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Sci Adv. 2018 Feb 28;4(2):eaar8082. doi: 10.1126/sciadv.aar8082. eCollection 2018 Feb.

TADs are 3D structural units of higher-order chromosome organization in Drosophila.

Author information

1
Institute of Human Genetics, CNRS, Univ Montpellier, Montpellier, France.
2
Univ Grenoble Alpes, CNRS, Grenoble INP, TIMC-IMAG, F-38000 Grenoble, France.
3
Centre de Biochimie Structurale, CNRS UMR5048, INSERM U1054, Univ Montpellier, 34090 Montpellier, France.

Abstract

Deciphering the rules of genome folding in the cell nucleus is essential to understand its functions. Recent chromosome conformation capture (Hi-C) studies have revealed that the genome is partitioned into topologically associating domains (TADs), which demarcate functional epigenetic domains defined by combinations of specific chromatin marks. However, whether TADs are true physical units in each cell nucleus or whether they reflect statistical frequencies of measured interactions within cell populations is unclear. Using a combination of Hi-C, three-dimensional (3D) fluorescent in situ hybridization, super-resolution microscopy, and polymer modeling, we provide an integrative view of chromatin folding in Drosophila. We observed that repressed TADs form a succession of discrete nanocompartments, interspersed by less condensed active regions. Single-cell analysis revealed a consistent TAD-based physical compartmentalization of the chromatin fiber, with some degree of heterogeneity in intra-TAD conformations and in cis and trans inter-TAD contact events. These results indicate that TADs are fundamental 3D genome units that engage in dynamic higher-order inter-TAD connections. This domain-based architecture is likely to play a major role in regulatory transactions during DNA-dependent processes.

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