2Δ或双缺失hxk1Δ hxk2Δ的突变酵母细胞与野生型细胞的生长情况,我们首次证实了HXK2是酵母细胞生长中的优势HXK。令人惊讶的是,无论是通过过表达还是缺失,操纵 HXK2 在酵母中的表达对亲本核小体组装的影响微乎其微,但却有明显的染色质不稳定性下降趋势。然而,用2-脱氧-D-葡萄糖(2-DG)靶向酵母细胞会显著增加染色质的不稳定性:我们的研究结果表明,在缺乏 HXK2 的酵母细胞中,替代 HXKs(如 HXK1 或葡萄糖激酶 1 (GLK1))在支持糖酵解过程中发挥作用,从而充分维持表观基因组的稳定性。我们的研究表明,2-DG 处理会增加表观遗传的不稳定性,但观察到的效果似乎取决于 Hxk2 的非糖酵解功能。因此,还需要进行更多的研究,以确定 2-DG 影响染色质稳定性的分子机制。
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The role of hexokinases in epigenetic regulation: altered hexokinase expression and chromatin stability in yeast.

Background: Human hexokinase 2 (HK2) plays an important role in regulating Warburg effect, which metabolizes glucose to lactate acid even in the presence of ample oxygen and provides intermediate metabolites to support cancer cell proliferation and tumor growth. HK2 overexpression has been observed in various types of cancers and targeting HK2-driven Warburg effect has been suggested as a potential cancer therapeutic strategy. Given that epigenetic enzymes utilize metabolic intermediates as substrates or co-factors to carry out post-translational modification of histones and nucleic acids modifications in cells, we hypothesized that altering HK2 expression could impact the epigenome and, consequently, chromatin stability in yeast. To test this hypothesis, we established genetic models with different yeast hexokinase 2 (HXK2) expression in Saccharomyces cerevisiae yeast cells and investigated the effect of HXK2-dependent metabolism on parental nucleosome transfer, a key DNA replication-coupled epigenetic inheritance process, and chromatin stability.

Results: By comparing the growth of mutant yeast cells carrying single deletion of hxk1Δ, hxk2Δ, or double-loss of hxk1Δ hxk2Δ to wild-type cells, we firstly confirmed that HXK2 is the dominant HXK in yeast cell growth. Surprisingly, manipulating HXK2 expression in yeast, whether through overexpression or deletion, had only a marginal impact on parental nucleosome assembly, but a noticeable trend with decrease chromatin instability. However, targeting yeast cells with 2-deoxy-D-glucose (2-DG), a clinical glycolysis inhibitor that has been proposed as an anti-cancer treatment, significantly increased chromatin instability.

Conclusion: Our findings suggest that in yeast cells lacking HXK2, alternative HXKs such as HXK1 or glucokinase 1 (GLK1) play a role in supporting glycolysis at a level that adequately maintains epigenomic stability. While our study demonstrated an increase in epigenetic instability with 2-DG treatment, the observed effect seemed to occur dependent on non-glycolytic function of Hxk2. Thus, additional research is needed to identify the molecular mechanism through which 2-DG influences chromatin stability.

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来源期刊
Epigenetics & Chromatin
Epigenetics & Chromatin GENETICS & HEREDITY-
CiteScore
7.00
自引率
0.00%
发文量
35
审稿时长
1 months
期刊介绍: Epigenetics & Chromatin is a peer-reviewed, open access, online journal that publishes research, and reviews, providing novel insights into epigenetic inheritance and chromatin-based interactions. The journal aims to understand how gene and chromosomal elements are regulated and their activities maintained during processes such as cell division, differentiation and environmental alteration.
期刊最新文献
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