Abstract
Muscle-invasive bladder cancer (MIBC) is a heterogeneous disease that often recurs despite aggressive treatment with neoadjuvant chemotherapy and (radical) cystectomy. Basal and luminal molecular subtypes have been identified that are linked to clinical characteristics and have differential sensitivities to chemotherapy. While it has been suggested that epigenetic mechanisms play a role in defining these subtypes, a thorough understanding of the biological mechanisms is lacking. This report details the first genome-wide analysis of histone methylation patterns of human primary bladder tumours by chromatin immunoprecipitations and next-generation sequencing (ChIP-seq). We profiled multiple histone marks: H3K27me3, a marker for repressed genes, and H3K4me1 and H3K4me3, which are indicators of active enhancers and active promoters. Integrated analysis of ChIP-seq data and RNA sequencing revealed that H3K4 mono-methylation demarcates MIBC subtypes, while no association was found for the other two histone modifications in relation to basal and luminal subtypes. Additionally, we identified differentially methylated H3K4me1 peaks in basal and luminal tumour samples, suggesting that active enhancers play a role in defining subtypes. Our study is the first analysis of histone modifications in primary bladder cancer tissue and provides an important resource for the bladder cancer community.
Highlights
Muscle-invasive bladder cancer (MIBC) is a heterogeneous disease that often recurs despite aggressive treatment with neoadjuvant chemotherapy and cystectomy
To investigate whether pathological features were associated with genome-wide changes in methylation marks at enhancers and promoters, we performed Chromatin immunoprecipitations (ChIP)-seq analyses using antibodies directed against multiple histone modifications
We analysed the mono-methylation of lysine 4 on histone 3 (H3K4me[1]; active enhancers), tri-methylation of lysine 4 on histone 3 (H3K4me[3]; active promoters) and the repressive mark, tri-methylation lysine 27 of histone 3 (H3K27me3)
Summary
Muscle-invasive bladder cancer (MIBC) is a heterogeneous disease that often recurs despite aggressive treatment with neoadjuvant chemotherapy and (radical) cystectomy. A collaborative effort combined transcriptome profiles from multiple cohorts and produced a consensus scheme with six molecular subtypes: luminal papillary, luminal nonspecified, luminal unstable, stroma-rich, basal/squamous, and neuroendocrine-like[12] These subtypes are characterized by differences in mutational profile, differentiation markers, infiltrating stromal and immune cells, and clinical outcome. These molecular subtypes appear to have differential sensitivities to neoadjuvant chemotherapy (NAC)[10,13] and checkpoint inhibitors[14,15], though prospective validation is still needed. We provide a detailed overview of three histone methylation marks that gives insight into the epigenetic differences between MIBC subtypes This unique data-set of genome-wide ChIP-seq data of histone methylation marks in primary bladder tumours will serve as a valuable new resource for the bladder cancer community
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