Histone tail analysis reveals H3K36me2 and H4K16ac as epigenetic signatures of diffuse intrinsic pontine glioma
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(2020) 39:261
RESEARCH
Open Access
Histone tail analysis reveals H3K36me2 and H4K16ac as epigenetic signatures of diffuse intrinsic pontine glioma Shejuan An1†, Jeannie M. Camarillo2†, Tina Yi-Ting Huang1, Daphne Li3, Juliette A. Morris2, Madeline A. Zoltek2, Jin Qi1, Mandana Behbahani4, Madhuri Kambhampati5, Neil L. Kelleher2,6, Javad Nazarian5,7,8, Paul M. Thomas2 and Amanda M. Saratsis1,6,9*
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 cooccurring 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. Keywords: DIPG, Histone, H3K27M, H3K36me2, H4K16ac
Background Pediatric high-grade glioma is the leading cause of cancer death in children [1]. Diffuse intrinsic pontine glioma (DIPG) is a high-grade glioma that arises in the brainstem, * Correspondence: [email protected] † Shejuan An and Jeannie M. Camarillo contributed equally to this work. 1 Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, USA 6 Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA Full list of author information is available at the end of the article
with an overall survival of only 11 months [2]. DIPG cannot be removed surgically, and there is no known effective treatment. Standard management is with radiotherapy, which temporarily relieves symptoms but only confers a survival benefit of three months [3]. Since DIPGs ultimately exhibit treatment resistance and disease progression, better understanding of tumor biology is desperately needed to identify effective therapeutic ther
