Linking Chromatin Fibers to Gene Folding by Hierarchical Looping

While much is known about DNA structure on the basepair level, this scale represents only a fraction of the structural levels involved in folding the genomic material. With recent advances in experimental and theoretical techniques, a variety of structures have been observed on the fiber, gene, and chromosome levels of genome organization. Here we view chromatin architecture from nucleosomes and fibers to genes and chromosomes, highlighting the rich structural diversity and fiber fluidity emerging from both experimental and theoretical techniques. In this context, we discuss our recently proposed folding mechanism, which we call "hierarchical looping", similar to rope flaking used in mountain climbing, where 10-nm zigzag chromatin fibers are compacted laterally into self-associating loops which then stack and fold in space. We propose that hierarchical looping may act as a bridge between fibers and genes as well as provide a mechanism to relate key features of interphase and metaphase chromosome architecture to genome structural changes. This motif emerged by analysis of ultrastructural internucleosome contact data by electron microscopy-assisted nucleosome interaction capture cross-linking experiments, in combination with mesoscale modeling. We suggest that while the local folding of chromatin can be regulated at the fiber level by adjustment of internal factors such as linker-histone binding affinities, linker DNA lengths, and divalent ion levels, hierarchical looping on the gene level can additionally be controlled by posttranslational modifications and external factors such as polycomb group proteins. From a combination of 3C data and mesoscale modeling, we suggest that hierarchical looping could also play a role in epigenetic gene silencing, as stacked loops may occlude access to transcription start sites. With advances in crystallography, single-molecule in vitro biochemistry, in vivo imaging techniques, and genome-wide contact data experiments, various modeling approaches are allowing for previously unavailable structural interpretation of these data at multiple spatial and temporal scales. An unprecedented level of productivity and opportunity is on the horizon for the chromatin structure field.