Active chromatin and transcription play a key role in chromosome partitioning into topologically associating domains
- Sergey V. Ulianov1,
- Ekaterina E. Khrameeva2,
- Alexey A. Gavrilov1,
- Ilya M. Flyamer1,
- Pavel Kos3,
- Elena A. Mikhaleva4,
- Aleksey A. Penin5,
- Maria D. Logacheva5,
- Maxim V. Imakaev6,
- Alexander Chertovich3,
- Mikhail S. Gelfand5,
- Yuri Y. Shevelyov4 and
- Sergey V. Razin1,7
- 1 Institute of Gene Biology RAS;
- 2 Skolkovo Institute of Science and Technology;
- 3 Lomonosov Moscow State University;
- 4 Institute of Molecular Genetics RAS;
- 5 Institute for Information Transmission Problems (the Kharkevich Institute) RAS;
- 6 Massachusetts Institute of Technology
- ↵* Corresponding author; email: sergey.v.razin{at}usa.net
Abstract
Recent advances enabled by the Hi-C technique have unraveled many principles of chromosomal folding that were subsequently linked to disease and gene regulation. In particular, Hi-C revealed that chromosomes of animals are organized into Topologically Associating Domains (TADs), evolutionary conserved compact chromatin domains that influence gene expression. Mechanisms that underlie partitioning of the genome into TADs remain poorly understood. To explore principles of TAD folding in Drosophila melanogaster, we performed Hi-C and PolyA+ RNA-seq in four cell lines of various origins (S2, Kc167, DmBG3-c2, and OSC). Contrary to previous studies, we find that regions between TADs (i.e. the inter-TADs and TAD boundaries) in Drosophila are only weakly enriched with the insulator protein dCTCF, while another insulator protein Su(Hw) is preferentially present within TADs. However, Drosophila inter-TADs harbor active chromatin and constitutively transcribed (housekeeping) genes. Accordingly, we find that binding of insulator proteins dCTCF and Su(Hw) predicts TAD boundaries much worse than active chromatin marks do. Interestingly, inter-TADs correspond to decompacted interbands of polytene chromosomes, whereas TADs mostly correspond to densely packed bands. Collectively, our results suggest that TADs are condensed chromatin domains depleted in active chromatin marks, separated by regions of active chromatin. We propose the mechanism of TAD self-assembly based on the ability of nucleosomes from inactive chromatin to aggregate, and lack of this ability in acetylated nucleosomal arrays. Finally, we test this hypothesis by polymer simulations, and find that TAD partitioning may be explained by different modes of inter-nucleosomal interactions for active and inactive chromatin.
- Received June 17, 2015.
- Accepted October 26, 2015.
- Published by Cold Spring Harbor Laboratory Press
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