Condensin-Driven Remodeling of X-Chromosome Topology during Dosage Compensation

By Emily Crane, Qian Bian, R. McCord, B. Lajoie, Bayly S. Wheeler, E. Ralston, S. Uzawa, Job Dekker, B. Meyer. Nature, 2015

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The three-dimensional organization of a genome plays a critical role in regulating gene expression, yet little is known about the machinery and mechanisms that determine higher-order chromosome structure. Here we perform genome-wide chromosome conformation capture analysis, fluorescent in situ hybridization (FISH), and RNA-seq to obtain comprehensive three-dimensional (3D) maps of the Caenorhabditis elegans genome and to dissect X chromosome dosage compensation, which balances gene expression between XX hermaphrodites and XO males. The dosage compensation complex (DCC), a condensin complex, binds to both hermaphrodite X chromosomes via sequence-specific recruitment elements on X (rex sites) to reduce chromosome-wide gene expression by half. Most DCC condensin subunits also act in other condensin complexes to control the compaction and resolution of all mitotic and meiotic chromosomes. By comparing chromosome structure in wild-type and DCC-defective embryos, we show that the DCC remodels hermaphrodite X chromosomes into a sex-specific spatial conformation distinct from autosomes. Dosage-compensated X chromosomes consist of self-interacting domains (∼1 Mb) resembling mammalian topologically associating domains (TADs). TADs on X chromosomes have stronger boundaries and more regular spacing than on autosomes. Many TAD boundaries on X chromosomes coincide with the highest-affinity rex sites and become diminished or lost in DCC-defective mutants, thereby converting the topology of X to a conformation resembling autosomes. rex sites engage in DCC-dependent long-range interactions, with the most frequent interactions occurring between rex sites at DCC-dependent TAD boundaries. These results imply that the DCC reshapes the topology of X chromosomes by forming new TAD boundaries and reinforcing weak boundaries through interactions between its highest-affinity binding sites. As this model predicts, deletion of an endogenous rex site at a DCC-dependent TAD boundary using CRISPR/Cas9 greatly diminished the boundary. Thus, the DCC imposes a distinct higher-order structure onto X chromosomes while regulating gene expression chromosome-wide.

Subfields: Molecular Biology, Plant Science

View Paper: https://www.semanticscholar.org/paper/57c1e95aff2ad5e656271ad2e1ed76b4287cf121

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Citations in the corpus

High-resolution TADs reveal DNA sequences underlying genome organization in flies (2017, background): “Since then, TADs have been discovered in other mouse and human cell lines (Dixon et al. 2012) as well as in other mammals (dog and macaque (Vietri Rudan et al. 2015), in flies (Sexton et al. 2012; Ramirez et al. 2015;Hou et al. 2012), worms (Crane et al. 2015) and yeast (Mizuguchi et al. 2014).”
A Compendium of Chromatin Contact Maps Reveal Spatially Active Regions in the Human Genome (2016, neutral): “Topological domains boundaries were identified at 40kb bin resolution using the previously described insulation score analysis approach, with two minor modifications (Crane et al., 2015).”
Genome-wide mapping and analysis of chromosome architecture (2016, methodology): “Similarly, a sliding insulation score approach was recently introduced that also transforms the Hi-C contact matrix into an intuitive 1D insulation score vector 90 .”
A pathway for mitotic chromosome formation (2018, methodology): “TAD boundaries were similar in position and strength to those in nonsynchronous cells, as determined using an insulation score calculated from a 250-kb sliding window (32) (fig.”
Ever-changing landscapes: transcriptional enhancers in development and evolution (2016, background): “For example, in C. elegans, TAD-like structures seem to predominantly occur on the X chromosomes of XX hermaphrodites and are driven by the dosage compensation complex (DCC), whereas autosomes are largely devoid of long-range chromosomal interactions (Crane et al., 2015).”
Targeted degradation of CTCF decouples local insulation of chromosome domains from genomic compartmentalization (2017, positive): “To local contact insulation analysis was based on the algorithm described in (Crane et al., 2015).”
Single-nucleus Hi-C reveals unique chromatin reorganization at oocyte-to-zygote transition (2017, neutral): “20, see Extended Data Fig.”