Abstract
An important unanswered question in chromatin biology is the extent to which long-range looping interactions change across developmental models, genetic perturbations, drug treatments, and disease states. Computational tools for rigorous assessment of cell type-specific loops across multiple biological conditions are needed. We present 3DeFDR, a simple and effective statistical tool for classifying dynamic loops across biological conditions from Chromosome-Conformation-Capture-Carbon-Copy (5C) and Hi-C data. Our work provides a statistical framework and open-source coding libraries for sensitive detection of cell type-specific loops in high-resolution 5C and Hi-C data from multiple cellular conditions.
Highlights
Chromosome-Conformation-Capture (3C)-based molecular techniques have recently been coupled with high-throughput sequencing to generate genome-wide maps of higher-order chromatin folding [1,2,3]
We set out to address a critical challenge in the analysis of looping interactions in 5C data: the paucity of methods for robustly classifying dynamic loops across multiple cellular conditions, a problem which becomes more challenging as the number of conditions increases
We developed, applied, and benchmarked 3DeFDR-5C using 5C data across three distinct cellular states: mouse embryonic stem (ES) cells cultured in 2i media representing a naive pluripotent state, mouse ES cells cultured in LIF/serum representing the primed pluripotency state, and primary neural progenitors isolated from neonatal mice representing a multipotent adult stem cell state in the neuroectoderm lineage (Additional file 1: Table S1) [32]
Summary
Chromosome-Conformation-Capture (3C)-based molecular techniques have recently been coupled with high-throughput sequencing to generate genome-wide maps of higher-order chromatin folding [1,2,3]. A number of massively parallel 3C-based technologies query genome folding in a protein-independent manner, including Hi-C, 4C, 5C, and Capture-C [4,5,6,7,8,9,10]. The two fragments in a given ligation junction can be identified using high-throughput sequencing, and their frequency of ligation is proportional to their spatial proximity across a population of cells. The protein-independent 3C technologies of Hi-C, 5C, and Capture-C can be used to create high-resolution spatial maps of genome folding on the scale of a few megabases to genome-wide coverage
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