Dynamics as a cause for the nanoscale organization of the genome

Abstract

13Chromatin 'blobs' were recently identified by live super-resolution imaging as pervasive, but transient and 14 dynamic structural entities consisting of a few associating nucleosomes. The origin and functional 15 implications of these blobs are, however, unknown. Following these findings, we explore whether causal 16 relationships exist between parameters characterizing the chromatin blob dynamics and structure, by 17 adapting a framework for spatio-temporal Granger-causality inference. Our analysis reveals that chromatin 18 dynamics is a key determinant of both blob area and local density. However, such causality can only be 19 demonstrated in small areas (10 -20%) of the nucleus, highlighting that chromatin dynamics and structure 20 at the nanoscale is dominated by stochasticity. Pixels for which the inter-blob distance can be effectively 21 demonstrated to depend on chromatin dynamics appears as clump in the nucleus, and display both a higher 22 blob density and higher local dynamics as compared with the rest of the nucleus. Furthermore, we show 23 that the theory of active semiflexible polymers can be invoked to provide potential mechanisms leading to 24 the organization of chromatin into blobs. Based on active motion-inducing effectors, this framework 25 qualitatively recapitulates experimental observations and predicts that chromatin blobs might be formed 26 stochastically by a collapse of local polymer segments consisting of a few nucleosomes. Our results 27 represent a first step towards elucidating the mechanisms that govern the dynamic and stochastic 28 organization of chromatin in a cell nucleus. 29 30 Keywords 31 Genome organization, chromatin dynamics, 4D genome, Deep-PALM, Granger-causality, active polymers 32 14,15 , thereby quantifying simultaneously the dynamics, size and distance between chromatin blobs in space 55 and time. These results indicated a strong relationship between the flow magnitude of blobs (i.e. their 56 dynamics) and their local density. Notably, the blob dynamics appear enhanced in regions of high blob 57 density and conversely isolated blobs in chromatin-void regions appear less mobile. 58This and other studies resulted in complex high-dimensional datasets, which reflect stochastic and 59 heterogeneous quantities characterizing chromatin in space and time. In order to allow inferences of 60Note that the second sum runs from 2 to in the base and the full model and the contribution of the cause-131 variable # is written explicitly in the latter. Granger-causality from # to is present if the predictions U of 132 the full model (including the past value of # ) are significantly better than those of the base model. 133 411 de Lyon for providing computational resources and further thank the Institut Rhônalpin des Systèmes 412 Complexe IXXI for supporting us. 413 414 Declaration of interests: The authors declare no competing financial interest. 415 416

Heterogeneous anomalous transport in cellular and molecular biology

“…Long-range directional movement of interphase chromatin was also found which was super-diffusive [231][232][233]. Similarly, Reprinted from [125] coherent movements over 1 µm distances by human RNA polymerase II molecules were observed over the entire nucleus in human cancer cells [234].…”