Breaking Boundaries in Histone Modification MS-Based Detection: A Tailored Search Strategy for Unrestricted Identification of Novel Epigenetic Marks

Histone post-translational modifications (PTMs) play a crucial role in regulating gene expression and maintaining DNA integrity, and their aberrations are linked to various diseases, including cancer. While lysine acetylation and methylation have been extensively studied, recent research has uncover...

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Vydané v:Molecular & cellular proteomics Ročník 24; číslo 11; s. 101080
Hlavní autori: Vai, Alessandro, Noberini, Roberta, Graziadei, Andrea, Polasky, Daniel A., Yu, Fengchao, Nesvizhskii, Alexey I., Bonaldi, Tiziana
Médium: Journal Article
Jazyk:English
Vydavateľské údaje: United States Elsevier Inc 01.11.2025
Predmet:
bioinformatics workflow
epigenetics
histone PTM discovery
mass spectrometry
post-translational modifications
pr
OS
MS
DMO
PTM
K
PIC
PSM
PRO
epigenetics
bioinformatics workflow
HiP-Frag
R
FDR
LC
mass spectrometry
me3
post-translational modifications
FA
DIA
histone PTM discovery
AGE
ISSN:1535-9476, 1535-9484, 1535-9484
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Shrnutí:Histone post-translational modifications (PTMs) play a crucial role in regulating gene expression and maintaining DNA integrity, and their aberrations are linked to various diseases, including cancer. While lysine acetylation and methylation have been extensively studied, recent research has uncovered additional PTMs that significantly contribute to chromatin structure and function. Mass spectrometry is the most effective analytical method for studying histone PTMs; however, computational limitations often restrict the analysis to common modifications. Unrestrictive search strategies have the potential to enable a more comprehensive characterization of the histone modification landscape. In this work, we systematically assess the application of unrestrictive search approaches to histone data. After evaluating the limitations of these methods, we develop a novel bioinformatics workflow, named HiP-Frag (histone PTM analysis with FragPipe), which enables the identification of 96 sites decorated with uncommon PTMs on core histones—60 of which were previously unreported—as well as 55 histone marks on linker histones, including 13 novel ones, purified from human cell lines and primary samples. The expanded histone PTM analysis enabled by this strategy is among the first to extract previously unexplored epigenetic information from mass spectrometry raw data. This approach paves the way for a facilitated and more streamlined identification of uncommon and yet unannotated histone modifications, supporting a deeper dissection of the histone code and the understanding of the potential biological role of the novel epigenetic marks. [Display omitted] •Novel histone post-translational modifications (PTMs) have emerged as regulators of chromatin structure.•Histone PTM analysis with FragPipe (HiP-Frag) is a workflow integrating closed, open, and detailed mass offset searches.•HiP-Frag simplifies the discovery of novel histone modifications.•HiP-Frag identified 60 novel PTMs on core histones and 13 on linker histones. This study introduces and describes HiP-Frag, a bioinformatics workflow that exploits unrestrictive search strategies to expand the analysis of histone post-translational modifications (PTMs) to unknown ones, from mass spectrometry data. By expanding the catalog of histone PTMs with 60 marks on core histones and 13 on linker histones, HiP-Frag enables a more comprehensive investigation of the histone code, giving access to previously unexplored epigenetic information.
Bibliografia:ObjectType-Article-1
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ISSN:1535-9476
1535-9484
1535-9484
DOI:10.1016/j.mcpro.2025.101080