Binding of an X-specific condensin correlates with a reduction in active histone modifications at gene regulatory elements

Abstract

Condensins are evolutionarily conserved protein complexes that are required for chromosome segregation during cell division and genome organization during interphase. In C. elegans, a specialized condensin, which forms the core of the dosage compensation complex (DCC) binds to and represses X chromosome transcription. Here, we analyzed DCC localization and effect of DCC depletion and binding on histone modifications, transcription factor binding, and gene expression using ChIP-seq and mRNA-seq. Across the X, DCC binding coincides with gene regulatory sites at active chromatin and not heterochromatin. DCC is required for reducing the levels of active histone modifications, including H3K4me3 and H3K27ac, but not repressive modification H3K9me3 on the X. In X-to-autosome fusion chromosomes, DCC spreading into the autosomal sequences locally reduces the level of H3K4me3 and gene expression. Together, our results suggest that DCC fine-tunes X chromosomal transcription by binding to and modulating the activity of gene regulatory elements through reducing activating histone modifications.

Condensin DC loads and spreads from recruitment sites to create loop-anchored TADs inC. elegans

“…Condensin DC represses transcription initiation by a factor of ~2 across the entire X chromosomes [26–28]. The level of condensin DC binding is proportional to repression as seen in X;A fusion chromosomes [36]. In ectopic recruitment experiments, the level of condensin DC binding in the autosomes is lower than that of the X (Figure 5A).…”

“…2) Loader spreading from the rex sites. It has been proposed that the condensin DC loaders also ‘spread,’ although to a lesser extent than condensin DC, leading to SDC-2, SDC-3, and DPY-30 enrichment at active promoters on the X-chromosome [32, 33, 36, 56]. One possible model is that these SDC-bound promoters function as secondary loading sites.…”

“…Hi-C analysis in C. elegans embryos indicated that eight strong rex sites function as TAD boundaries and form long-range rex-rex loops on the X chromosomes [39, 40]. Recruitment of condensin DC leads to spreading to the entire chromosome, accumulating at hundreds of enhancers, promoters, and other accessible gene regulatory elements [36].…”

“…Second, the spreading of the complex can be distinguished from recruitment using X to autosome (X;A) fusion chromosomes [34]. Third, since the complex only binds to the X chromosomes, autosomes serve as internal controls, allowing sensitive measurement using genomics approaches [33,[35][36][37].…”

Increased gene dosage and mRNA expression from chromosomal duplications in C. elegans

“…DCC is recruited specifically to the X chromosomes by several cis-regulatory elements on the X (M c D onel et al 2006; E rcan et al 2007; J ans et al 2009; A lbritton and E rcan 2017). Recruitment leads to spreading of the complex to nearby chromatin, creating robust binding across the X chromosomes (A lbritton et al 2017; S treet et al 2019).…”