Abstract
Animal interphase chromosomes are organized into topologically associating domains (TADs). How TADs are formed is not fully understood. Here, we combined high-throughput chromosome conformation capture and gene silencing to obtain insights into TAD dynamics in Xenopus tropicalis embryos. First, TAD establishment in X. tropicalis is similar to that in mice and flies and does not depend on zygotic genome transcriptional activation. This process is followed by further refinements in active and repressive chromatin compartments and the appearance of loops and stripes. Second, within TADs, higher self-interaction frequencies at one end of the boundary are associated with higher DNA occupancy of the architectural proteins CTCF and Rad21. Third, the chromatin remodeling factor ISWI is required for de novo TAD formation. Finally, TAD structures are variable in different tissues. Our work shows that X. tropicalis is a powerful model for chromosome architecture analysis and suggests that chromatin remodeling plays an essential role in de novo TAD establishment.
Highlights
The structure of topologically associating domains (TADs) is relatively stable and resilient to environmental perturbations[8,9] and their architecture is evolutionarily conserved in eukaryotes[4,10,11]
Consistent with the effects of morpholinos, α-amanitin treatment delayed and aborted embryo development, resulting in embryos dying around s11 (Fig. 4c and Extended Data Fig. 7c) but without affecting the formation of TAD structures (Fig. 4i,j and Extended Data Fig. 7d– f). These results show that the de novo establishment of TADs in X. tropicalis does not seem to be stringently dependent on transcription, which is similar to fruit flies and mice[18,19,20] but distinct from human embryogenesis[32]
We showed that in X. tropicalis, TADs are established at zygotic genome activation (ZGA)
Summary
The structure of TADs is relatively stable and resilient to environmental perturbations[8,9] and their architecture is evolutionarily conserved in eukaryotes[4,10,11]. Disruption of TAD borders can lead to developmental disorders and even tumorigenesis; this underlines the importance of three-dimensional (3D) genome organization in gene regulation[12,13,14,15]. The establishment of chromatin architecture during embryogenesis provides an initial spatial frame that may guide proper genome organization, chromatin interaction and gene regulation[16]. Deletion of the cohesin complex component double-strand-break repair protein rad[21] homolog (Rad21) alone was enough to abolish the establishment of TADs27. Other proteins, including CCCTC-binding factor (CTCF), the cohesin antagonist
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