Abstract
In specific cases, chromatin clearly forms long-range loops that place distant regulatory elements in close proximity to transcription start sites, but we have limited understanding of many loops identified by Chromosome Conformation Capture (such as Hi-C) analyses. In efforts to elucidate their characteristics and functions, we have identified highly interacting regions (HIRs) using intra-chromosomal Hi-C datasets with a new computational method based on looking at the eigenvector that corresponds to the smallest eigenvalue (here unity). Analysis of these regions using ENCODE data shows that they are in general enriched in bound factors involved in DNA damage repair and have actively transcribed genes. However, both highly transcribed regions as well as transcriptionally inactive regions can form HIRs. The results also indicate that enhancers and super-enhancers in particular form long-range interactions within the same chromosome. The accumulation of DNA repair factors in most identified HIRs suggests that protection from DNA damage in these regions is essential for avoidance of detrimental rearrangements.
Highlights
The chromatin in eukaryotic cells is not randomly organized, as various domains have been shown to occupy distinct ‘territories’ within the nucleus[1,2,3,4]
We developed a new method to transform two-dimensional Hi-C contact maps into one-dimensional profiles. This method differs from topological associated domains (TADs) and A/B-finding techniques involving the construction of correlation matrices finding clusters with Principal Component Analysis (PCA)[25]
We find that predicted enhancers and super-enhancers are potentially involved in long-range interactions and interestingly that most genomic regions with a high number of contacts are bound by DNA damage repair factors
Summary
The chromatin in eukaryotic cells is not randomly organized, as various domains have been shown to occupy distinct ‘territories’ within the nucleus[1,2,3,4]. Visualization of chromosome conformation data as heat maps has revealed that the genome is partitioned into 3D compartments, inter alia topological associated domains (TADs) and A/B compartments[8,9,10] Loci located within such domains tend to interact highly with each other and TADs’ boundaries are reportedly enriched in insulators and highly expressed genes[8,9,11,12,13]. Our method involves direct use of Hi-C data (after a simple element-wise manipulation), and extraction of the eigenvector for the smallest eigenvalue (here, unity), where the values are proportional to the interactivity (or number of contacts) for a particular genomic region Using this method, we find that in line with previous observations some regions cluster by functions such as active transcription and Polycomb repression. We find that predicted enhancers and super-enhancers are potentially involved in long-range interactions and interestingly that most genomic regions with a high number of contacts are bound by DNA damage repair factors
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