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Analysis method for chromatin topological domain boundaries

A topology and chromatin technology, applied in the field of chromatin structure analysis, can solve the problems of low accuracy, high computational complexity, and unsuitable Hi-C matrix for detecting topological domains.

Active Publication Date: 2019-03-08
TSINGHUA UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] However, all the above methods mainly have the following problems: high computational complexity, not suitable for high-resolution Hi-C matrices; low accuracy in detecting topological domains, especially low sensitivity, etc.

Method used

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  • Analysis method for chromatin topological domain boundaries
  • Analysis method for chromatin topological domain boundaries
  • Analysis method for chromatin topological domain boundaries

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0146] Example 1 Comparison between HiCDB and existing CDB detection methods.

[0147] This example compares the performance of detection methods for different CDBs using medium-resolution (40kb) and higher-resolution (10kb) raw Hi-C data, and measures several quantitative criteria, including CDB number, identity, protein Combines enrichment, robustness, and time complexity. Based on a 40kb dataset, HiCDB was compared with Armatus, DI, HiCseg, IC-Finder, Insulation, and TopDom. In the 10-kb dataset, DI and HiCseg were excluded from the comparison due to their excessive computational time complexity. It was also included in the comparison because Arrowhead was designed for Hi-C experiments at chromatin loop-level resolution and invoked a smaller number of domain boundaries than other methods for 40-kb datasets.

[0148] First, the consistency of each method was analyzed to reflect the accuracy of CDB detection ( figure 2 A and B). HiCDB detected 5768 CDBs, the highest amon...

Embodiment 2

[0153] Example 2 HiCDB can accurately identify smaller-scale CDBs.

[0154] This embodiment compares the CDB distance distribution identified by different methods ( Figure 5 A). Armatus tends to detect many small regions clustered together on both datasets ( Figure 5 C). In the 40kb dataset, the average distance between CDBs detected by HiCDB is 505kb, which is the shortest among all methods except Armatus. Using 10-kb data, the distance between CDBs identified by HiCDB, Arrowhead, TopDom and IC-Finder is about 200 kb. It is worth noting that the CDB distance distributions for Arrowhead and TopDom have two peaks, implying that a small fraction of CDBs detected by these two methods are closely located to each other ( Figure 5 C).

[0155] Due to the high signal-to-noise ratio of deep sequencing data, the CDB detected based on the 10kb chromatin adjacency matrix was more accurate and complete than that based on the 40kb matrix. Next, the CDB detected by more than two me...

Embodiment 3

[0158] Example 3 CDB-enriched structural proteins and cell-specific transcription factors detected by HiCDB

[0159] This example verifies the binding sites of CDB predicted by HiCDB to Hi-C ring, ChIA-PET ring and transcription factors. All analyzes were performed on the GM12878 cell line.

[0160] First, CDBs predicted by HiCDB were overlaid with chromHMM annotations to show the relationship of these CDBs to chromatin state. In the 40-kb dataset, CDB was significantly enriched for insulators (2.11-fold) and promoters (1.75-fold). Meanwhile, CDBs detected in the 10-kb dataset were enriched for active promoters (5.86-fold), insulators (3.36-fold) and enhancers (3.23-fold).

[0161] The CDB was subsequently compared with another characteristic Hi-C chromatin loop extracted on HiCCUPHi-C data. It was found that 56% of CDBs were anchored to Hi-C chromatin loops ( Figure 6 ). Of the genomic locations identified only as CDBs but not Hi-C chromatin loop anchors, 25% coincided ...

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Abstract

The invention relates to an analysis method for chromatin structures, and specifically relates to an analysis method for chromatin topological domain boundaries.

Description

technical field [0001] The invention relates to an analysis method for chromatin structure, in particular to an analysis method for analyzing the boundary of chromatin topology domains. Background technique [0002] Chromatin structure and its role in gene regulation and cellular identity have attracted extensive attention in cell biology research. Advances in sequencing and imaging technologies have further enabled rapid progress in understanding chromatin structure. Among them, one of the most prominent features in the chromatin structure is the rectangular block with enhanced contact frequency on the diagonal of the chromatin interaction matrix observed in the Hi-C data, which was first reported in the 40Kb resolution Hi-C Figure (Hi-C map) observed, and named as topologically associating domains (topologically associating domains, TADs). Topological domains are three-dimensional structures formed by continuous large fragments of chromatin folding and winding, and chrom...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): G16B15/00G16B25/00C12Q1/6886C12Q1/6883
CPCC12Q1/6883C12Q1/6886C12Q2600/156
Inventor 陈阳陈凤玲李贵鹏张奇伟
Owner TSINGHUA UNIV
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