Abstract
Chromosome structure is a crucial regulatory factor for a wide range of nuclear processes. Chromosome conformation capture (3C)-based experiments combined with computational modelling are pivotal for unveiling 3D chromosome structure. Here, we introduce TADdyn, a tool that integrates time-course 3C data, restraint-based modelling, and molecular dynamics to simulate the structural rearrangements of genomic loci in a completely data-driven way. We apply TADdyn on in situ Hi-C time-course experiments studying the reprogramming of murine B cells to pluripotent cells, and characterize the structural rearrangements that take place upon changes in the transcriptional state of 21 genomic loci of diverse expression dynamics. By measuring various structural and dynamical properties, we find that during gene activation, the transcription starting site contacts with open and active regions in 3D chromatin domains. We propose that these 3D hubs of open and active chromatin may constitute a general feature to trigger and maintain gene transcription.
Highlights
Chromosome structure is a crucial regulatory factor for a wide range of nuclear processes
TADdyn is based on the following methodological steps (“Methods” and Fig. 1): (i) collection of experimental data, (ii) representation of selected chromatin regions using a bead-spring polymer model, (iii) conversion of experimental data into time-dependent restraints, (iv) application of steered molecular dynamics to simulate the adaptation of chromatin models to satisfy the imposed restraints, and (v) analysis of the conformation dynamics
We applied TADdyn to a previously published in situ Highthroughput chromosome conformation capture (Hi–C) interaction time-series dataset (GEO accession number GSE96611)
Summary
Chromosome structure is a crucial regulatory factor for a wide range of nuclear processes. Complementary, thermodynamics-based approaches[14,15,16,17,18,19,20,21,22] use physics-based principles to test specific interactions or interaction mechanisms to explain the molecular origins of the contact patterns obtained in 3C-based experiments Together, these theoretical strategies provide insights into chromatin conformation[16,17,23,24] and the possible mechanisms that form chromosome territories[18], compartments[19] and topologically associating domains (TADs)[20,22,25,26]. Approaches designed for the simulation of time-dependent conformational changes (4D) are urgently needed To fill this gap, we introduce TADdyn, a computational method allowing to model 3D structural transitions of chromatin using time-resolved Hi–C datasets. TADdyn simulations are compatible with the formation of 3D hubs[37] as a general mechanism to modulate gene transcription
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