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They found that dysregulation of these CRs results in structural abnormalities in chromatins and epigenetic alterations of numerous cancer-associated genes, which finally lead to increased tumor volume, extracapsular extension, and metastases in prostate cancer patients ( 8). have observed that CHD8 and CTCF (two chromatin remodelers) are up-regulated and down-regulated, respectively, in prostate tumor samples. In addition, a number of CRs have been found to be dysregulated in gene expression across cancer types. Moreover, patients with DNMT3A mutations have poor prognosis compared with those without such mutations ( 7). have found that genetic alteration of DNMT3A (a DNA methylation transferase) can induce genome-wide alterations of DNA methylation and gene expression. For example, it is widely accepted that mutations can perturb CR functions. An increasing number of studies have found that dysfunction of CRs can occur at different molecular levels. The alteration of epigenetic marks is a prevalent feature in cancer ( 6). Chromatin remodelers are a special type of CRs that can disrupt the contact between nucleosomes and DNA, shuffle nucleosomes around, replace them or remove them from the chromatin, and cause abnormal epigenetic modifications ( 1, 2, 5). Writers and erasers usually play roles in adding and removing certain modifications and from specific cytosine or histone residues, as in methylation and demethylation ( 1, 2, 5). Readers usually contain specific domains that can recognize specific cytosine or histone residues and determine the modification type and state ( 1, 2, 5).
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DNA methylators and histone modifiers can code and decode various modifications on cytosine and histone residues and are usually further divided into readers, writers, and erasers ( 4, 5). According to regulatory roles in epigenetics, CRs are usually grouped into three major categories: DNA methylators, histone modifiers, and chromatin remodelers ( 1–3). Chromatin regulators (CRs) are indispensable upstream regulatory factors of epigenetics. Our integrative analysis reveals specific determinants of CRs across cancer types and presents a resource for investigating disease-associated CRs.Įpigenetics, the study of stable, heritable traits that are not attributable to changes in the DNA sequence, has emerged as a means of elucidating critical regulation in cancer. Finally, we have made a user-friendly web interface-FACER (Functional Atlas of Chromatin Epigenetic Regulators) available for exploring clinically relevant CRs for the development of CR biomarkers and therapeutic targets. Common CRs tend to be histone modifiers and chromatin remodelers with fundamental roles, whereas specialized CRs are involved in context-dependent functions. In addition, we identified common and specific CRs by assessing their prevalence across cancer types. Comparative network analysis revealed principles of CR regulatory specificity and functionality. By integration of DNA mutation, genome-wide methylation, transcriptional/post-transcriptional regulation, and protein interaction networks with clinical outcomes, we identified CRs associated with cancer subtypes and clinical prognosis as potential oncogenic drivers. Here, we performed genome-wide analyses and constructed molecular signatures and network profiles of functional CRs in over 10 000 tumors across 33 cancer types.
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However, little is known about the extent of CR deregulation in cancer, and less is known about their common and specialized roles across various cancers. Epigenetic alterations, a well-recognized cancer hallmark, are driven by chromatin regulators (CRs).