Role of Structural Maintenance of Chromosomes (SMC) complexes in interphase genome folding in Caenorhabditis elegans

Das, Moushumi (2022). Role of Structural Maintenance of Chromosomes (SMC) complexes in interphase genome folding in Caenorhabditis elegans (Unpublished). (Dissertation, University of Bern, Institute of Cell Biology)

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Recent studies have shown that the highly conserved Structural Maintenance of Chromosomes (SMC) complexes such as cohesin and condensin, are involved in organizing the interphase genome. However, these complexes are classically known to function in mitosis and meiosis, which makes it difficult to evaluate the functional consequences of their absence in animals. Here we use Caenorhabditis elegans, an animal, 90% of whose cells are post- mitotic at birth. Similar to mammals, it has three SMC complexes: cohesin, condensin I and condensin II. Additionally, condensin IDC, a variant of condensin I, is involved in X chromosome dosage compensation (DC). To uncover which SMC complex(es) organise the C. elegans interphase genome and evaluate functional consequences of genome folding, we constructed strains in which we can acutely inactivate in vivo specific SMC complexes in fully differentiated animals. Using those strains, we captured changes in chromatin structures post cleavage using Hi-C. Our data shows global genome decompaction in the absence of condensin I/IDC. There is reinforcement of A and B compartments in the autosomes and loss of TADs in the X chromosome. Remarkably, we observe appearance of multiple loops along the entire length of the X chromosome, indicating the possible involvement of other complexes in organizing the X-topology. Meanwhile, condensin I/IDC cleavage shows no obvious phenotypic changes yet leads to up-regulation of X-linked genes and lifespan reduction. Since both condensin I and IDC are cleaved, this raises the question whether the impact we observe is due to global genome unfolding or is it X-specific related. To distinguish between these two hypotheses, we selectively degrade SDC-3, a protein subunit of the X-targeting complex of condensin IDC. Degradation of SDC-3 result in up-regulation of X-linked genes and reduction in lifespan, confirming that global genome decompaction has no direct consequence, however, the X chromosome specific function of condensin IDC is important for the animals’ survival.

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