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TAD-based topological correlation domain analysis is what, I believe that many inexperienced people do not know what to do, this article summarizes the causes of the problem and solutions, through this article I hope you can solve this problem.

Using the lower-resolution Hi-C genome interaction map, scientists are gaining insight into the spatial structure of chromatin. This article mainly introduces the structure of TAD, and its full name is as follows

Topologically Assocaited Domain

Topological association domain is a chromatin structural unit first discovered in mammalian cells. The corresponding article was published in nature with the following title

Topological Domains in Mammalian Genomes Identified by Analysis of Chromatin Interactions

pubmed's link is as follows

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3356448/

When the resolution of Hi-C genome interaction map was increased to less than 100kb, some self-interaction regions were found in the interaction map, which are shown as follows

The genome interaction map is essentially a symmetric matrix in which the information on both sides of the diagonal is equal. The image above only takes information from one diagonal of the original matrix, so it looks like a large triangle, and the base of the triangle corresponds to the diagonal of the original matrix.

In the image above, the intensity of the interaction changes from weak to strong, and the color of the cells changes from white to red. It can be seen that there are some small triangular regions repeated at the bottom edge. Almost all of these regions are red, indicating that the interaction frequency between chromatin fragments in these regions is high. Such regions are called self-interaction regions, while the interaction frequency between adjacent triangular regions is low, as shown in the figure below.

Red triangles correspond to interaction information for regions within TADs, while black areas correspond to interaction information between TADs. The interaction map of triangles corresponds to small triangles with many red lines on the bottom, and the interaction areas corresponding to triangles are all white. Scientists define this repeated domain with high internal interaction frequency and low inter-group interaction frequency as topologically associated domain (TAB), corresponding to the model in the figure below.

A and B correspond to two TADs, and there is a boundary between the TADs, which is called the TAB boundary. In order to accurately identify TADs in chromatin, a directionality index statistic, DI, is defined, with the following formula:

Reduce the resolution to 40kb, for each 40kb bin, A represents the interaction reads of this bin with the upstream 2MB region, B represents the interaction reads of this bin with the downstream 2MB region, and E represents the mean of A and B, using an algorithm similar to chi-square test statistics. The null hypothesis is that this bin interacts with upstream and downstream at the same frequency. If the interaction frequency is consistent with upstream and downstream, the value of DI approaches 0. as shown in the following figure

You can see that from the beginning to the end of TAB, DI has a gradual decrease from positive to zero, then negative, and decreasing. At the TAB boundary, DI value suddenly approaches 0, because the interaction frequency between upstream and downstream at the boundary is almost the same. According to this distribution law of DI, combined with hidden Markov model, more than 2200 TAB regions are finally identified in mouse embryonic stem cells, with an average length of 880kb.

Further identification and analysis of TADs in two different cell lines of human and mouse showed that TADs were relatively stable in different cells or tissues and had certain conservation among different species. The results were shown in the figure below.

To further explore the distribution characteristics of TAD on chromatin, the scientists analyzed the distribution of various marks within the boundaries of TAD. First CTCF, the results are shown below

CTCF was found to be enriched at TAB boundaries, but not all CTCF were concentrated at TAB boundaries. Therefore, the distribution of other marks, including histone modifications, was further explored. The results are as follows

H3K4me3, H3K36me3, TSS, SINE repeat elements were found to be enriched. The distribution of genes was further analyzed, and the results were as follows

Housekeeping genes were found to be enriched at TAB boundaries.

TADs, a relatively stable and evolutionarily conserved chromatin structural unit in mammals, were identified by Hi-C interaction maps with a resolution of 40kb.

After reading the above content, do you know how to analyze the topological correlation domain in TAD? If you still want to learn more skills or want to know more related content, welcome to pay attention to the industry information channel, thank you for reading!

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