Abstract
BackgroundThe relationship between transcription and the 3D chromatin structure is debated. Multiple studies have shown that transcription affects global Cohesin binding and 3D genome structures. However, several other studies have indicated that inhibited transcription does not alter chromatin conformations.ResultsWe provide the most comprehensive evidence to date to demonstrate that transcription plays a relatively modest role in organizing the local, small-scale chromatin structures in mammalian cells. We show degraded Pol I, Pol II, and Pol III proteins in mESCs cause few or no changes in large-scale 3D chromatin structures, selected RNA polymerases with a high abundance of binding sites or active promoter-associated interactions appear to be relatively more affected after the degradation, transcription inhibition alters local, small loop domains, as indicated by high-resolution chromatin interaction maps, and loops with bound Pol II but without Cohesin or CTCF are identified and found to be largely unchanged after transcription inhibition. Interestingly, Pol II depletion for a longer time significantly affects the chromatin accessibility and Cohesin occupancy, suggesting that RNA polymerases are capable of affecting the 3D genome indirectly. These direct and indirect effects explain the previous inconsistent findings on the influence of transcription inhibition on the 3D genome.ConclusionsWe conclude that Pol I, Pol II, and Pol III loss alters local, small-scale chromatin interactions in mammalian cells, suggesting that the 3D chromatin structures are pre-established and relatively stable.
Highlights
The relationship between transcription and the 3D chromatin structure is debated
Acute degradation of Pol I, Pol II, and Pol III in the mESCs with auxin-inducible degron technology To investigate the roles of RNA polymerase proteins in 3D chromatin organization, we subjected mESCs to RNA polymerase degradation with degron technology
A/B compartments and Topologically associating domain (TAD) structures were largely unchanged after acute depletion of Pol I, Pol II, and Pol III Previous studies on the relationships between transcription and 3D genome usually focused on Pol II [3, 39,40,41]; here, we investigated Pol I, Pol II, and Pol III separately for their roles in the 3D genome
Summary
The relationship between transcription and the 3D chromatin structure is debated. Multiple studies have shown that transcription affects global Cohesin binding and 3D genome structures. Recent studies combining knockouts and inhibition showed that transcription could relocate Cohesin over mammalian chromatin [15], indicating that Pol II may regulate the 3D genome via its impact on Cohesin. As the D. melanogaster genome has a much higher gene density than the mammalian genome, inhibiting D. melanogaster transcription significantly alters chromatin interactions both within and between domains, but has very little effect on the 3D topology of TADs [12,13,14]. It is unclear whether Pol II regulates 3D chromatin landscapes via Cohesin directly
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