Abstract:BackgroundChronic lymphocytic leukemia (CLL) has been a good model system to understand the functional role of 5-methylcytosine (5-mC) in cancer progression. More recently, an oxidized form of 5-mC, 5-hydroxymethylcytosine (5-hmC) has gained lot of attention as a regulatory epigenetic modification with prognostic and diagnostic implications for several cancers. However, there is no global study exploring the role of 5-hydroxymethylcytosine (5-hmC) levels in CLL. Herein, using mass spectrometry and hMeDIP-seque… Show more
“…1 a). Consistent with previous studies, the average gene body profiles revealed a dip around the transcription start site (TSS) and transcription end site (TES) regions [ 30 ]. Fig.…”
Section: Resultssupporting
confidence: 89%
“…5-Hydroxymethylcytosine has been shown to be depleted in various human cancers and is known to be more concentrated in differentiated cells [ 23 , 27 ]. Stem cells, which are closest to the basal epithelial cells in HNSCCs, are known to have lower 5hmC levels, especially in the gene and enhancer regions required for differentiation [ 28 , 30 ]. For our purposes, those differentiation-specific regions would be epithelial and keratinocyte-specific genic and enhancer regions.…”
Background
Head and neck squamous cell carcinoma (HNSCC) is the sixth most prevalent cancer worldwide, with human papillomavirus (HPV)-related HNSCC rising to concerning levels. Extensive clinical, genetic and epigenetic differences exist between HPV-associated HNSCC and HPV-negative HNSCC, which is often linked to tobacco use. However, 5-hydroxymethylation (5hmC), an oxidative derivative of DNA methylation and its heterogeneity among HNSCC subtypes, has not been studied.
Results
We characterized genome-wide 5hmC profiles in HNSCC by HPV status and subtype in 18 HPV(+) and 18 HPV(−) well-characterized tumors. Results showed significant genome-wide hyper-5hmC in HPV(−) tumors, with both promoter and enhancer 5hmC able to distinguish meaningful tumor subgroups. We identified specific genes whose differential expression by HPV status is driven by differential hydroxymethylation. CDKN2A (p16), used as a key biomarker for HPV status, exhibited the most extensive hyper-5hmC in HPV(+) tumors, while HPV(−) tumors showed hyper-5hmC in CDH13, TIMP2, MMP2 and other cancer-related genes. Among the previously reported two HPV(+) subtypes, IMU (stronger immune response) and KRT (more keratinization), the IMU subtype revealed hyper-5hmC and up-regulation of genes in cell migration, and hypo-5hmC with down-regulation in keratinization and cell junctions. We experimentally validated our key prediction of higher secreted and intracellular protein levels of the invasion gene MMP2 in HPV(−) oral cavity cell lines.
Conclusion
Our results implicate 5hmC in driving differences in keratinization, cell junctions and other cancer-related processes among tumor subtypes. We conclude that 5hmC levels are critical for defining tumor characteristics and potentially used to define clinically meaningful cancer patient subgroups.
“…1 a). Consistent with previous studies, the average gene body profiles revealed a dip around the transcription start site (TSS) and transcription end site (TES) regions [ 30 ]. Fig.…”
Section: Resultssupporting
confidence: 89%
“…5-Hydroxymethylcytosine has been shown to be depleted in various human cancers and is known to be more concentrated in differentiated cells [ 23 , 27 ]. Stem cells, which are closest to the basal epithelial cells in HNSCCs, are known to have lower 5hmC levels, especially in the gene and enhancer regions required for differentiation [ 28 , 30 ]. For our purposes, those differentiation-specific regions would be epithelial and keratinocyte-specific genic and enhancer regions.…”
Background
Head and neck squamous cell carcinoma (HNSCC) is the sixth most prevalent cancer worldwide, with human papillomavirus (HPV)-related HNSCC rising to concerning levels. Extensive clinical, genetic and epigenetic differences exist between HPV-associated HNSCC and HPV-negative HNSCC, which is often linked to tobacco use. However, 5-hydroxymethylation (5hmC), an oxidative derivative of DNA methylation and its heterogeneity among HNSCC subtypes, has not been studied.
Results
We characterized genome-wide 5hmC profiles in HNSCC by HPV status and subtype in 18 HPV(+) and 18 HPV(−) well-characterized tumors. Results showed significant genome-wide hyper-5hmC in HPV(−) tumors, with both promoter and enhancer 5hmC able to distinguish meaningful tumor subgroups. We identified specific genes whose differential expression by HPV status is driven by differential hydroxymethylation. CDKN2A (p16), used as a key biomarker for HPV status, exhibited the most extensive hyper-5hmC in HPV(+) tumors, while HPV(−) tumors showed hyper-5hmC in CDH13, TIMP2, MMP2 and other cancer-related genes. Among the previously reported two HPV(+) subtypes, IMU (stronger immune response) and KRT (more keratinization), the IMU subtype revealed hyper-5hmC and up-regulation of genes in cell migration, and hypo-5hmC with down-regulation in keratinization and cell junctions. We experimentally validated our key prediction of higher secreted and intracellular protein levels of the invasion gene MMP2 in HPV(−) oral cavity cell lines.
Conclusion
Our results implicate 5hmC in driving differences in keratinization, cell junctions and other cancer-related processes among tumor subtypes. We conclude that 5hmC levels are critical for defining tumor characteristics and potentially used to define clinically meaningful cancer patient subgroups.
“…2.9 | Methylated DNA immunoprecipitation and hydroxymethylated DNA immunoprecipitation assays MEDIP and hMEDIP assays were performed as previously described. 19,20 The genomic DNA was extracted with a DNA extraction kit (TIANGEN, DP304), and ultrasound was used to break the DNA into DNA fragments about 200 to 600 bp in size. The 5hmC and 5mC DNA fragments were enriched using MEDIP kit (ActiveMotif, 55009) or hMEDIP kit (ActiveMotif, 55010), following the manufacturer's instruments.…”
Chemotherapy‐induced neuropathic pain is a common dose‐limiting side effect of cancer treatment but the underlying mechanisms are largely unknown. Here, we used a whole‐genome expression microarray and gene ontology analysis to identify the upregulation of a sequence‐specific DNA‐binding protein, HOXA6, in the spinal dorsal horn on Day 10 after injection of rats with oxaliplatin. Genetic disruption of HOXA6 with siRNAs alleviated mechanical allodynia after oxaliplatin administration. Reduced representation bisulfite sequencing assays indicated that oxaliplatin decreased the methylation levels of the SOX10 promoter but not of HOXA6. TET1 was also upregulated by oxaliplatin. Genetic disruption of TET1 with siRNA blocked the promoter demethylation of SOX10 and the upregulation of HOXA6 and SOX10. Importantly, inhibition of SOX10 by intrathecal application of SOX10 siRNA ameliorated the mechanical allodynia induced by oxaliplatin and downregulated the expression of HOXA6. Consistently, overexpression of SOX10 through intraspinal injection of AAV‐SOX10‐EGFP produced mechanical allodynia and upregulated the expression of spinal dorsal horn HOXA6. Moreover, chromatin immunoprecipitation assays demonstrated that oxaliplatin increased the binding of SOX10 to the promoter region of HOXA6. Taken together, our data suggest that HOXA6 upregulation through the TET1‐mediated promoter demethylation of SOX10 may contribute to oxaliplatin‐induced neuropathic pain.
“…Interestingly, several studies have associated 5-hmC with transcriptional activation mediated by enhancers, both in embryonic and differentiated cells [28,30]. Like DNA methylation, hydroxymethylation has also been observed to be deregulated in various human pathologies such as degenerative diseases like Parkinson's, Alhzeimer's, and different cancer types [31,36]. In the first thorough study exploring 5 hydroxymethylcytosine…”
Purpose of Review The development and progression of chronic lymphocytic leukemia (CLL), a highly heterogenous B cell malignancy, are influenced by both genetic and environmental factors. Environmental factors, including pharmacological interventions, can affect the epigenetic landscape of CLL and thereby determine the CLL phenotype, clonal evolution, and clinical outcome. In this review, we critically present the latest advances in the field of CLL epigenomics/epigenetics in order to provide a systematic overview of to-date achievements and highlight the potential of epigenomics approaches in light of novel treatment therapies. Recent Findings Recent technological advances have enabled broad and precise mapping of the CLL epigenome. The identification of CLL-specific DNA methylation patterns has allowed for accurate CLL subtype definition, a better understanding of clonal origin and evolution, and the discovery of reliable biomarkers. More recently, studies have started to unravel the prognostic, predictive, and therapeutic potential of mapping chromatin dynamics and histone modifications in CLL. Finally, analysis of non-coding RNA expression has indicated their contribution to disease pathogenesis and helped to define prognostic subsets in CLL. Summary Overall, the potential of CLL epigenomics for predicting treatment response and resistance is mounting, especially with the advent of novel targeted CLL therapies.
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