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组蛋白尾部分析显示 H3K36me2 和 H4K16ac 是弥漫性内在脑桥胶质瘤的表观遗传特征。

Histone tail analysis reveals H3K36me2 and H4K16ac as epigenetic signatures of diffuse intrinsic pontine glioma.

机构信息

Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.

Department of Chemistry, Molecular Biosciences and Proteomics Center of Excellence, Northwestern University, Evanston, IL, 60208, USA.

出版信息

J Exp Clin Cancer Res. 2020 Nov 25;39(1):261. doi: 10.1186/s13046-020-01773-x.

DOI:10.1186/s13046-020-01773-x
PMID:33239043
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7687710/
Abstract

BACKGROUND

Diffuse intrinsic pontine glioma (DIPG) is an aggressive pediatric brainstem tumor. Most DIPGs harbor a histone H3 mutation, which alters histone post-translational modification (PTM) states and transcription. Here, we employed quantitative proteomic analysis to elucidate the impact of the H3.3K27M mutation, as well as radiation and bromodomain inhibition (BRDi) with JQ1, on DIPG PTM profiles.

METHODS

We performed targeted mass spectrometry on H3.3K27M mutant and wild-type tissues (n = 12) and cell lines (n = 7).

RESULTS

We found 29.2 and 26.4% of total H3.3K27 peptides were H3.3K27M in mutant DIPG tumor cell lines and tissue specimens, respectively. Significant differences in modification states were observed in H3.3K27M specimens, including at H3K27, H3K36, and H4K16. In addition, H3.3K27me1 and H4K16ac were the most significantly distinct modifications in H3.3K27M mutant tumors, relative to wild-type. Further, H3.3K36me2 was the most abundant co-occurring modification on the H3.3K27M mutant peptide in DIPG tissue, while H4K16ac was the most acetylated residue. Radiation treatment caused changes in PTM abundance in vitro, including increased H3K9me3. JQ1 treatment resulted in increased mono- and di-methylation of H3.1K27, H3.3K27, H3.3K36 and H4K20 in vitro.

CONCLUSION

Taken together, our findings provide insight into the effects of the H3K27M mutation on histone modification states and response to treatment, and suggest that H3K36me2 and H4K16ac may represent unique tumor epigenetic signatures for targeted DIPG therapy.

摘要

背景

弥漫性内在脑桥神经胶质瘤（DIPG）是一种侵袭性的儿童脑干肿瘤。大多数 DIPG 存在组蛋白 H3 突变，这会改变组蛋白的翻译后修饰（PTM）状态和转录。在这里，我们采用定量蛋白质组学分析来阐明 H3.3K27M 突变以及辐射和溴结构域抑制（BRDi）与 JQ1 对 DIPG PTM 谱的影响。

方法

我们对 H3.3K27M 突变体和野生型组织（n=12）和细胞系（n=7）进行了靶向质谱分析。

结果

我们发现突变型 DIPG 肿瘤细胞系和组织标本中总 H3.3K27 肽的 29.2%和 26.4%为 H3.3K27M。在 H3.3K27M 标本中观察到修饰状态的显著差异，包括 H3K27、H3K36 和 H4K16。此外，与野生型相比，H3.3K27me1 和 H4K16ac 是 H3.3K27M 突变肿瘤中最显著不同的修饰。此外，H3.3K36me2 是 DIPG 组织中 H3.3K27M 突变肽上最丰富的共发生修饰，而 H4K16ac 是最乙酰化的残基。辐射处理导致体外 PTM 丰度发生变化，包括 H3K9me3 增加。JQ1 处理导致体外 H3.1K27、H3.3K27、H3.3K36 和 H4K20 的单甲基化和二甲基化增加。

结论

综上所述，我们的研究结果提供了对 H3K27M 突变对组蛋白修饰状态和治疗反应的影响的深入了解，并表明 H3K36me2 和 H4K16ac 可能代表针对 DIPG 治疗的独特肿瘤表观遗传特征。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0e85/7687710/ae4aadae7271/13046_2020_1773_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0e85/7687710/72aa1b60d066/13046_2020_1773_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0e85/7687710/a0cb2fced482/13046_2020_1773_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0e85/7687710/cce7477fe364/13046_2020_1773_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0e85/7687710/3b59246d33a9/13046_2020_1773_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0e85/7687710/0a1b8ac28037/13046_2020_1773_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0e85/7687710/ae4aadae7271/13046_2020_1773_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0e85/7687710/72aa1b60d066/13046_2020_1773_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0e85/7687710/a0cb2fced482/13046_2020_1773_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0e85/7687710/cce7477fe364/13046_2020_1773_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0e85/7687710/3b59246d33a9/13046_2020_1773_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0e85/7687710/0a1b8ac28037/13046_2020_1773_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0e85/7687710/ae4aadae7271/13046_2020_1773_Fig6_HTML.jpg

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