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Comments on Anderson, Erika et al. (2017) International Worm Meeting "X chromosome topology driven by condensin binding to eight high-affinity sites." (0)
Overview
Anderson, Erika, Bian, Qian, Schartner, Caitlin, & Meyer, Barbara J. (2017). X chromosome topology driven by condensin binding to eight high-affinity sites presented in International Worm Meeting. Unpublished information; cite only with author permission.
Interphase chromosome structure is regulated at multiple length scales, and each level of organization controls nuclear functions such as transcription, replication, and recombination. To learn how these structures are formed, we dissected the mechanism by which a condensin complex imposes a distinct, higher-order structure across X chromosomes of C. elegans hermaphrodites. Here our deletion analysis of the endogenous X revealed that architectural proteins can remodel chromosome-wide topology by binding to a small number of sites. The dosage compensation complex (DCC), a specialized condensin complex, is recruited to dozens of specific sites (rex sites) on both hermaphrodite X chromosomes and represses X-linked gene expression by half. The DCC establishes a higher-order structure composed of megabase-scale topologically associating domains (TADs) that is distinct from the structure of autosomes and male X chromosomes. The DCC-dependent TAD boundaries all contain a strong rex site, and the DCC promotes long-range interactions both between rex sites at TAD boundaries and between rex sites within TADs. To discern the contributions of these different rex-site interactions to TAD boundary formation, we deleted the eight rex sites at DCC-dependent TAD boundaries and examined X structure using an updated in-nucleus Hi-C protocol that detects distant interactions efficiently. In the rex-delete strain, the specific loops between adjacent DCC-dependent TAD boundaries were eliminated. All eight DCC-dependent boundaries were lost or significantly weakened, producing a structure that recapitulates the X structure of a DCC mutant. Therefore, though the DCC binds dozens of sites on X, the TAD boundaries are established by binding to these eight high-affinity sites. Disruption of TAD structure by deleting a series of cis elements uniquely allows us to assess the effects of TAD boundaries on gene expression. The rex-deleted worms lack strong dosage compensation phenotypes, indicating that TAD boundaries alone are insufficient to enact full repression of X gene expression. Ongoing sensitive gene expression assays are determining whether TAD boundary disruption causes local or subtle transcriptional changes. Intra-TAD interactions present in wild-type and rex-delete animals but absent in DCC mutants likely underlie mechanisms that control X gene expression. Furthermore, Hi-C results showed that in C. briggsae, which also uses a condensin DCC, X chromosomes have a unique TAD structure compared to that of autosomes, even though the rex sites are in different locations relative to C. elegans' sites. Hi-C also revealed errors in C. briggsae's genome assembly, which are now being corrected based on Hi-C data. This improved genome assembly facilitates studies of how condensin's role in shaping higher-order chromosome structure is maintained as its binding sites evolve.
Affiliation:
- HHMI and UC Berkeley, Berkeley, CA