不同类型衰老中血管平滑肌细胞组蛋白H3修饰、HP1 α水平和分布以及转录组的衰老相关改变

IF 8.2 2区 生物学 Q1 CELL BIOLOGY
Agnieszka Gadecka, Marta Koblowska, Helena Kossowska, Roksana Iwanicka-Nowicka, Dorota Janiszewska, Grażyna Mosieniak, Krzysztof Bojakowski, Krzysztof Goryca, Anna Bielak-Zmijewska
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引用次数: 0

摘要

背景:细胞衰老是导致机体衰老和年龄相关疾病的基本过程。伴随细胞衰老的变化涉及细胞核结构、染色质结构、DNA损伤和基因表达等。有些变化对所有类型的衰老都是普遍的,但有些特征对给定的衰老诱导剂或细胞类型是典型的。本研究的目的是分析体外血管平滑肌细胞(VSMCs)中染色质修饰的衰老相关改变,并寻找衰老类型(复制性、RS和应力诱导的过早衰老,SIPS)的差异。将这些改变与来自动脉粥样硬化斑块(离体)的VSMCs中观察到的变化进行比较,并评估其普遍性,与衰老成纤维细胞中的变化进行比较。方法:我们研究了作为异染色质和常染色质标记的HP1α和H3修饰的水平和分布(H3K9me3, H3K27me3, H3K4me3, H3K9me3, H3K9Ac - WB和IF),转录组学谱的改变(DNA芯片,qPCR),基因组中H3K4me3, H3K9me3和HP1α蛋白的分布(ChIP-seq),以及参与组蛋白翻译后修饰的酶的表达(DNA芯片,qPCR, WB, IF)。结果:我们的研究结果表明,H3K4me3和H3K9me3修饰和HP1α的下降是所有测试细胞和衰老类型的普遍标志,尽管变化的程度取决于衰老诱导剂。H3K4me3和H3K9me3在VSMCs基因组中的分布取决于衰老类型,转录组学分析确定了每种类型特有的基因和过程。结论:我们表征了衰老和细胞类型依赖性的染色质相关蛋白和酶的变化,这些蛋白和酶参与组蛋白H3修饰,从而影响衰老相关基因的表达。我们可以得出结论,某些类似的改变发生在离体衰老的VSMCs中,尽管个体间的差异通常使它们模糊不清。我们的结果清楚地表明,不仅年轻细胞和衰老细胞之间存在差异,而且SIPS细胞和RS细胞之间也存在差异。不同SIPS类型之间的细微差异表明,不同的应激源激活了相同的细胞机制。这项研究可以作为寻找可能用于区分SIPS和RS的因素的起点,这反过来可能有助于确定导致加速衰老的条件。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Senescence-associated alterations in histone H3 modifications, HP1 alpha levels and distribution, and in the transcriptome of vascular smooth muscle cells in different types of senescence.

Background: Cellular senescence is a fundamental process leading to organismal aging and age-related diseases. Alterations accompanying cellular senescence concern, among others, nucleus architecture, chromatin structure, DNA damage and gene expression. Some changes are universal for all types of senescence, but some characteristics are typical for a given senescence inductor or cell type. The aim of the study was to analyze senescence-associated alterations in chromatin modifications and look for differences depending on senescence type (replicative, RS and stress-induced premature senescence, SIPS) in vascular smooth muscle cells (VSMCs) in vitro. The alterations were compared with those observed in VSMCs derived from atherosclerotic plaques (ex vivo) and, to assess their universality, with those in senescent fibroblasts.

Methods: We investigated the level and distribution of HP1α and H3 modifications that are markers of hetero- and euchromatin (H3K9me3, H3K27me3, H3K4me3, H3K9Ac - WB and IF), alterations in the transcriptomic profile (DNA microarray, qPCR), H3K4me3, H3K9me3 and HP1α protein distribution in the genome (ChIP-seq), and expression of enzymes involved in histone post-translational modifications (DNA microarray, qPCR, WB, IF).

Results: Our results have shown that the decline in H3K4me3 and H3K9me3 modifications and in HP1α is a universal hallmark of senescence in all tested cell and senescence types, although the extent of the change depends on the senescence inductor. The distribution of H3K4me3 and H3K9me3 in the genome of VSMCs depends on the senescence type, and the transcriptomic analysis identified genes and processes specific to each type.

Conclusions: We characterized senescence and cell type-dependent changes in chromatin-associated proteins and enzymes involved in histone H3 decoration which, in consequence, impact senescence-associated gene expression. We can conclude that certain similar alterations occur in senescent VSMCs ex vivo, although inter-individual differences usually obscure them. Our results clearly showed that differences existed not only between young and senescent cells but also between SIPS and RS ones. The subtle differences between various SIPS types suggest that various stressors activate the same cellular mechanisms. This study can serve as a starting point to search for factors that may be used to distinguish between SIPS and RS, which in turn could be helpful in defining conditions responsible for accelerated aging.

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来源期刊
CiteScore
11.00
自引率
0.00%
发文量
180
期刊介绍: Cell Communication and Signaling (CCS) is a peer-reviewed, open-access scientific journal that focuses on cellular signaling pathways in both normal and pathological conditions. It publishes original research, reviews, and commentaries, welcoming studies that utilize molecular, morphological, biochemical, structural, and cell biology approaches. CCS also encourages interdisciplinary work and innovative models, including in silico, in vitro, and in vivo approaches, to facilitate investigations of cell signaling pathways, networks, and behavior. Starting from January 2019, CCS is proud to announce its affiliation with the International Cell Death Society. The journal now encourages submissions covering all aspects of cell death, including apoptotic and non-apoptotic mechanisms, cell death in model systems, autophagy, clearance of dying cells, and the immunological and pathological consequences of dying cells in the tissue microenvironment.
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