Chromatin Folding in Relation to Human Genome Function

TL;DR

This study uses fluorescence in situ hybridization to measure 3D chromatin distances, revealing that chromatin folds as a globular polymer with variable compaction, influencing genome function and transcription in human cells.

Contribution

It provides the first systematic physical measurement of chromatin folding in human nuclei and models it as a globular polymer, linking structure to function.

Findings

Chromatin folding can be described as a globular polymer model.

Different genomic domains show variations in compaction and Kuhn length.

Chromatin exhibits multiple folding regimes at different length scales.

Abstract

Three-dimensional (3D) chromatin structure is closely related to genome function, in particular transcription. However, the folding path of the chromatin fiber in the interphase nucleus is unknown. Here, we systematically measured the 3D physical distance between pairwise labeled genomic positions in gene-dense, highly transcribed domains and gene-poor less active areas on chromosomes 1 and 11 in G1 nuclei of human primary fibroblasts, using fluorescence in situ hybridization. Interpretation of our results and those published by others, based on polymer physics, shows that the folding of the chromatin fiber can be described as a polymer in a globular state (GS), maintained by intra-polymer attractive interactions that counteract self-avoidance forces. The GS polymer model is able to describe chromatin folding in as well the highly expressed domains as the lowly expressed ones, indicating that they differ in Kuhn length and chromatin compaction. Each type of genomic domain constitutes an ensemble of relatively compact globular folding states, resulting in a considerable cellto- cell variation between otherwise identical cells. We present evidence for different polymer folding regimes of the chromatin fiber on the length scale of a few mega base pairs and on that of complete chromosome arms (several tens of Mb). Our results present a novel view on the folding of the chromatin fiber in interphase and open the possibility to explore the nature of the intra-chromatin fiber interactions.