Link to bioRxiv paper:
http://biorxiv.org/cgi/content/short/2023.07.06.547894v1?rss=1

Authors: Rajshekar, S., Adame-Arana, O., Bajpai, G., Lin, K., Colmenares, S., Safran, S., Karpen, G. H.

Abstract:
Nucleoli are surrounded by Peri-Centromeric Heterochromatin (PCH), reflecting a close spatial association between the two largest biomolecular condensates in eukaryotic nuclei. We have investigated how this highly conserved organization is established de novo during early Drosophila development and whether these distinct condensates influence each other's 3D organization. High-resolution live imaging revealed a highly dynamic process in which the PCH progressively surrounds nucleoli through a series of stage-specific intermediates. To assess interplay between the condensates, nucleolus assembly was eliminated by deleting the ribosomal RNA genes (rDNA), resulting in increased PCH compaction and subsequent reorganization to a hollow shell. In addition, in embryos lacking rDNA, some nucleolar proteins were abnormally redistributed into new bodies or 'neocondensates,' including enrichment in the PCH hollow core. These observations, combined with computational modeling, led to the hypothesis that nucleolar-PCH associations are mediated by a hierarchy of affinities between PCH, nucleoli, and 'amphiphilic' protein(s) that interact with both nucleolar and PCH components. We identified the nucleolar protein Pitchoune as a candidate for such an amphiphilic protein because it also contains a PCH-interaction motif and fills the PCH hollow core in embryos lacking rDNA. Together, these results unveil a dynamic program for establishing nucleolar-PCH associations during animal development, demonstrate that nucleoli are required for normal PCH organization, and identify Pitchoune as a likely molecular link for stabilizing PCH-nucleolar associations. Finally, we propose that disrupting affinity hierarchies could cause cellular disease phenotypes by liberating components that form 'neocondensates' or other abnormal structures through self-association and secondary affinities.

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