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Histone tail analysis reveals H3K36me2 and H4K16ac as epigenetic signatures of diffuse intrinsic pontine glioma
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 t...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7687710/ https://www.ncbi.nlm.nih.gov/pubmed/33239043 http://dx.doi.org/10.1186/s13046-020-01773-x |
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author | An, Shejuan Camarillo, Jeannie M. Huang, Tina Yi-Ting Li, Daphne Morris, Juliette A. Zoltek, Madeline A. Qi, Jin Behbahani, Mandana Kambhampati, Madhuri Kelleher, Neil L. Nazarian, Javad Thomas, Paul M. Saratsis, Amanda M. |
author_facet | An, Shejuan Camarillo, Jeannie M. Huang, Tina Yi-Ting Li, Daphne Morris, Juliette A. Zoltek, Madeline A. Qi, Jin Behbahani, Mandana Kambhampati, Madhuri Kelleher, Neil L. Nazarian, Javad Thomas, Paul M. Saratsis, Amanda M. |
author_sort | An, Shejuan |
collection | PubMed |
description | 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13046-020-01773-x. |
format | Online Article Text |
id | pubmed-7687710 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-76877102020-11-30 Histone tail analysis reveals H3K36me2 and H4K16ac as epigenetic signatures of diffuse intrinsic pontine glioma An, Shejuan Camarillo, Jeannie M. Huang, Tina Yi-Ting Li, Daphne Morris, Juliette A. Zoltek, Madeline A. Qi, Jin Behbahani, Mandana Kambhampati, Madhuri Kelleher, Neil L. Nazarian, Javad Thomas, Paul M. Saratsis, Amanda M. J Exp Clin Cancer Res Research 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13046-020-01773-x. BioMed Central 2020-11-25 /pmc/articles/PMC7687710/ /pubmed/33239043 http://dx.doi.org/10.1186/s13046-020-01773-x Text en © The Author(s) 2020 Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Research An, Shejuan Camarillo, Jeannie M. Huang, Tina Yi-Ting Li, Daphne Morris, Juliette A. Zoltek, Madeline A. Qi, Jin Behbahani, Mandana Kambhampati, Madhuri Kelleher, Neil L. Nazarian, Javad Thomas, Paul M. Saratsis, Amanda M. Histone tail analysis reveals H3K36me2 and H4K16ac as epigenetic signatures of diffuse intrinsic pontine glioma |
title | Histone tail analysis reveals H3K36me2 and H4K16ac as epigenetic signatures of diffuse intrinsic pontine glioma |
title_full | Histone tail analysis reveals H3K36me2 and H4K16ac as epigenetic signatures of diffuse intrinsic pontine glioma |
title_fullStr | Histone tail analysis reveals H3K36me2 and H4K16ac as epigenetic signatures of diffuse intrinsic pontine glioma |
title_full_unstemmed | Histone tail analysis reveals H3K36me2 and H4K16ac as epigenetic signatures of diffuse intrinsic pontine glioma |
title_short | Histone tail analysis reveals H3K36me2 and H4K16ac as epigenetic signatures of diffuse intrinsic pontine glioma |
title_sort | histone tail analysis reveals h3k36me2 and h4k16ac as epigenetic signatures of diffuse intrinsic pontine glioma |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7687710/ https://www.ncbi.nlm.nih.gov/pubmed/33239043 http://dx.doi.org/10.1186/s13046-020-01773-x |
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