The silencing factor Sir3 is a molecular bridge that sticks together distant loci

Abstract

<jats:title>ABSTRACT</jats:title><jats:p>Physical contacts between distant loci contribute to regulate genome function. However, the molecular mechanisms responsible for settling and maintaining such interactions remain poorly understood. Here we investigate the well conserved interactions between heterochromatin loci. In budding yeast, the 32 telomeres cluster in 3-5 foci in exponentially growing cells. This clustering is functionally linked to the formation of heterochromatin in subtelomeric regions through the recruitment of the silencing complex SIR composed of Sir2/3/4. Combining microscopy and Hi-C on strains expressing different alleles of <jats:italic>SIR3</jats:italic>, we show that the binding of Sir3 directly promotes long range contacts between distant regions, including the rDNA, telomeres, and internal Sir3 bound sites. Furthermore, we unveil a new property of Sir3 in promoting rDNA compaction. Finally, using a synthetic approach we demonstrate that Sir3 can bond loci belonging to different chromosomes together, when targeted to these loci, independently of its interaction with its known partners (Rap1, and Sir4), Sir2 activity or chromosome context. Altogether these data suggest that Sir3 represents an uncommon example of protein able to bridge directly distant loci.</jats:p>

Transcription Factor Dynamics

“…Transcription has long been proposed to occur in stable, self-assembled "hubs" that could outlive the binding of individual components (Cook 1999;Edelman and Fraser 2012), similar to larger subnuclear structures such as the nucleolus (Phair and Misteli 2000). Consistent with the hub model, a variety of factors form clusters in cells: sequence-specific TFs (Liu et al 2014;Mir et al 2017Mir et al , 2018Chong et al 2018;Basu et al 2020;Li et al 2020b), coactivators (Cho et al 2018;Sabari et al 2018;Guo et al 2019;Li et al 2019Li et al , 2020bZamudio et al 2019), Pol II (see below), splicing factors (Guo et al 2019), corepressors (Treen et al 2020), repressive complexes (Wollman et al 2017;Plys et al 2019;Ruault et al 2020), chromatin modifiers (Tatavosian et al 2019), and HP1 (heterochromatin pro-tein 1) (Strom et al 2017;Erdel et al 2020;Li et al 2020a). Contrasting with the model of a stable factory, cluster lifetimes are generally short (Cisse et al 2013).…”

“…Clustered enhancers confer robustness (Tsai et al 2019) and constitute a flexible platform able to encode a variety of regulatory responses (Ezer et al 2014). Similar to activators, repressors may also bring together distant loci (Ruault et al 2020). Finally, clusters could facilitate nuclear exploration by guiding TFs to specialized compartments (Hansen et al 2020;Nguyen et al 2020).…”