Oncohistones: Exposing the nuances and vulnerabilities of epigenetic regulation

Mitchener, Michelle M.; Muir, Tom W.

doi:10.1016/j.molcel.2022.07.008

Cited by 25 publications

(24 citation statements)

References 131 publications

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“…H3C1 is a member of histone family ( 30 ). Missense mutations in histone related genes promote tumor progression, a process known as oncohistones, which is a major challenge for tumor treatment ( 31 , 32 ). Yi.H et al revealed for the first time that high expression of histone deacetylase 7 (HDAC7) was closely associated with poor in EC, suggesting that HDAC7 is a potential cancer-promoting agent ( 33 ).…”

Section: Discussionmentioning

confidence: 99%

Prognostic model construction and validation of esophageal cancer cellular senescence-related genes and correlation with immune infiltration

Zheng

Lin²,

Wu³

et al. 2023

Front. Surg.

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IntroductionCellular senescence is a cellular response to stress, including the activation of oncogenes, and is characterized by irreversible proliferation arrest. Restricted studies have provided a relationship between cellular senescence and immunotherapy for esophageal cancer.MethodsIn the present study, we obtained clinical sample of colon cancer from the TCGA database and cellular senescence-related genes from MSigDB and Genecard datasets. Cellular senescence-related prognostic genes were identified by WGCNA, COX, and lasso regression analysis, and a cellular senescence-related risk score (CSRS) was calculated. We constructed a prognostic model based on CSRS. Validation was performed with an independent cohort that GSE53625. Three scoring systems for immuno-infiltration analysis were performed, namely ssGSEA analysis, ESTIMATE scores and TIDE scores.ResultFive cellular senescence-related genes, including H3C1, IGFBP1, MT1E, SOX5 and CDHR4 and used to calculate risk score. Multivariate regression analysis using cox regression model showed that cellular senescence-related risk scores (HR=2.440, 95% CI=1.154-5.159, p=0.019) and pathological stage (HR=2.423, 95% CI=1.119-5.249, p=0.025) were associated with overall survival (OS). The nomogram model predicts better clinical benefit than the American Joint Committee on Cancer (AJCC) staging for prognosis of patients with esophageal cancer with a five-year AUC of 0.946. Patients with high CSRS had a poor prognosis (HR=2.93, 95%CI=1.74-4.94, p<0.001). We observed differences in the distribution of CSRS in different pathological staging and therefore performed a subgroup survival analysis finding that assessment of prognosis by CSRS independent of pathological staging. Comprehensive immune infiltration analysis and functional enrichment analysis suggested that patients with high CSRS may develop immunotherapy resistance through mechanisms of deacetylation and methylation.DiscussionIn summary, our study suggested that CSRS is a prognostic risk factor for esophageal cancer. Patients with high CSRS may have worse immunotherapy outcomes.

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Section: Discussionmentioning

confidence: 99%

Prognostic model construction and validation of esophageal cancer cellular senescence-related genes and correlation with immune infiltration

Zheng

Lin²,

Wu³

et al. 2023

Front. Surg.

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“…Since several of our cell lines are cancers derived from the lineages we analyze, it is also important to note that the differences in histone modification relationships we observe may relate to the dysregulation of epigenetic factors common to many cancers. [65][66][67] It appears that regardless of divergence of particular combinations of histone marks that are involved in compartment and lamin association status in a given cell type, the resulting spatial organization state produces consistent gene regulatory principles.…”

Section: Discussionmentioning

confidence: 99%

Differential contributions of nuclear lamina association and genome compartmentalization to gene regulation

Das

Martin

McCord

2022

Preprint

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Interactions of chromatin with the nuclear lamina play a significant role in properly organizing the genome in 3D space and in regulating gene expression. Genome wide studies have inferred the global association between the lamina, heterochromatin, gene repression and the B genomic compartment, and repositioning genes to the lamina can result in their repression. However, there are scenarios in which these features are discordant and, in those cases, the relative contribution to gene regulation of genomic compartment, chromatin, and lamin association status can be examined. Here we compared datasets from cell lines representing different states of differentiation across different cell type lineages to examine the relationships between changes in genomic compartmentalization, lamin association, and gene expression. With these data, we could examine, for example, what gene expression changes occur when a B compartment region is moved from the nuclear interior to the nuclear lamina and what differences exist between lamin associated and internal A compartment regions. In general, we observed an additive rather than redundant effect in which lamin association and compartment status both contribute to gene expression state. However, we found that cell type lineages differed in whether compartment status or lamin association had a dominant influence on gene expression. Finally, we identified conserved trends of how compartment and lamin association status influence the likelihood that gene expression will be induced or repressed in response to a physiochemical treatment.

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“…Unlike the above-mentioned strategies to capture the binding partners of a given epigenetic mark, this study converted a reader into a photoaffinity probe for the identification of proteins, both histone and nonhistone ones, whose Kac mark is recognized by the reader. Similar methods have also been applied to map the modification-dependent interactomes of several other epigenetic readers, including CBX1 (Chromobox protein 1), BPTF, BRD1, TAF1, and ATAD2B (ATPase Family AAA Domain Containing 2B). − In addition to interactions mediated by epigenetic marks, alterations in the epigenetic interactome induced by oncohistones, namely the somatic mutations of histones that drive oncogenesis and development of different types of tumors, have been attracting increasing attention in the field. , For example, the H3K27M and H3K36M mutations were found to inhibit the corresponding methyltransferases that deposit these two methylation marks. Photo-cross-linking-based assays showed that the replacement of lysine by methionine or other unnatural amino acids carrying hydrophobic side-chains could enhance the binding affinity between the methyltransferases and the corresponding histone peptides, and therefore block the enzyme activity. − As a result, the overall H3K27/36 methylation levels were decreased, leading to altered epigenetic landscapes driving oncogenesis.…”

Section: Discussionmentioning

confidence: 99%

“…176−180 In addition to interactions mediated by epigenetic marks, alterations in the epigenetic interactome induced by oncohistones, namely the somatic mutations of histones that drive oncogenesis and development of different types of tumors, have been attracting increasing attention in the field. 181,182 For example, the H3K27M and H3K36M mutations were found to inhibit the corresponding methyltransferases that deposit these two methylation marks. Photocross-linking-based assays showed that the replacement of lysine by methionine or other unnatural amino acids carrying hydrophobic side-chains could enhance the binding affinity between the methyltransferases and the corresponding histone peptides, and therefore block the enzyme activity.…”

Section: ■ Outlookmentioning

confidence: 99%

Photo-Cross-Linking To Delineate Epigenetic Interactome

et al. 2022

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Covalent modifications of DNA and histones are key cellular epigenetic marks to regulate gene functions. Most of these epigenetic marks are added or removed by corresponding enzymes known as writers and erasers, whose catalytic activities normally rely on the presence of cellular metabolites as cofactors. Epigenetic marks can either directly alter the chromatin structure and dynamics through changing the intra-/internucleosomal histone–histone and histone–DNA interactions or recruit readers that further bring in other proteins with chromatin-modifying/remodeling activities to reshape the local and regional chromatin organization. In these two ways, epigenetic modifications modulate diverse DNA-templated processes, such as gene transcription, DNA replication, and DNA damage repair. Therefore, elucidation of the regulatory mechanisms and biological significance of epigenetic marks requires the identification and characterization of the protein–protein, protein–nucleic acid, and protein–small molecule interactions that control the underlying epigenetic processes. Here, we review the recent advances in using photo-cross-linking strategies to interrogate the epigenetic interactome, focusing on the protein–protein interactions mediated by epigenetic marks in histone tails. We also discuss future directions of developing photo-cross-linking-based tools and methods toward the investigation of the binding events in nucleosomal/chromatinic contexts, and toward the in situ capture of the epigenetic interactome in live cells or even organisms.

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Oncohistones: Exposing the nuances and vulnerabilities of epigenetic regulation

Cited by 25 publications

References 131 publications

Prognostic model construction and validation of esophageal cancer cellular senescence-related genes and correlation with immune infiltration

Prognostic model construction and validation of esophageal cancer cellular senescence-related genes and correlation with immune infiltration

Differential contributions of nuclear lamina association and genome compartmentalization to gene regulation

Photo-Cross-Linking To Delineate Epigenetic Interactome

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