Abstract
Using molecular dynamics simulations, we show here that growing plectonemes resulting from transcription-induced supercoiling have the ability to actively push cohesin rings along chromatin fibres. The pushing direction is such that within each topologically associating domain (TAD) cohesin rings forming handcuffs move from the source of supercoiling, constituted by RNA polymerase with associated DNA topoisomerase TOP1, towards borders of TADs, where supercoiling is released by topoisomerase TOPIIB. Cohesin handcuffs are pushed by continuous flux of supercoiling that is generated by transcription and is then progressively released by action of TOPIIB located at TADs borders. Our model explains what can be the driving force of chromatin loop extrusion and how it can be ensured that loops grow quickly and in a good direction. In addition, the supercoiling-driven loop extrusion mechanism is consistent with earlier explanations proposing why TADs flanked by convergent CTCF binding sites form more stable chromatin loops than TADs flanked by divergent CTCF binding sites. We discuss the role of supercoiling in stimulating enhancer promoter contacts and propose that transcription of eRNA sends the first wave of supercoiling that can activate mRNA transcription in a given TAD.
Highlights
In recent years, technological development of Chromosome Conformation Capture (3C) techniques resulted in a rapid succession of ever more illuminating insights into organization of chromosomes in eukaryotic cells [1,2,3,4,5,6,7]
This simple model is to explain how supercoiling is introduced in our simulations and it serves as an introduction to more complex models where supercoiling can be dissipated by action of topoisomerases located at borders of modelled topologically associating domain (TAD)
We showed here how transcription-induced supercoiling can actively push cohesin rings and drive chromatin loop extrusion implicated in TADs formation
Summary
Technological development of Chromosome Conformation Capture (3C) techniques resulted in a rapid succession of ever more illuminating insights into organization of chromosomes in eukaryotic cells [1,2,3,4,5,6,7]. Since 2012 it is known that interphase chromosomes are composed of sequentially arranged, up to megabase-long chromatin domains that show increased frequency of internal contacts [2,3,9]. These domains were given the name of topological domains [2] or topologically associating domains (TADs) [3] in a reference to topological domains characterized earlier in bacterial chromosomes [10]. It is accepted that the role of TADs is to facilitate contacts between cis-regulatory elements of gene expression located in the same TAD [8], we still do not know what causes the increased frequency of contacts within TADs and how TADs are generated
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