Abstract
Whole-exome and whole-genome sequencing have revealed millions of somatic mutations associated with different human cancers, and the vast majority of them are located outside of coding sequences, making it challenging to directly interpret their functional effects. With the rapid advances in high-throughput sequencing technologies, genome-scale long-range chromatin interactions were detected, and distal target genes of regulatory elements were determined using three-dimensional (3D) chromatin looping. Herein, we present OncoBase (http://www.oncobase.biols.ac.cn/), an integrated database for annotating 81 385 242 somatic mutations in 68 cancer types from more than 120 cancer projects by exploring their roles in distal interactions between target genes and regulatory elements. OncoBase integrates local chromatin signatures, 3D chromatin interactions in different cell types and reconstruction of enhancer-target networks using state-of-the-art algorithms. It employs informative visualization tools to display the integrated local and 3D chromatin signatures and effects of somatic mutations on regulatory elements. Enhancer-promoter interactions estimated from chromatin interactions are integrated into a network diffusion system that quantitatively prioritizes somatic mutations and target genes from a large pool. Thus, OncoBase is a useful resource for the functional annotation of regulatory noncoding regions and systematically benchmarking the regulatory effects of embedded noncoding somatic mutations in human carcinogenesis.
Highlights
Noncoding variants are capable of causing common diseases and account for the vast majority of heritability [1]
Mapping variants to the whole genome indicate that disease-associated single nucleotide polymorphisms (SNPs) are strongly enriched in regulatory elements, especially those activated in relevant cell types [6]
The noncoding regions possess many functional elements based on one dimensional (1D) epigenomic features and three-dimensional (3D) spatial long-range interactions that could help to build accurate enhancer-promoter regulatory pairs; integrating noncoding variants with 1D coordinated epigenetic profiles and 3D long-range interactions in specific tissue/cell types will provide a promising direction to finemap causal regulatory variants and understand underlying regulatory mechanisms in human diseases
Summary
Noncoding variants are capable of causing common diseases and account for the vast majority of heritability [1]. The rapid development of chromosome conformation capture (3C)-based technologies, such as ChIA-PET [32,33], 5C [34] and Hi-C [35,36,37], has provided increased datasets on the 3D architecture of the human genome Studies based on these technologies have uncovered models on how regulatory elements regulate the expression of distal target genes [36,38,39]. OncoBase provides a series of informative tables, publishable figures and a network diffusion scoring system to help researchers discover the regulatory roles of noncoding somatic mutations in human cancers based on their 1D and 3D genomic features
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