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. 2018 Jan 15;9(1):188.
doi: 10.1038/s41467-017-02526-9.

Sub-kb Hi-C in D. melanogaster reveals conserved characteristics of TADs between insect and mammalian cells

Qi Wang  1 , Qiu Sun  1 , Daniel M Czajkowsky  2 , Zhifeng Shao  3
Affiliations

Sub-kb Hi-C in D. melanogaster reveals conserved characteristics of TADs between insect and mammalian cells

Qi Wang et al. Nat Commun. .

Abstract

Topologically associating domains (TADs) are fundamental elements of the eukaryotic genomic structure. However, recent studies suggest that the insulating complexes, CTCF/cohesin, present at TAD borders in mammals are absent from those in Drosophila melanogaster, raising the possibility that border elements are not conserved among metazoans. Using in situ Hi-C with sub-kb resolution, here we show that the D. melanogaster genome is almost completely partitioned into >4000 TADs, nearly sevenfold more than previously identified. The overwhelming majority of these TADs are demarcated by the insulator complexes, BEAF-32/CP190, or BEAF-32/Chromator, indicating that these proteins may play an analogous role in flies as that of CTCF/cohesin in mammals. Moreover, extended regions previously thought to be unstructured are shown to consist of small contiguous TADs, a property also observed in mammals upon re-examination. Altogether, our work demonstrates that fundamental features associated with the higher-order folding of the genome are conserved from insects to mammals.

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Conflict of interest statement

The authors declare no competing financial interests.

Figures

Fig. 1
Fig. 1
The Drosophila genome is fully partitioned into contiguous TADs including within previously annotated “inter-TADs” regions. a Heatmaps from the left arm of chromosome 3. The left panel shows a heatmap of a 2.8 Mb region of this arm at 20 kb resolution, revealing well-defined super-TADs (blue bars at the bottom) and inter-super-TADs (red bars at the bottom), consistent with previous findings. At higher resolution (~200 bp), the heatmap shows that both the super-TADs (right upper panel) and the inter-super-TADs (right lower panel) are composed of small contiguous TADs. The blue (red) bars in these panels now refer to TADs within the super-TADs (inter-super-TADs). b The size distribution of the TADs annotated from the fragment-limited resolution map. The median size of the TADs is 13 kb. c The number of TADs within the super-TADs (blue bars) and inter-super-TADs (red bars)
Fig. 2
Fig. 2
The TADs are demarcated by pairs of insulator proteins. a The locations of known Drosophila insulator proteins, together with the TADs identified in this work, are shown for a 200 kb segment of chr3R. Shown are the positions of class I insulator proteins (that includes BEAF-32 and CP190), as obtained from Flybase, as well as the peak locations of the individual insulator proteins (BEAF-32, CP190, and Chromator) characterized in the modENCODE project. Also shown in the bottom row are the positions of the insulator protein pairs, BEAF-32/CP190, or BEAF-32/Chromator. b Venn diagram showing the genome-wide co-localization of these insulator proteins and insulator protein pairs at the TAD borders. c Logistic regression models to examine the predictive power of the insulator protein pairs (left panel) or transcriptionally active epigenetic modifications or transcriptional levels (right panel) of TAD borders
Fig. 3
Fig. 3
Epigenetic modifications only correlate with higher-order folding of the TADs but not the folding of individual TADs. a The TADs could be classified into four major types according to the enrichment of 15 histone modifications and non-histone chromosomal proteins within each TAD (Supplementary Methods). Shown is an example of the distribution of these types with active (orange bar below the heatmap), inactive (blue bar), polycomb (green bar), and undetermined (gray bar) chromatin within the TADs in a 380 kb region of chr3R. Inset: the extent of DNA condensation within the TADs, as determined from the average of contact frequencies between loci within the TAD. b Comparison of the frequency with which active or inactive TADs tend to interact with their immediately neighboring TADs. The upper heatmap shows the positions of the TADs, while the lower heatmap shows the significance of the observed contacts, with those colored red (blue) exhibiting much greater (lower) interaction strength than expected by chance (Methods) in a 530 kb region of chr2R. c The relative interaction strength (as shown in b) between pairs of TADs. A active, I inactive, P polycomb
Fig. 4
Fig. 4
The human genome is also partitioned into contiguous small TADs within previously described “inter-TAD” regions at least in part. Shown are four examples of Hi-C data of GM12878 lymphoblastoid cells determined by Rao et al. In each panel, the main figure is the heatmap of the indicated chromosomal position at 5 kb resolution, with the domains annotated by these authors indicated by the color bars above each figure. Note that there were smaller TADs within larger TADs identified in this previous work, reflected in the three different levels in the annotated TADs. The bars colored red reflect the inter-TAD regions, while those colored blue are the TADs. The inset of each panel is an expanded region of an inter-TAD region. The TADs annotated using the Armatus software are shown below the heatmap. Also shown are the locations of CTCF (orange arrows) and cohesin components (Rad21 and Smc3, green and brown arrows. respectively), as determined previously
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