Large scale chromosome folding is stable against local changes in chromatin structure

Abstract

Characterizing the link between small-scale chromatin structure and large-scale chromosome folding during interphase is a prerequisite for understanding transcription. Yet, this link remains poorly investigated. Here, we introduce a simple biophysical model where interphase chromosomes are described in terms of the folding of chromatin sequences composed of alternating blocks of fibers with different thicknesses and flexibilities, and we use it to study the influence of sequence disorder on chromosome behaviors in space and time. By employing extensive computer simulations,we thus demonstrate that chromosomes undergo noticeable conformational changes only on length-scales smaller than 10 5 basepairs and time-scales shorter than a few seconds, and we suggest there might exist effective upper bounds to the detection of chromosome reorganization in eukaryotes. We prove the relevance of our framework by modeling recent experimental FISH data on murine chromosomes. Author SummaryA key determining factor in many important cellular processes as DNA transcription, for instance, the specific composition of the chromatin fiber sequence has a major influence on chromosome folding during interphase. Yet, how this is achieved in detail remains largely elusive. In this work, we explore this link by means of a novel quantitative computational polymer model for interphase chromosomes where the associated chromatin filaments are composed of mixtures of fibers with heterogeneous physical properties. Our work suggests a scenario where chromosomes undergo only limited reorganization, namely on length-scales below 10 5 basepairs and time-scales shorter than a few seconds. Our conclusions are supported by recent FISH data on murine chromosomes.

Reorganization of inter‐ chromosomal interactions in the 2q37‐deletion syndrome

“…By analyzing human Hi-C data (Dixon et al, 2015), we found evidence that the deleted intra-chromosomal interactions could support BDMR pathogenesis. Our conclusions are further supported by a recent computational polymer model that showed that local chromatin reorganization can happen in scales < 10 5 bp (Florescu et al, 2016).…”

Polymer Simulations of Heteromorphic Chromatin Predict the 3-D Folding of Complex Genomic Loci

“…We reasoned that because our model assumed a homomorphic fibre, variation between cell types could only arise from differences in the TF binding or CTCF locations as loop extruder anchor sites. However, it is known that chromatin fibres can adopt alternate configurations 1,2,25,26 , and recent RICC-seq experiments suggest there are two main local structural motifs, associated with chromatin fibres: a more open and a more compact conformation 27 . It has also been suggested that acetylation marks regions of disrupted chromatin [27][28][29] , and indeed RICC-seq data showed a more open chromatin structure was correlated with H3K27ac 27 .…”

Loops, TADs, Compartments, and Territories are Elastic and Robust to Dramatic Nuclear Volume Swelling

“…Interestingly, this result coincides with the computational predictions obtained from polymer physics models. Polymer models have predicted that local changes at the scale of unfolding the 30 nm fiber would not affect the larger scale conformations of the chromosome (Florescu et al 2016). These results suggest that fundamental polymer properties of the genome allow local chromatin unfolding without dramatic disruption of larger scale chromosome organization.…”